22 Endocrine Diseases - Bài viết - Bệnh Học
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22 Endocrine Diseases

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Endocrine Diseases
William E. Clutter
Evaluation of Thyroid Function
General Principles
The major hormone secreted by the thyroid is thyroxine (T4), which is converted by deiodinases in many tissues to the more potent triiodothyronine (T3). Both are bound reversibly to plasma proteins, primarily thyroxine-binding globulin (TBG). Only the free (unbound) fraction enters cells and produces biological effects. T4 secretion is stimulated by thyroid-stimulating hormone (TSH). In turn, TSH secretion is inhibited by T4, forming a negative feedback loop that keeps free T4 levels within a narrow normal range. Diagnosis of thyroid disease is based on clinical findings, palpation of the thyroid, and measurement of plasma TSH and thyroid hormones.1
Thyroid palpation determines the size and consistency of the thyroid and the presence of nodules, tenderness, or a thrill.
Plasma TSH is the initial test of choice in most patients with suspected thyroid disease, except when thyroid function is not in a steady state.2 TSH levels are elevated in very mild primary hypothyroidism and are suppressed to <0.1 microunits/mL in very mild hyperthyroidism. Thus, a normal plasma TSH level excludes hyperthyroidism and primary hypothyroidism. Because even slight changes in thyroid hormone levels affect TSH secretion, abnormal TSH levels are not specific for clinically important thyroid disease. Changes in plasma TSH lag behind changes in plasma T4, and TSH levels may be misleading when plasma T4 levels are changing rapidly, as during treatment of hyperthyroidism.
Plasma TSH is mildly elevated (up to 20 microunits/mL) in some euthyroid patients with nonthyroidal illnesses and in mild (also known as subclinical) hypothyroidism.
TSH levels may be suppressed to < 0.1 microunits/mL in severe nonthyroidal illness, in mild (also known as subclinical) hyperthyroidism, and during treatment with dopamine or high doses of glucocorticoids. Also, TSH levels remain <0.1 microunits/mL for some time after hyperthyroidism is corrected.
TSH levels are usually within the reference range in secondary hypothyroidism and are not useful for detection of this rare form of hypothyroidism.
Plasma free T4 confirms the diagnosis and assesses the severity of hyperthyroidism when plasma TSH is <0.1 microunits/mL. It is also used to diagnose secondary hypothyroidism and adjust thyroxine therapy in patients with pituitary disease. Most laboratories measure free T4 by analog immunoassays. Total T4 assays are less reliable and should not be used, except when free T4 is artifactually elevated by heparin treatment (see Table 22-1).
Free T4 measured by equilibrium dialysis is the most reliable measure of clinical thyroid status, but results seldom are rapidly available. It is needed only in rare cases in which the diagnosis is not clear from measurement of plasma TSH and free T4 by analog immunoassay.
Effect of nonthyroidal illness on thyroid function tests.3 Many illnesses alter thyroid tests without causing true thyroid dysfunction (the nonthyroidal illness or euthyroid
sick syndrome). These changes must be recognized to avoid mistaken diagnosis and therapy.
TABLE 22-1 Effects of Drugs on Thyroid Function Tests
Effect
Drug
Decreased free and total T4
True hypothyroidism (TSH elevated)
Iodine (amiodarone, radiographic contrast)
Lithium
Inhibition of TSH secretion
Glucocorticoids
Dopamine
Multiple mechanisms (TSH normal)
Phenytoin
Decreased total T4 only
Decreased TBG (TSH normal)
Androgens
Inhibition of T4 binding to TBG (TSH normal)
Furosemide (high doses)
Salicylates
Increased free and total T4
True hyperthyroidism (TSH <0.1 microunits/mL)
Iodine (amiodarone, radiographic contrast)
Inhibited T4 to T3 conversion (TSH normal)
Amiodarone
Increased free T4 only
Displacement of T4 from TBG in vitro (TSH normal)
Heparin, low molecular weight heparin
Increased total T4 only
Increased TBG (TSH normal)
Estrogens, tamoxifen
T3 = triiodothyronine; T4 = thyroxine; TBG = thyroxine-binding globulin; TSH = thyroid-stimulating hormone.
 The low T3 syndrome occurs in many illnesses, during starvation, and after trauma or surgery. Conversion of T4 to T3 is decreased, and plasma T3 levels are low. Plasma free T4 and TSH levels are normal. This may be an adaptive response to illness, and thyroid hormone therapy is not beneficial.
The low T4 syndrome occurs in severe illness. Plasma total T4 levels fall due to decreased levels of TBG and perhaps due to inhibition of T4 binding to TBG. Plasma free T4 measured by equilibrium dialysis usually remains normal. However, when measured by commonly available analog immunoassays, free T4 may be low. TSH levels decrease early in severe illness, sometimes to <0.1 microunits/mL. During recovery they rise, sometimes to levels higher than the normal range (although rarely >20 microunits/mL).
A number of drugs affect thyroid function tests (Table 22-1). Iodine-containing drugs (amiodarone and radiographic contrast media) may cause hyperthyroidism or hypothyroidism in susceptible patients. Other drugs alter thyroid function tests, especially plasma total T4, without causing true thyroid dysfunction. In general, plasma TSH levels are a reliable guide to determining whether true hyperthyroidism or hypothyroidism is present.
Hypothyroidism
General Principles
Etiology
Primary hypothyroidism (due to disease of the thyroid itself) accounts for >90% of cases.4
Chronic lymphocytic thyroiditis (Hashimoto disease)5 is the most common cause and may be associated with Addison disease and other endocrine deficits. Its prevalence is greater in women and increases with age.
Iatrogenic hypothyroidism due to thyroidectomy or radioactive iodine (RAI,131I) therapy is also common.
Transient hypothyroidism occurs in postpartum thyroiditis and subacute thyroiditis, usually after a period of hyperthyroidism.
Drugs that may cause hypothyroidism include iodine-containing drugs, lithium, interferon-α, interleukin-2, and thalidomide.
Secondary hypothyroidism due to TSH deficiency is uncommon but may occur in any disorder of the pituitary or hypothalamus. However, it rarely occurs without other evidence of pituitary disease.
Clinical Findings
Most symptoms of hypothyroidism are nonspecific and develop gradually. They include cold intolerance, fatigue, somnolence, poor memory, constipation, menorrhagia, myalgias, and hoarseness.
Signs include slow tendon reflex relaxation, bradycardia, facial and periorbital edema, dry skin, and nonpitting edema (myxedema). Mild weight gain may occur, but hypothyroidism does not cause marked obesity. Rare manifestations include hypoventilation, pericardial or pleural effusions, deafness, and carpal tunnel syndrome.
Laboratory findings may include hyponatremia and elevated plasma levels of cholesterol, triglycerides, and creatine kinase. The electrocardiogram (ECG) may show low voltage and T-wave abnormalities.
Diagnosis
Hypothyroidism is readily treatable and should be suspected in any patient with compatible symptoms, especially in the presence of a diffuse goiter or a history of RAI therapy or thyroid surgery.
In suspected primary hypothyroidism, plasma TSH is the best initial diagnostic test.
A normal value excludes primary hypothyroidism, and a markedly elevated value (>20 microunits/mL) confirms the diagnosis.
Mild elevation of plasma TSH (<20 microunits/mL) may be due to nonthyroidal illness, but usually indicates mild (or subclinical) primary hypothyroidism, in which thyroid function is impaired but increased secretion of TSH maintains plasma free T4 levels within the reference range. These patients may have nonspecific symptoms that are compatible with hypothyroidism and a mild increase in serum cholesterol and low-density lipoprotein cholesterol. They develop clinical hypothyroidism at a rate of 2.5% per year.
If secondary hypothyroidism is suspected because of evidence of pituitary disease, plasma free T4 should be measured.
Plasma TSH levels are usually within the reference range in secondary hypothyroidism and cannot be used alone to make this diagnosis. Patients with secondary hypothyroidism should be evaluated for other pituitary hormone deficits and for a mass lesion of the pituitary or hypothalamus (see Anterior Pituitary Gland Dysfunction).
In severe nonthyroidal illness, the diagnosis of hypothyroidism may be difficult.3 Plasma total T4 and free T4 measured by routine assays may be low.
Plasma TSH is the best initial diagnostic test. A normal TSH value is strong evidence that the patient is euthyroid, except when there is evidence of pituitary or hypothalamic disease or in patients treated with dopamine or high doses of glucocorticoids. Marked elevation of plasma TSH (>20 microunits/mL) establishes the diagnosis of primary hypothyroidism.
Moderate elevations of plasma TSH (< 20 microunits/mL) may occur in euthyroid patients with nonthyroidal illness and are not specific for hypothyroidism.
Plasma free T4 should be measured if TSH is moderately elevated, or if secondary hypothyroidism is suspected, and patients should be treated for hypothyroidism if plasma free T4 is low. Thyroid function in these patients should be re-evaluated after recovery from illness.
Therapy
Thyroxine is the drug of choice. The average replacement dose is 1.6 mcg/kg PO daily, and most patients require doses between 75 and 150 mcg/daily. In elderly patients, the average replacement dose is somewhat lower. The need for lifelong treatment should be emphasized. Thyroxine should be taken 30 minutes before a meal, since dietary fiber interferes with its absorption, and should not be taken with medications that affect its absorption (see below).
Initiation of therapy. Young, otherwise healthy adults should be started on 100 mcg/daily. This regimen gradually corrects hypothyroidism, as several weeks are required to reach steady-state plasma levels of T4. Symptoms begin to improve within a few weeks. In otherwise healthy elderly patients, the initial dose should be 50 mcg/daily. Patients with cardiac disease should be started on 25÷50 mcg/daily and monitored carefully for exacerbation of cardiac symptoms.
Dose adjustment and follow-up.
In primary hypothyroidism, the goal of therapy is to maintain plasma TSH within the normal range. Plasma TSH should be measured 2÷3 months after initiation of therapy. The dose of thyroxine then should be adjusted in 12- to 25-mcg increments at intervals of 6÷8 weeks until plasma TSH is normal. Thereafter, annual TSH measurement is adequate to monitor therapy. TSH should also be measured in the first trimester of pregnancy, since the thyroxine dose requirement increases at this time. Overtreatment, indicated by a subnormal TSH, should be avoided since it increases the risk of osteoporosis and atrial fibrillation.
In secondary hypothyroidism, plasma TSH cannot be used to adjust therapy. The goal of therapy is to maintain the plasma free T4 near the middle of the reference range. The dose of thyroxine should be adjusted at 6- to 8-week intervals until this goal is achieved. Thereafter, annual measurement of plasma free T4 is adequate to monitor therapy.
Coronary artery disease may be exacerbated by treatment of hypothyroidism. The dose of thyroxine should be increased slowly in patients with coronary artery disease, with careful attention to worsening angina, heart failure, or arrhythmias.
Situations in which thyroxine dose requirements change. Difficulty in controlling hypothyroidism is most often due to poor compliance with therapy. Observed therapy may be necessary in some cases. Other causes of increasing thyroxine requirement include:
Malabsorption due to intestinal disease or drugs that interfere with thyroxine absorption (e.g., calcium carbonate, ferrous sulfate, cholestyramine, sucralfate, aluminum hydroxide)
Drug interactions that increase thyroxine clearance (e.g., estrogen, rifampin, carbamazepine, phenytoin) or block conversion of T4 to T3 (amiodarone)
Pregnancy, in which thyroxine requirements often increase in the first trimester (see below)
Gradual failure of remaining endogenous thyroid function after RAI treatment of hyperthyroidism
Thyroxine dose increases by an average of 50% in the first half of pregnancy.6 In women with primary hypothyroidism, plasma TSH should be measured as soon as pregnancy is confirmed and monthly thereafter through the second trimester. The thyroxine dose should be increased as needed to maintain plasma TSH within the normal range.
Mild (or subclinical) hypothyroidism should be treated with thyroxine if any of the following are present: (a) symptoms compatible with hypothyroidism, (b) a goiter, (c) hypercholesterolemia that warrants treatment, or (d) the plasma TSH is >10 microunits/mL.7 Untreated patients should be monitored annually, and thyroxine should be started if symptoms develop or serum TSH increases to >10 microunits/mL.
Urgent therapy for hypothyroidism is rarely necessary. Most patients with hypothyroidism and concomitant illness can be treated in the usual manner. However, hypothyroidism may impair survival in critical illness by contributing to hypoventilation, hypotension, hypothermia, bradycardia, or hyponatremia. Little evidence supports the contention that severe hypothyroidism alone causes coma or shock; most reports of alleged “myxedema coma” predate recognition that nonthyroidal illness itself lowers thyroid hormone levels.
Hypoventilation and hypotension should be treated intensively, along with any concomitant diseases. Confirmatory tests (plasma TSH and free T4) should be obtained before thyroid hormone therapy is started in a severely ill patient.
Thyroxine, 50÷100 mcg IV, can be given q6÷8h for 24 hours, followed by 75÷100 mcg IV daily until oral intake is possible. Replacement therapy should be continued in the usual manner if the diagnosis of hypothyroidism is confirmed. No clinical trials have determined the optimum method of thyroid hormone replacement, but this method rapidly alleviates thyroxine deficiency while minimizing the risk of exacerbating underlying coronary disease or heart failure. Such rapid correction is warranted only in extremely ill patients. Vital signs and cardiac rhythm should be monitored carefully to detect early signs of exacerbation of heart disease. Hydrocortisone, 50 mg IV q8h, is usually recommended during rapid replacement of thyroid hormone, because such therapy may precipitate adrenal crisis in patients with adrenal failure.
Hyperthyroidism
General Principles
Etiology
Graves disease8 causes most cases of hyperthyroidism, especially in young patients. This autoimmune disorder may also cause proptosis (exophthalmos) and pretibial myxedema, neither of which is found in other causes of hyperthyroidism.
Toxic multinodular goiter (MNG) is a common cause of hyperthyroidism in older patients.
Unusual causes include iodine-induced hyperthyroidism (usually precipitated by drugs such as amiodarone or radiographic contrast media), thyroid adenomas, subacute thyroiditis (painful tender goiter with transient hyperthyroidism), painless thyroiditis (nontender goiter with transient hyperthyroidism, most often seen in the postpartum period), and surreptitious ingestion of thyroid hormone. TSH-induced hyperthyroidism is extremely rare.
Clinical Findings
Symptoms include heat intolerance, weight loss, weakness, palpitations, oligomenorrhea, and anxiety.
Signs include brisk tendon reflexes, fine tremor, proximal weakness, stare, and eyelid lag. Cardiac abnormalities may be prominent, including sinus tachycardia, atrial fibrillation, and exacerbation of coronary artery disease or heart failure.
In the elderly, hyperthyroidism may present with only atrial fibrillation, heart failure, weakness, or weight loss, and a high index of suspicion is needed to make the diagnosis.
Diagnosis
Hyperthyroidism should be suspected in any patient with compatible symptoms, as it is a readily treatable disorder that may become very debilitating.
 
TABLE 22-2 Differential Diagnosis of Hyperthyroidism
Type of goiter
Diagnosis
Diffuse, nontender goiter
Graves' disease or painless thyroiditis
Multiple thyroid nodules
Toxic multinodular goiter
Single thyroid nodule
Thyroid adenoma
Tender painful goiter
Subacute thyroiditis
Normal thyroid gland
Graves' disease, painless thyroiditis or factitious hyperthyroidism
 Plasma TSH is the best initial diagnostic test, as a TSH level >0.1 microunits/mL excludes clinical hyperthyroidism. If plasma TSH is <0.1 microunits/mL, plasma free T4 should be measured to determine the severity of hyperthyroidism and as a baseline for therapy. If plasma free T4 is elevated, the diagnosis of clinical hyperthyroidism is established.
If plasma TSH is < 0.1 microunits/mL but free T4 is normal, the patient may have clinical hyperthyroidism due to elevation of plasma T3 alone; therefore, plasma T3 should be measured in this case.
Very mild (or subclinical) hyperthyroidism may suppress TSH to <0.1 microunits/mL, and therefore suppression of TSH alone does not confirm that symptoms are due to hyperthyroidism.
TSH may also be suppressed by severe nonthyroidal illness (see Evaluation of Thyroid Function). A third-generation TSH assay with a detection limit of 0.02 microunits/mL may be helpful in patients with suppressed TSH and nonthyroidal illness. Most patients with clinical hyperthyroidism have plasma TSH levels that are <0.02 microunits/mL in such assays, whereas nonthyroidal illness rarely suppresses TSH to this degree.2
Differential Diagnosis
The etiology of hyperthyroidism affects the choice of therapy. Differentiating features include (Table 22-2):
The presence of proptosis or pretibial myxedema, seen only in Graves' disease (although many patients with Graves' disease lack these signs)
A diffuse nontender goiter, consistent with Graves' disease or painless thyroiditis
Recent pregnancy, neck pain, or recent iodine administration, suggesting causes other than Graves' disease
In rare cases, 24-hour RAI uptake (RAIU) is needed to distinguish Graves' disease or toxic MNG (in which RAIU is elevated) from postpartum thyroiditis, iodine-induced hyperthyroidism, or factitious hyperthyroidism (in which RAIU is very low).
Thyroid imaging with ultrasound or radionuclide scan is not useful in hyperthyroidism.
Treatment
Therapy9
Some forms of hyperthyroidism (subacute or postpartum thyroiditis) are transient and require only symptomatic therapy.
A β-adrenergic antagonist (such as atenolol 25÷100 mg daily) is used to relieve symptoms of hyperthyroidism, such as palpitations, tremor, and anxiety, until hyperthyroidism is controlled by definitive therapy, or until transient forms of hyperthyroidism subside. The dose is adjusted to alleviate symptoms and tachycardia, then reduced gradually as hyperthyroidism is controlled.
Verapamil at an initial dose of 40÷80 mg PO tid can be used to control tachycardia in patients with contraindications to β-adrenergic antagonists.
Three methods are available for definitive therapy (none of which controls hyperthyroidism rapidly): RAI, thionamides, and subtotal thyroidectomy.
During treatment, patients are followed by clinical evaluation and measurement of plasma free T4. Plasma TSH is useless in assessing the initial response to therapy, as it remains suppressed until after the patient becomes euthyroid.
Regardless of the therapy used, all patients with Graves' disease require lifelong follow-up for recurrent hyperthyroidism or development of hypothyroidism.
Choice of definitive therapy
In Graves' disease, RAI therapy is the treatment of choice for almost all patients. It is simple and highly effective, but cannot be used in pregnancy. Propylthiouracil (PTU) should be used to treat hyperthyroidism in pregnancy. Thionamides achieve long-term control in fewer than half of patients with Graves' disease and they carry a small risk of life-threatening side effects. Thyroidectomy should be used in patients who refuse RAI therapy and who relapse or develop side effects with thionamide therapy.
Other causes of hyperthyroidism. Toxic MNG and toxic adenoma should be treated with RAI (except in pregnancy). Transient forms of hyperthyroidism due to thyroiditis should be treated symptomatically with atenolol. Iodine-induced hyperthyroidism is treated with thionamides and atenolol until the patient is euthyroid. Although treatment of some patients with amiodarone-induced hyperthyroidism with glucocorticoids has been advocated, nearly all patients with amiodarone-induced hyperthyroidism respond well to thionamide therapy.10
RAI therapy
A single dose permanently controls hyperthyroidism in 90% of patients, and further doses can be given if necessary.
A pregnancy test is done immediately before therapy in potentially fertile women.
A 24-hour RAIU is usually measured and used to calculate the dose.
Thionamides interfere with RAI therapy and should be stopped at least 3 days before treatment. If iodine treatment has been given, it should be stopped at least 2 weeks before RAI therapy.
Most patients with Graves' disease are treated with 8÷10 mCi, although treatment of toxic MNG requires higher doses.
Follow-up. Usually, several months are needed to restore euthyroidism. Patients are evaluated at 4- to 6-week intervals, with assessment of clinical findings and plasma free T4.
If thyroid function stabilizes within the normal range, the interval between follow-up visits is gradually increased to annual intervals.
If symptomatic hypothyroidism develops, thyroxine therapy is started (see Hypothyroidism).
If symptomatic hyperthyroidism persists after 6 months, RAI treatment is repeated.
Side effects
Hypothyroidism occurs in most patients within the first year and continues to develop at a rate of approximately 3% per year thereafter.
Because of the release of stored hormone, a slight rise in plasma T4 may occur in the first 2 weeks after therapy. This development is important only in patients with severe cardiac disease, which may worsen as a result. Such patients should be treated with thionamides to restore euthyroidism and to deplete stored hormone before treatment with RAI.
No convincing evidence has been found that RAI has a clinically important effect on the course of Graves' eye disease.
It does not increase the risk of malignancy. No increase in congenital abnormalities has been found in the offspring of women who conceive after RAI therapy, and the radiation exposure to the ovaries is low, comparable to that from common diagnostic radiographs.
Thionamides.11 Methimazole and PTU inhibit thyroid hormone synthesis. PTU also inhibits extrathyroidal deiodination of T4 to T3. Once thyroid hormone stores are depleted (after several weeks to months), T4 levels decrease. These drugs have no permanent effect on thyroid function. In the majority of patients with Graves' disease, hyperthyroidism recurs within 6 months after therapy is stopped. Spontaneous remission of Graves' disease occurs in approximately one-third of patients during thionamide therapy and, in this minority, no other treatment may be needed. Remission is more likely in mild, recent-onset hyperthyroidism and if the goiter is small.
Initiation of therapy. Before starting therapy, patients must be warned of side effects and precautions. Usual starting doses are PTU, 100÷200 mg PO tid, or methimazole, 10÷40 mg PO daily; higher initial doses can be used in severe hyperthyroidism.
Follow-up. Restoration of euthyroidism takes up to several months.
Patients are evaluated at 4-week intervals with assessment of clinical findings and plasma free T4. If plasma free T4 levels do not fall after 4÷8 weeks, the dose should be increased. Doses as high as PTU, 300 mg PO qid, or methimazole, 60 mg PO daily, may be required.
Once the plasma free T4 level falls to normal, the dose is adjusted to maintain plasma free T4 within the normal range.
No consensus exists on the optimal duration of therapy, but periods of 6 months to 2 years are used most commonly. Patients must be monitored carefully for recurrence of hyperthyroidism after the drug is stopped.
Side effects are most likely to occur within the first few months of therapy.
Minor side effects include rash, urticaria, fever, arthralgias, and transient leukopenia.
Agranulocytosis occurs in 0.3% of patients treated with thionamides. Other life-threatening side effects include hepatitis, vasculitis, and drug-induced lupus erythematosus. These complications usually resolve if the drug is stopped promptly.
Patients must be warned to stop the drug immediately if jaundice or symptoms suggestive of agranulocytosis develop (e.g., fever, chills, sore throat) and to contact their physician promptly for evaluation. Routine monitoring of the white blood cell (WBC) is not useful for detecting agranulocytosis, which develops suddenly.
Subtotal thyroidectomy. This procedure provides long-term control of hyperthyroidism in most patients.
Surgery may trigger a perioperative exacerbation of hyperthyroidism, and patients should be prepared for surgery by one of two methods.
A thionamide is given until the patient is nearly euthyroid (see section. IV.D). Supersaturated potassium iodide (SSKI), 40÷80 mg (one to two drops) PO bid, is then added 1÷2 weeks before surgery. Both drugs are stopped postoperatively.
Atenolol (50÷100 mg daily) is started 1÷2 weeks before surgery. The dose of atenolol is increased, if necessary, to reduce the resting heart rate below 90 beats/min and is continued for 5÷7 days postoperatively. SSKI is dosed as above.
Follow-up. Clinical findings and plasma free T4 and TSH should be assessed 4÷6 weeks after surgery.
If thyroid function is normal, the patient is seen at 3 and 6 months, then annually.
If symptomatic hypothyroidism develops, thyroxine therapy is started (see Hypothyroidism).
Mild hypothyroidism after subtotal thyroidectomy may be transient, and asymptomatic patients can be observed for a further 4÷6 weeks to determine whether hypothyroidism will resolve spontaneously.
Hyperthyroidism persists or recurs in 3%÷7% of patients.
Complications of thyroidectomy include hypothyroidism in 30%÷50% of patients and hypoparathyroidism in 3%. Rare complications include permanent vocal cord
paralysis, due to recurrent laryngeal nerve injury, and perioperative death. The complication rate appears to depend on the experience of the surgeon.
Mild (or subclinical) hyperthyroidism is present when the plasma TSH is suppressed to <0.1 microunits/mL but the patient has no symptoms that are definitely caused by hyperthyroidism, and plasma levels of free T4 and T3 are normal.7
Subclinical hyperthyroidism increases the risk of atrial fibrillation in patients older than 60 years and those with heart disease, and predisposes to osteoporosis in postmenopausal women; it should be treated in these groups of patients.
Asymptomatic young patients with mild Graves' disease can be observed for spontaneous resolution of hyperthyroidism, or the development of symptoms or increasing free T4 levels that warrant treatment.
Urgent therapy is warranted when hyperthyroidism exacerbates heart failure or acute coronary syndromes, and in rare patients with severe hyperthyroidism complicated by fever and delirium. Concomitant diseases should be treated intensively, and confirmatory tests (serum TSH and free T4) should be obtained before therapy is started.
PTU, 300 mg PO q6h, should be started immediately.
Iodide (SSKI, one to two drops PO q12h) should be started 1 hour after the first dose of PTU, to inhibit thyroid hormone secretion rapidly.
Propranolol, 40 mg PO q6h (or an equivalent dose IV), should be given to patients with angina or myocardial infarction, and the dose should be adjusted to prevent tachycardia. Propranolol may benefit some patients with heart failure and marked tachycardia but can further impair left ventricular systolic function. In patients with clinical heart failure, it should be given only with careful monitoring of left ventricular function.
Plasma free T4 is measured every 4÷6 days. When free T4 approaches the normal range, the doses of PTU and iodine are gradually decreased. RAI therapy should be scheduled 2 weeks after iodine is stopped.
Hyperthyroidism in pregnancy.12 If hyperthyroidism is suspected, plasma TSH should be measured. Plasma TSH declines in early pregnancy, but rarely to <0.1 microunits/mL.
If TSH is <0.1 microunits/mL, the diagnosis should be confirmed by measurement of plasma free T4.
RAI is contraindicated in pregnancy, and therefore patients should be treated with PTU. The dose should be adjusted at 4-week intervals to maintain the plasma free T4 near the upper limit of the normal range. The dose required often decreases in the later stages of pregnancy.
Atenolol, 25÷50 mg PO daily, can be used to relieve symptoms while awaiting the effects of PTU.
The fetus and neonate should be monitored carefully for hyperthyroidism.
Euthyroid Goiter
General Principles
The diagnosis of euthyroid goiter is based on palpation of the thyroid and evaluation of thyroid function. If the thyroid is enlarged, the examiner should determine whether the enlargement is diffuse or multinodular, or whether a single palpable nodule is present. All three forms of euthyroid goiter are common, especially in women.
Thyroid scans or ultrasonography provide no useful additional information about goiters that are diffuse or multinodular by palpation and should not be performed in these patients.
Furthermore, 30%÷50% of people have nonpalpable thyroid nodules that are detectable by ultrasound. These nodules rarely have any clinical importance, but their incidental discovery may lead to unnecessary diagnostic testing and treatment.13
Diffuse goiter
Almost all euthyroid diffuse goiters in the United States are due to chronic lymphocytic thyroiditis (Hashimoto's thyroiditis).5 Since Hashimoto thyroiditis may also cause hypothyroidism, plasma TSH should be measured even in patients who are clinically euthyroid.
Small diffuse goiters usually are asymptomatic, and therapy is seldom required.
Symptomatic diffuse goiters may shrink with suppression of plasma TSH to the lower part of the normal range by thyroxine therapy. If thyroxine is not given, the patient should be monitored regularly for the development of hypothyroidism.
Multinodular goiter
Multinodular goiter (MNG) is common in older patients, especially women. Most patients are asymptomatic and require no treatment.
In a few patients, hyperthyroidism (toxic MNG) develops (see Hyperthyroidism).
In rare patients, the gland compresses the trachea or esophagus, causing dyspnea or dysphagia, and treatment is required. Thyroxine treatment has little if any effect on the size of MNGs. RAI therapy reduces gland size and relieves symptoms in most patients. Subtotal thyroidectomy can also be used to relieve compressive symptoms.
Evaluation for thyroid carcinoma with needle biopsy is warranted if one nodule is disproportionately enlarged.
Single Thyroid Nodules
Single palpable thyroid nodules are usually benign, but about 5% are thyroid carcino- mas.14
Clinical findings that increase the likelihood of carcinoma include the presence of cervical lymphadenopathy, a history of radiation to the head or neck in childhood, and a family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndromes type 2A or 2B. A hard fixed nodule, recent nodule growth, or hoarseness due to vocal cord paralysis also suggests malignancy.
However, most patients with thyroid carcinomas have none of these risk factors, and all palpable single thyroid nodules should be evaluated with needle aspiration biopsy.15 Patients with thyroid carcinoma should be managed in consultation with an endocrinologist.
Nodules with benign cytology should be re-evaluated periodically by palpation. Thyroxine therapy has little or no effect on the size of single thyroid nodules and is not indicated.16
Radionuclide thyroid scans cannot distinguish benign from malignant nodules and should not be performed. The management of nonpalpable thyroid nodules discovered incidentally by ultrasound is controversial.17
Adrenal Failure
General Principles
Etiology
Adrenal failure may be due to disease of the adrenal glands (primary adrenal failure, Addison's disease), with deficiency of both cortisol and aldosterone and elevated plasma adrenocorticotropic hormone (ACTH), or to ACTH deficiency caused by disorders of the pituitary or hypothalamus (secondary adrenal failure), with deficiency of cortisol alone.
Primary adrenal failure18 is most often due to autoimmune adrenalitis, which may be associated with other endocrine deficits (e.g., hypothyroidism).
Infections of the adrenal gland such as tuberculosis and histoplasmosis also may cause adrenal failure.
Hemorrhagic adrenal infarction may occur in the postoperative period, in coagulation disorders and hypercoagulable states, and in sepsis. Adrenal hemorrhage often causes abdominal or flank pain and fever; computed tomography (CT) scan of the abdomen reveals high-density bilateral adrenal masses.
Adrenal failure may develop in patients with AIDS, caused by disseminated cytomegalovirus, mycobacterial or fungal infection, or adrenal lymphoma.
Less common etiologies include adrenoleukodystrophy that causes adrenal failure in young males, and drugs such as ketoconazole and etomidate that inhibit steroid hormone synthesis and can cause adrenal failure.
Secondary adrenal failure is due most often to glucocorticoid therapy; ACTH suppression may persist for a year after therapy is stopped. Any disorder of the pituitary or hypothalamus can cause ACTH deficiency, but other evidence of these disorders is usually obvious.
Clinical Findings
Clinical findings in adrenal failure are nonspecific, and without a high index of suspicion, the diagnosis of this potentially lethal but readily treatable disease is easily missed.
Symptoms include anorexia, nausea, vomiting, weight loss, weakness, and fatigue. Orthostatic hypotension and hyponatremia are common.
Usually, symptoms are chronic, but shock may develop suddenly, and is fatal unless promptly treated. Often, this adrenal crisis is triggered by illness, injury, or surgery. All these symptoms are due to cortisol deficiency and occur in both primary and secondary adrenal failure.
Hyperpigmentation (due to marked ACTH excess) and hyperkalemia and volume depletion (due to aldosterone deficiency) occur only in primary adrenal failure.
Diagnosis19
Adrenal failure should be suspected in patients with hypotension, weight loss, persistent nausea, hyponatremia, or hyperkalemia.
The cosyntropin (Cortrosyn) stimulation test is used for diagnosis. Cosyntropin, 250 mcg, is given IV or IM, and plasma cortisol is measured 30 minutes later. The normal response is a stimulated plasma cortisol >20 mcg/dL. This test detects primary and secondary adrenal failure, except within a few weeks of onset of pituitary dysfunction (e.g., shortly after pituitary surgery; see Anterior Pituitary Gland Dysfunction).
The distinction between primary and secondary adrenal failure is usually clear.
Hyperkalemia, hyperpigmentation, or other autoimmune endocrine deficits indicate primary adrenal failure, whereas deficits of other pituitary hormones, symptoms of a pituitary mass (e.g., headache, visual field loss), or known pituitary or hypothalamic disease indicate secondary adrenal failure.
If the cause is unclear, the plasma ACTH level distinguishes primary adrenal failure (in which it is markedly elevated) from secondary adrenal failure.
Most cases of primary adrenal failure are due to autoimmune adrenalitis, but other causes should be considered. Radiographic evidence of adrenal enlargement or calcification indicates that the cause is infection or hemorrhage.
Patients with secondary adrenal failure should be tested for other pituitary hormone deficiencies and should be evaluated for a pituitary or hypothalamic tumor (see Anterior Pituitary Gland Dysfunction).
Therapy20
Adrenal crisis with hypotension must be treated immediately. Patients should be evaluated for an underlying illness that precipitated the crisis.
If the diagnosis of adrenal failure is known, hydrocortisone, 100 mg IV q8h, should be given, and 0.9% saline with 5% dextrose should be infused rapidly until hypotension is corrected. The dose of hydrocortisone is decreased gradually over several days as symptoms and any precipitating illness resolve, then changed to oral maintenance therapy. Mineralocorticoid replacement is not needed until the dose of hydrocortisone is <100 mg/d.
If the diagnosis of adrenal failure has not been established, a single dose of dexamethasone, 10 mg IV, should be given, and a rapid infusion of 0.9% saline with 5% dextrose should be started. A Cortrosyn stimulation test should be performed. Dexamethasone is used because it does not interfere with measurement of plasma cortisol. After the 30-minute plasma cortisol measurement, hydrocortisone, 100 mg IV q8h, should be given until the test result is known.
Maintenance therapy in all patients with adrenal failure requires cortisol replacement with prednisone; most patients with primary adrenal failure also require replacement of aldosterone with fludrocortisone.
Prednisone, 5 mg PO every morning, should be started. The dose is then adjusted with the goal being the lowest dose that relieves the patient's symptoms, to prevent osteoporosis and other signs of Cushing syndrome. Most patients require doses between 4 mg PO every morning and 5 mg PO every morning and 2.5 mg every evening. Concomitant therapy with rifampin, phenytoin, or phenobarbital accelerates glucocorticoid metabolism and increases the dose requirement.
During illness, injury, or the perioperative period, the dose of prednisone must be increased.
For minor illnesses, the patient should double the dose for 3 days. If the illness resolves, the maintenance dose is resumed.
Vomiting requires immediate medical attention, with IV glucocorticoid therapy and IV fluid. Patients can be given a 4-mg vial of dexamethasone to be self-administered IM for vomiting or severe illness if medical care is not immediately available.
For severe illness or injury, hydrocortisone, 50 mg IV q8h, should be given, with the dose tapered as severity of illness wanes. The same regimen is used in patients undergoing surgery, with the first dose of hydrocortisone given preoperatively. The dose can be tapered to maintenance therapy by 2÷3 days after uncomplicated surgery.
In primary adrenal failure, fludrocortisone, 0.1 mg PO daily, should be given, along with liberal salt intake. The dose is adjusted to maintain blood pressure (BP; supine and standing) and serum potassium within the normal range; the usual dosage is 0.05÷0.2 mg PO daily.
Patients should be educated in management of their disease, including adjustment of prednisone dose during illness. They should wear a medical identification tag or bracelet.
Cushing's Syndrome
General Principles
Cushing's syndrome21 is most often iatrogenic, due to therapy with glucocorticoid drugs.
ACTH-secreting pituitary microadenomas (Cushing's disease) account for 80% of cases of endogenous Cushing's syndrome.
Adrenal tumors and ectopic ACTH secretion account for the remainder.
Clinical findings
Findings include truncal obesity, rounded face, fat deposits in the supraclavicular fossae and over the posterior neck, hypertension, hirsutism, amenorrhea, and depression.
More specific findings include thin skin, easy bruising, reddish striae, proximal muscle weakness, and osteoporosis.
Diabetes mellitus develops in some patients.
Hyperpigmentation or hypokalemic alkalosis suggests Cushing's syndrome due to ectopic ACTH secretion.
Diagnosis
Diagnosis is based on increased cortisol excretion and lack of normal feedback inhibition of ACTH and cortisol secretion.22
The best initial test is the 24-hour urine cortisol measurement test. Alternatively, an overnight dexamethasone suppression test (1 mg dexamethasone given PO at 11:00 p.m.; plasma cortisol measured at 8:00 a.m. the next day; normal range: plasma cortisol <2 mcg/dL) may be performed. Both tests are very sensitive, and a normal value virtually excludes the diagnosis. If the overnight dexamethasone suppression test is abnormal, 24-hour urine cortisol should be measured.
If the 24-hour urine cortisol excretion is more than four times the upper limit of the reference range in a patient with compatible clinical findings, the diagnosis of Cushing's syndrome is established.
In patients with milder elevations of urine cortisol, a low-dose dexamethasone suppression test should be performed. Dexamethasone, 0.5 mg PO q6h, is given for 48 hours, starting at 8:00 a.m.. Urine cortisol is measured during the last 24 hours, and plasma cortisol is measured 6 hours after the last dose of dexamethasone. Failure to suppress plasma cortisol to <2 mcg/dL and urine cortisol to less than the normal reference range is diagnostic of Cushing's syndrome.
Testing should not be done during severe illness or depression, which may cause false-positive results. Phenytoin therapy also causes a false-positive test by accelerating metabolism of dexamethasone.
Random plasma cortisol levels are not useful for diagnosis, because the wide range of normal values overlaps those of Cushing's syndrome. After the diagnosis of Cushing's syndrome is made, tests to determine the cause are best done in consultation with an endocrinologist.
Incidental Adrenal Nodules
General Principles
Adrenal nodules are a common incidental finding on abdominal imaging studies.
Most incidentally discovered nodules are benign adrenocortical tumors that do not secrete excess hormone, but the differential diagnosis includes adrenal adenomas causing Cushing's syndrome or primary hyperaldosteronism, pheochromocytoma, adrenocortical carcinoma, and metastatic cancer.23
Evaluation
The imaging characteristics of the nodule may suggest a diagnosis but are not specific enough to obviate further evaluation.24
In patients without a known malignancy elsewhere, the diagnostic issues are whether a syndrome of hormone excess or an adrenocortical carcinoma is present. Patients should be evaluated for hypertension, symptoms suggestive of pheochromocytoma (episodic headache, palpitations, and sweating) and signs of Cushing's syndrome (see Cushing's Syndrome).
Plasma potassium and dehydroepiandrosterone sulfate should be measured, and an overnight dexamethasone suppression test should be performed.
Pheochromocytoma should be tested for by either plasma fractionated metanephrines or 24-hour urine catecholamines and metanephrines.25
Patients who have potentially resectable cancer elsewhere and in whom an adrenal metastasis must be excluded may require needle biopsy of the nodule.
Pheochromocytoma should be excluded before biopsy.
Management26
Patients with hypertension and hypokalemia should be evaluated for primary hyperaldosteronism in consultation with an endocrinologist.
An abnormal overnight dexamethasone suppression test should be evaluated further (see Cushing's Syndrome).
If clinical or biochemical evidence of a pheochromocytoma is found, the nodule should be resected after appropriate α-adrenergic blockade with phenoxybenzamine.
Elevation of plasma dehydroepiandrosterone sulfate or a large nodule suggests adrenocortical carcinoma. A policy of resecting all nodules >4 cm in diameter appropriately treats the great majority of adrenal carcinomas while minimizing the number of benign nodules that are removed unnecessarily.27
Most incidental nodules are <4 cm in diameter, do not produce excess hormone, and do not require therapy. At least one repeat imaging procedure 3÷6 months later is recommended to ensure that the nodule is not enlarging rapidly (which would suggest an adrenal carcinoma).
Anterior Pituitary Gland Dysfunction
General Principles
The anterior pituitary gland secretes prolactin, growth hormone, and four trophic hormones: corticotropin (ACTH), thyrotropin (TSH), and the gonadotropins, luteinizing hormone and follicle-stimulating hormone. Each trophic hormone stimulates a specific target gland.
Anterior pituitary function is regulated by hypothalamic hormones that reach the pituitary via portal veins in the pituitary stalk. The predominant effect of hypothalamic regulation is to stimulate secretion of pituitary hormones, except for prolactin, which is inhibited by hypothalamic dopamine production.
Secretion of trophic hormones is also regulated by negative feedback by their target gland hormone, and the normal pituitary response to target hormone deficiency is increased secretion of the appropriate trophic hormone.
Anterior pituitary dysfunction can be caused by disorders of either the pituitary or hypothalamus.
Pituitary adenomas are the most common pituitary disorder. They are classified by size and function.
Microadenomas are <10 mm in diameter and cause clinical manifestations only if they produce excess hormone. They are too small to produce hypopituitarism or mass effects.
Macroadenomas are >10 mm in diameter and may produce any combination of pituitary hormone excess, hypopituitarism, and mass effects (headache, visual field loss).
Secretory adenomas produce prolactin, growth hormone, or ACTH.
Nonsecretory macroadenomas may cause hypopituitarism or mass effects.
Nonsecretory microadenomas are common incidental radiographic findings, seen in approximately 10% of the normal population, and do not require therapy.28
Other pituitary or hypothalamic disorders, such as head trauma, pituitary surgery or radiation, and postpartum pituitary infarction (Sheehan's syndrome) may cause hypopituitarism. Other tumors of the pituitary or hypothalamus (e.g., craniopharyngioma,
metastases), inflammatory disorders (e.g., sarcoidosis, histiocytosis X), and infections (e.g., tuberculosis) may cause hypopituitarism or mass effects.
Clinical Findings
Pituitary and hypothalamic disorders may present in several ways.
In hypopituitarism (deficiency of one or more pituitary hormones), gonadotropin deficiency is most common, causing amenorrhea in women and androgen deficiency in men. Secondary hypothyroidism or adrenal failure rarely occurs alone. Secondary adrenal failure causes deficiency of cortisol but not of aldosterone; hyperkalemia and hyperpigmentation do not occur, although life-threatening adrenal crisis may develop.
Hormone excess most commonly results in hyperprolactinemia, which can be due to a secretory adenoma or to nonsecretory lesions that damage the hypothalamus or pituitary stalk. Growth hormone excess (acromegaly) and ACTH and cortisol excess (Cushing's disease) are caused by secretory adenomas.
Mass effects due to pressure on adjacent structures, such as the optic chiasm, include headaches and loss of visual fields or acuity. Hyperprolactinemia also may be due to mass effect. Pituitary apoplexy is sudden enlargement of a pituitary tumor due to hemorrhagic necrosis.
Asymptomatic pituitary adenomas
If a microadenoma is found on imaging done for another purpose, the patient should be evaluated for clinical evidence of hyperprolactinemia, Cushing's disease, or acromegaly.
Plasma prolactin should be measured, and tests for acromegaly and Cushing's syndrome should be performed if symptoms or signs of these disorders are evident.
If no pituitary hormone excess exists, therapy is not required. Whether such patients need repeat imaging is not established, but the risk of enlargement is clearly small.28
Incidental discovery of a macroadenoma is unusual. Patients should be evaluated for hormone excess and hypopituitarism. Most macroadenomas should be treated since they are likely to grow further.
Diagnosis of Hypopituitarism
Hypopituitarism may be suspected in the presence of clinical signs of target hormone deficiency (e.g., hypothyroidism) or pituitary mass effects.
Laboratory evaluation for hypopituitarism begins with evaluation of target hormone function, including plasma free T4 and a Cortrosyn stimulation test (see Adrenal Failure).
If recent onset of secondary adrenal failure is suspected (within a few weeks of evaluation), the patient should be treated empirically with glucocorticoids and should be tested later, since the Cortrosyn stimulation test cannot detect secondary adrenal failure of recent onset.
In men, plasma testosterone should be measured. The best evaluation of gonadal function in women is the menstrual history.
If a target hormone is deficient, its trophic hormone is measured to determine whether target gland dysfunction is secondary to hypopituitarism. An elevated trophic hormone level indicates primary target gland dysfunction. In hypopituitarism, trophic hormone levels are not elevated and are usually within (not below) the reference range. Thus, pituitary trophic hormone levels can be interpreted only with knowledge of target hormone levels, and measurement of trophic hormone levels alone is useless in the diagnosis of hypopituitarism. If pituitary disease is obvious, target hormone deficiencies may be assumed to be secondary, and trophic hormones need not be measured.
Anatomic evaluation of the pituitary gland and hypothalamus is done best by magnetic resonance imaging (MRI). However, hyperprolactinemia and Cushing's disease may be caused by microadenomas too small to be seen with current techniques. The prevalence of incidental microadenomas should be kept in mind when interpreting MRIs. Visual acuity and visual fields should be tested when imaging suggests compression of the optic chiasm.
Treatment of Hypopituitarism
Deficient target hormones should be replaced.
Secondary adrenal failure should be treated immediately, especially if patients are to undergo surgery (see Adrenal Failure).
Treatment of secondary hypothyroidism should be monitored by measurement of plasma free T4 (see Hypothyroidism).
Infertility due to gonadotropin deficiency may be correctable, and patients who wish to conceive should be referred to an endocrinologist.
Treatment of growth hormone deficiency in adults has been advocated by some, but the benefits, risks and cost effectiveness of this therapy are not established.29
Treatment of pituitary macroadenomas generally requires transsphenoidal surgical resection, except for prolactin-secreting tumors.
Hyperprolactinemia30
General Principles
In women, the most common causes of pathologic hyperprolactinemia are prolactin-secreting pituitary microadenomas and idiopathic hyperprolactinemia (Table 22-3).
In men, the most common cause is a prolactin-secreting macroadenoma.
Hypothalamic or pituitary lesions that cause deficiency of other pituitary hormones often cause hyperprolactinemia.
Medications are an important cause in both men and women.31
Clinical Findings
In women, hyperprolactinemia causes amenorrhea or irregular menses and infertility. Only approximately half of these women have galactorrhea. Prolonged estrogen deficiency increases the risk of osteoporosis.
In men, hyperprolactinemia causes androgen deficiency and infertility but not gynecomastia; mass effects and hypopituitarism are common.
 
TABLE 22-3 Major Causes of Hyperprolactinemia
Pregnancy and lactation
Prolactin-secreting pituitary adenoma (prolactinoma)
Idiopathic hyperprolactinemia
Drugs (e.g., phenothiazines, metoclopramide, risperidone, verapamil)
Interference with synthesis or transport of hypothalamic dopamine
   Hypothalamic lesions
   Nonsecretory pituitary macroadenomas
Primary hypothyroidism
Chronic renal failure
Diagnosis
Hyperprolactinemia is common in young women, and plasma prolactin should be measured in women with amenorrhea, whether or not galactorrhea is present. Mild elevations should be confirmed by repeat measurements.
The history should include medications and symptoms of pituitary mass effects or hypothyroidism.
Laboratory evaluation should also include plasma TSH and a pregnancy test in women.
Prolactin levels of >200 ng/mL occur only in prolactinomas, and levels between 100 and 200 ng/mL strongly suggest this diagnosis. Levels <100 ng/mL may be due to any cause except prolactin-secreting macroadenoma, and such levels in a patient with a large pituitary mass indicate that it is a nonfunctioning tumor rather than a prolactinoma.
Testing for hypopituitarism is needed only in patients with a macroadenoma or hypothalamic lesion. Pituitary imaging should be performed in most cases, as large nonfunctional pituitary or hypothalamic tumors may present with hyperprolactinemia.
Therapy
Microadenomas and idiopathic hyperprolactinemia.
Most patients are treated because of infertility or to prevent estrogen deficiency and osteoporosis.
Some women may be observed without therapy by periodic follow-up of prolac-tin levels and symptoms. In most patients, hyperprolactinemia does not worsen, and prolactin levels sometimes return to normal. Enlargement of microadenomas is rare.
The dopamine agonists bromocriptine and cabergoline suppress plasma prolactin and restore normal menses and fertility in most women.
Initial dosages are bromocriptine, 1.25÷2.5 mg PO at bedtime with a snack, or cabergoline, 0.25 mg twice a week.
Plasma prolactin levels are initially obtained at 2- to 4-week intervals, and doses are adjusted until the lowest dose required to maintain prolactin in the normal range is reached. In general, the maximally effective doses are bromocriptine 2.5 mg tid and cabergoline 1.5 mg twice a week.
Side effects include nausea and orthostatic hypotension, which can be minimized by increasing the dose gradually, and usually resolve with continued therapy. Side effects are less severe with cabergoline.
Initially, patients should use barrier contraception, as fertility may be restored quickly.
Women who want to become pregnant should be managed in consultation with an endocrinologist.
Women who do not want to become pregnant should be followed with clinical evaluation and plasma prolactin levels every 6÷12 months. Every 2 years, plasma prolactin should be measured after bromocriptine has been withdrawn for several weeks, to determine whether the drug is still needed. Follow-up imaging studies are not warranted unless prolactin levels increase substantially.
Transsphenoidal resection of prolactin-secreting microadenomas is used only in the rare patient who does not respond to or cannot tolerate dopamine agonists. Prolactin levels usually return to normal, but up to one-half of patients experience relapse.
Prolactin-secreting macroadenomas should be treated with a dopamine agonist, which usually suppresses prolactin levels to normal, reduces tumor size, and improves or corrects abnormal visual fields in 90% of cases.
If mass effects are present, the dose should be increased to maximally effective levels over a period of several weeks. Visual field tests, if initially abnormal, should be repeated 4÷6 weeks after therapy is started.
Pituitary imaging should be repeated 3÷6 months after initiation of therapy. If tumor shrinkage and correction of visual abnormalities are satisfactory, therapy can be continued indefinitely, with periodic monitoring of plasma prolactin levels.
The full effect on tumor size may take more than 6 months. Further pituitary imaging is probably not warranted unless prolactin levels rise despite therapy.
Transsphenoidal surgery is indicated to relieve mass effects and to prevent further tumor growth if the tumor does not shrink or if visual field abnormalities persist during dopamine agonist therapy. However, the likelihood of surgical cure of hyperprolactinemia due to a macroadenoma is low, and most patients require further therapy with a dopamine agonist.
Women with prolactin-secreting macroadenomas should not become pregnant unless the tumor has been resected surgically, as the risk of symptomatic enlargement during pregnancy is 15%÷35%. Barrier contraception is essential during dopamine agonist treatment.
Acromegaly32
General Principles
Acromegaly is the syndrome caused by growth hormone excess in adults and is due to a growth hormone÷secreting pituitary adenoma in the vast majority of cases.
Clinical findings include thickened skin and enlargement of hands, feet, jaw, and forehead. Arthritis or carpal tunnel syndrome may develop, and the pituitary adenoma may cause headaches and vision loss. Mortality from cardiovascular disease is increased.
Diagnosis
Plasma insulinlike growth factor I (IGF-1), which mediates most effects of growth hormone, is the best diagnostic test. Marked elevations establish the diagnosis.
If IGF-1 levels are only moderately elevated, the diagnosis can be confirmed by giving 75 mg glucose orally and measuring serum growth hormone q30min for 2 hours. Failure to suppress growth hormone to <1 ng/mL confirms the diagnosis of acromegaly. Once the diagnosis is made, the pituitary should be imaged.
Therapy
The treatment of choice is transsphenoidal resection of the pituitary adenoma. Most patients have macroadenomas, and complete tumor resection with cure of acromegaly often is impossible. If IGF-1 levels remain elevated after surgery, radiotherapy is used to prevent regrowth of the tumor and to control acromegaly.
The somatostatin analog octreotide in depot form can be used to suppress growth hormone secretion while awaiting the effect of radiation. A dose of 10÷30 mg IM monthly suppresses IGF-1 to normal in most patients.33 Side effects include cholelithiasis, diarrhea, and mild abdominal discomfort.
Pegvisomant is a new growth hormone antagonist that lowers IGF-1 to normal in almost all patients.34 The dose is 10÷30 mg SC daily. Few side effects have been reported, but patients should be monitored for pituitary adenoma enlargement and transaminase elevation.
Metabolic Bone Disease
Osteomalacia
Osteomalacia is characterized by defective mineralization of osteoid. Bone biopsy reveals increased thickness of osteoid seams and decreased mineralization rate, assessed by tetracycline labeling.
General Principles
Etiologies
Dietary vitamin D deficiency
Malabsorption of vitamin D and calcium due to intestinal, hepatic, or biliary disease.
Disorders of vitamin D metabolism (e.g., renal disease, vitamin D÷dependent rickets)
Vitamin D resistance
Chronic hypophosphatemia
Renal tubular acidosis
Hypophosphatasia
Therapy with anticonvulsants, fluoride, etidronate, or aluminum compounds.
Clinical Findings
Clinical findings include diffuse skeletal pain, proximal muscle weakness, waddling gait, and propensity to fractures.
Radiographic findings include osteopenia and radiolucent bands perpendicular to bone surfaces (pseudofractures or Looser zones).
Serum alkaline phosphatase is elevated. Serum phosphorus, calcium, or both may be decreased.
Diagnosis
Osteomalacia should be suspected in a patient with osteopenia, elevated serum alkaline phosphatase, and either hypophosphatemia or hypocalcemia.
Serum 25-hydroxyvitamin D (25[OH]D) levels may be low, establishing the diagnosis of vitamin D deficiency or malabsorption.
Radiography of the chest, pelvis, and hips may reveal characteristic pseudofractures.
Treatment
Dietary vitamin D deficiency can initially be treated with vitamin D, 50,000 IU PO weekly for several weeks, to replete body stores, followed by long-term therapy with 400÷1,000 International Units/d. Preparations include calcium supplements that contain vitamin D (Os-Cal + D, 125 International Units/250- or 500-mg tablet), many multivitamins (400 International Units/tablet), and vitamin D drops (200 International Units/drop or 8,000 International Units/mL).
Malabsorption of vitamin D may require therapy with high doses, ranging from 50,000 International Units PO per week to 50,000 International Units PO daily. The dose should be adjusted to maintain serum 25(OH)D levels within the normal range. Calcitriol 0.5÷2.0 mcg PO daily can also be used. Calcium supplements, 1 g PO daily÷tid, may also be required. Serum 25(OH)D, serum calcium, and 24-hour urine calcium should be monitored every 3÷6 months to avoid hypercalcemia or hypercalciuria. If the underlying disease responds to therapy, the dose of vitamin D must be reduced accordingly.
Paget's Disease35
General Principles
Paget's disease of bone is a focal skeletal disorder characterized by rapid, disorganized bone remodeling. It usually occurs after age 40 and most often affects the pelvis, femur, spine, and skull.
Clinical manifestations include bone pain and deformity, degenerative arthritis, pathologic fractures, neurologic deficits due to nerve root or cranial nerve compression (including deafness), and, rarely, high-output heart failure and osteogenic sarcoma.
Most patients are asymptomatic, with disease discovered incidentally because of elevated serum alkaline phosphatase or a radiograph taken for other reasons.
Diagnosis
The radiographic appearance is usually diagnostic. A bone scan will reveal areas of skeletal involvement which can be confirmed by radiography. Serum alkaline phosphatase is elevated, reflecting the activity and extent of disease. Serum and urine calcium are usually normal but may increase with immobilization, as after a fracture.
Management
Indications for therapy include (a) bone pain due to Paget's disease, (b) nerve compression syndromes, (c) pathologic fracture, (d) elective skeletal surgery, (e) progressive skeletal deformity, (f) immobilization hypercalcemia, and (g) asymptomatic involvement of weight-bearing bones or the skull.
Bisphosphonates inhibit excessive bone resorption, relieve symptoms, and restore serum alkaline phosphatase to normal in most patients. The effectiveness of therapy is monitored by measuring serum alkaline phosphatase. Patients are treated with a course of therapy with alendronate, 40 mg/d for 6 months, or risedronate, 30 mg/d for 2 months. Serum alkaline phosphatase is monitored every 3 months. Therapy can be repeated when serum alkaline phosphatase rises above normal. Bisphosphonates may cause esophagitis, and are not recommended in patients with renal insufficiency.
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