Chapter 37: Endocrine Disorders

Thyroid disorders affect 1 in 200 adults but are more common in women and with advancing age. The incidence of hypothyroidism, for instance, is 0.3–5 cases per 1000 individuals per year, including 7% of women and 3% of men aged 60–89 years. Hypothyroidism is much more common than hyperthyroidism, nodular disease, or thyroid cancer. Thyroid nodules occur in 4–8% of all individuals and, like other thyroid problems, increase in incidence with age.

Thyroid disease is more common in people who have conditions such as diabetes or other autoimmune diseases (eg, lupus); in those with a family history of thyroid disease or a history of head and neck irradiation; and in patients who use certain medications, including amiodarone and lithium. Recent guidelines from the American Thyroid Association suggest that all adults have their serum thyroid-stimulating hormone (TSH) concentrations measured, beginning at age 35 and every 5 years thereafter.

HYPOTHYROIDISM

General Considerations

Causes of hypothyroidism are outlined in Table 37-1. The most common noniatrogenic condition causing hypothyroidism in the United States is Hashimoto thyroiditis. Other common causes are post–Graves disease, thyroid irradiation, and surgical removal of the thyroid. Hypothyroidism may also occur secondary to hypothalamic or pituitary dysfunction, most commonly in patients who have received intracranial irradiation or surgical removal of a pituitary adenoma. In addition, some patients may have mild elevations of TSH despite normal thyroxine levels, a condition termed subclinical hypothyroidism.

Clinical Findings

A. Symptoms and Signs

Patients with hypothyroidism present with a constellation of symptoms that can involve every organ system. Symptoms include lethargy, weight gain, hair loss, dry skin, slowed mentation or forgetfulness, depressed affect, cold intolerance, constipation, hair loss, muscle weakness, abnormal menstrual periods (or infertility), and fluid retention. Because of the range of symptoms seen in hypothyroidism, clinicians must have a high index of suspicion, especially in high-risk populations. In older patients, hypothyroidism can be confused with Alzheimer disease or other conditions that cause dementia. In women, hypothyroidism is often confused with depression.

Physical findings that can occur with hypothyroidism include low blood pressure, bradycardia, nonpitting edema, generalized hair thinning along with hair loss in the outer third of the eyebrows, skin drying, and a diminished relaxation phase of reflexes. The thyroid gland in a patient with chronic thyroiditis may be enlarged, atrophic, or of normal size. Thyroid nodules are common in patients with Hashimoto thyroiditis.

B. Laboratory Findings

The most valuable test for hypothyroidism is the sensitive TSH assay. Measurement of the free thyroxine (T₄) level may also be helpful. TSH is elevated and free T₄ decreased in overt hypothyroidism (Table 37-2). Other laboratory findings may include hyperlipidemia and hyponatremia. Hashimoto thyroiditis, an autoimmune condition, is one of the most common causes of hypothyroidism. Testing for thyroid autoantibodies (antiperoxidase, antithyroglobulin) is positive in 95% of patients with Hashimoto thyroiditis.

Patients with associated subclinical hypothyroidism have a high TSH level (usually in the 5–10 μIU/mL range) in conjunction with normal free T₄ level. Between 3% and 20% of these patients will eventually develop overt hypothyroidism. Patients who test positive for thyroid antibodies are at increased risk.

Treatment

In patients with primary hypothyroidism, therapy should begin with thyroid hormone replacement. In patients with secondary hypothyroidism, further investigation with provocative testing of the pituitary can be performed to determine whether the cause is a hypothalamic or pituitary problem.

Most healthy adult patients with hypothyroidism require ∼1.6 μg/kg of thyroid replacement, with requirements falling to 1 μg/kg for the elderly. The initial dosage may range from 12.5 μg to a full replacement dose of 100–150 μg of levothyroxine (0.10–0.15 mg/d). Doses will vary depending on age, weight, cardiac status, duration, and severity of the hypothyroidism. Therapy should be titrated after at least 6 weeks following any change in levothyroxine dose. The serum TSH level is the most important measure to gauge the dose.

Treatment of subclinical hypothyroidism remains controversial. Subclinical hypothyroidism is characterized by a serum TSH above the upper reference limit in combination with a normal free thyroxine (T₄) at a time when thyroid function has been stable for several weeks, the hypothalamic-pituitary-thyroid axis is normal, and there is no recent or ongoing severe illness The prevalence of subclinical hypothyroidism is ~5–10%, more common in white older women. The American Association of Clinical Endocrinologists (AACE) guidelines suggest treating patients with TSH levels of >10 μIU/mL as well as those with TSH levels between 5 and 10 μIU/mL in conjunction with goiter or positive antithyroid peroxidase antibodies, or both (level of evidence for American Thyroid Association recommendations: level 3 or 4, clinical consensus based on the literature). Others base any therapeutic intervention on the individual situation (pregnancy status, cardiovascular risk factors, etc).

Once the TSH level reaches the normal range, the frequency of testing can be decreased. Each patient’s regimen must be individualized, but the usual follow-up after TSH is stable is at 6 months; the history and physical examination should be repeated on a routine basis thereafter.

Thyroid hormone absorption can be affected by malabsorption, age, and concomitant medications such as cholestyramine, ferrous sulfate, sucralfate, calcium, and some antacids containing aluminum hydroxide. Drugs such as anticonvulsants affect thyroid hormone binding, whereas others such as rifampin and sertraline hydrochloride may accelerate levothyroxine metabolism, necessitating a higher replacement dose. The thyroid dose may also need to be adjusted during pregnancy. There has been some interest in using a combination of T₄ and triiodothyronine (T₃) or natural thyroid preparations in pregnant women with hypothyroidism, but studies to date have been small and findings inconsistent.

Pregnant women with thyroid dysfunction need close attention. Overt maternal hypothyroidism is known to have serious adverse effects on the fetus. The Endocrine Society has developed practice guidelines that address the management of thyroid dysfunction during pregnancy and postpartum.

HYPERTHYROIDISM

General Considerations

Hyperthyroidism has several causes. The most common is toxic diffuse goiter (Graves disease), an autoimmune disorder caused by immunoglobulin G (IgG) antibodies that bind to TSH receptors, initiating the production and release of thyroid hormone. Other causes include toxic adenoma; toxic multinodular goiter (Plummer disease); painful subacute thyroiditis; silent thyroiditis, including lymphocytic and postpartum thyroiditis; iodine-induced hyperthyroidism (eg, related to amiodarone therapy); oversecretion of pituitary TSH; trophoblastic disease (very rare); and excess exogenous thyroid hormone secretion.

Clinical Findings

A. Symptoms and Signs

Patients with hyperthyroidism usually present with progressive nervousness, tremor, palpitations, weight loss, dyspnea on exertion, fatigue, difficulty concentrating, heat intolerance, and frequent bowel movements or diarrhea. Physical findings include a rapid pulse and elevated blood pressure, with the systolic pressure increasing to a greater extent than the diastolic pressure, creating a wide pulse-pressure hypertension. Exophthalmos (in patients with Graves disease), muscle weakness, sudden paralysis, dependent low extremity edema, or pretibial myxedema may also be present. Cardiac arrhythmias such as atrial fibrillation may be evident on physical examination or electrocardiogram, and a resting tremor may be noted on physical examination.

In patients with subacute thyroiditis, symptoms of hyperthyroidism are generally transient and resolve in a matter of weeks. There may be a recent history of a head and neck infection, fever, and severe neck tenderness. Postpartum thyroiditis may occur in the first few months after delivery. Both types of thyroiditis may have a transient hyperthyroid phase, a euthyroid phase, and occasionally a later hypothyroid phase.

B. Laboratory and Imaging Evaluation

Hyperthyroidism is detected by a decreased sensitive TSH assay and confirmed, if necessary, by the finding of an elevated free T₄ level. Testing for thyroid autoantibodies, including TSH receptor antibodies (TRAb) or thyroid-stimulating immunoglobulins (TSI), may be done as necessary. Once hyperthyroidism is identified, radionucleotide uptake and scanning of the thyroid, preferably with iodine-123, is useful to determine whether hyperthyroidism is secondary to Graves disease, an autonomous nodule, or thyroiditis (ie, by showing activity and anatomy of the thyroid). In scans of patients with Graves disease, there is increased uptake on radionucleotide imaging with diffuse hyperactivity. In contrast, nodules demonstrate limited areas of uptake with surrounding hypoactivity, and in subacute thyroiditis, uptake is patchy and decreased overall.

Complications

Thyroid storm represents an acute hypermetabolic state associated with the sudden release of large amounts of thyroid hormone. This occurs most often in Graves disease but can occur in acute thyroiditis. Individuals with thyroid storm present with confusion, fever, restlessness, and sometimes with psychosislike symptoms. Physical examination shows tachycardia, elevated blood pressure, and sometimes fever. Cardiac dysrhythmias may be present or develop. Patients will have other signs of high-output heart failure (dyspnea on exertion, peripheral vasoconstriction) and may exhibit signs of cardiac or cerebral ischemia. Thyroid storm is a medical crisis requiring prompt attention and reversal of the metabolic demands from the acute hyperthyroidism.

Treatment

A. Radioactive Iodine

Radioactive iodine is the treatment of choice for Graves disease (GD) in adult patients who are not pregnant. Pretreatment with methimazole prior to radioactive iodine therapy for GD should be considered in patients who are at increased risk for complications due to worsening of hyperthyroidism (ie, those who are extremely symptomatic or have free T₄ estimated at 2–3 times the upper limit of normal). Treatment with β-adrenergic blockers should be done prior to radioactive iodine therapy in patients with GD who are at increased risk for complications due to worsening of hyperthyroidism (ie, those who are extremely symptomatic or have free T₄ estimates 2–3 times the upper limit of normal). Iodine-131 has also been used on an individual basis in patients aged <20 years. To date, studies have shown no evidence of adverse effects on fertility, congenital malformations, or increased risk of cancer in women who were treated with radioactive iodine during their childbearing years or in their offspring. Patients should be advised to postpone pregnancy for at least 6 months postablation therapy.

Radioactive iodine should not be used in breastfeeding mothers. There is also concern that the administration of radioactive iodine in patients with active ophthalmopathy may accelerate progression of eye disease. For this reason, some experts initially treat Graves disease with oral suppressive therapy until the ophthalmologic disease has stabilized.

B. Pharmacotherapy

Antithyroid drugs are well tolerated and successful at blocking the production and release of thyroid hormone in patients with Graves disease. These drugs work by blocking the organification of iodine. Methimazole is the drug of choice in patients who choose antithyroid drug therapy for GD, except during the first trimester of pregnancy when propylthiouracil is preferred. Methimazole is administered once a day, and is associated with a reduced risk of major side effects such as agranulocytosis and hepatic injury compared to propylthiouracil (PTU). Patients need a baseline complete blood count, including white count with differential, and a liver profile including bilirubin and transaminases before starting antithyroid drug therapy for GD.

β-adrenergic blockade should be given to elderly patients with symptomatic thyrotoxicosis and to other thyrotoxic patients with resting heart rates of >90 bpm or coexistent cardiovascular if there are no relative contraindications such as bronchospasm.

C. Surgical Intervention

Surgery is reserved for patients in whom medication and radioactive iodine ablation are not acceptable treatment strategies or in whom a large goiter is present that compresses nearby structures or is disfiguring.

D. Treatment of Thyroid Storm

For patients with thyroid storm, aggressive initial therapy is essential to prevent complications. Treatment should include the administration of high doses of PTU (100 mg every 6 hours) to quickly block thyroid release and reduce peripheral conversion of T₄ to T₃. In addition, high doses of β-blockers (propranolol, 1–5 mg intravenously or 20–80 mg orally every 4 hours) can be used to control tachycardia and other peripheral symptoms of thyrotoxicosis. Hydrocortisone (200–300 mg/d) is used to prevent possible adrenal crisis.

E. Postablation Follow-up

Follow-up is necessary to evaluate possible hypothyroidism postablation. Follow-up can begin 6 weeks after therapy and continue on a regular basis until there is evidence of early hypothyroidism, as confirmed by an elevated TSH level. Therapy should then be started as described earlier in the discussion of hypothyroidism.

THYROID NODULES

General Considerations

Thyroid nodules are a common clinical finding, reported in 37% of patients on the basis of palpation. The prevalence of diagnosed thyroid nodules has increased dramatically since the early 1990s because of the widespread use of ultrasonography for the evaluation of thyroid and nonthyroid neck conditions. Autopsy data indicate that thyroid nodules may be present in 50% of the population. Thyroid nodules are more common in women, the elderly, patients with a history of head and neck irradiation, and those with a history of iodine deficiency.

Pathogenesis

Thyroid nodules may be associated with benign or malignant conditions. Benign causes include multinodular goiter, Hashimoto thyroiditis, simple or hemorrhagic cysts, follicular adenomas, and subacute thyroiditis. Malignant causes include carcinoma (papillary, follicular, Hürthle cell, medullary, or anaplastic), primary thyroid lymphoma, and metastatic malignant lesion.

Clinical Findings

A. Symptoms and Signs

Many patients with thyroid nodules are asymptomatic. Often the nodule is discovered incidentally on physical examination or by imaging studies ordered for unrelated reasons. Evaluation is needed to rule out malignancy. A thorough history should be obtained, including any history of benign or malignant thyroid disease (see sections on hyper- and hypothyroidism, earlier) and head or neck irradiation. Patients should be asked about recent pregnancy, characteristics of the nodule, and any neck symptoms (eg, pain, rate of swelling, hoarseness, swelling of lymph nodes).

Several features of the history are associated with an increased risk of malignancy in a thyroid nodule. These include prior head and neck irradiation, family history of medullary carcinoma or multiple endocrine neoplasia syndrome type 2, age <20 years or >70 years, male gender, and rapid growth of a nodule. Physical findings that should raise clinical suspicion of malignancy include firm consistency, cervical adenopathy, and symptoms such as persistent hoarseness, dysphonia, dysphagia, or dyspnea.

B. Laboratory and Diagnostic Findings

Laboratory and diagnostic evaluation relies on ultrasound, measurement of TSH level, and fine-needle aspiration (FNA). Ultrasound is not useful as a universal screening tool but can be helpful in screening patients whose history places them at high risk for developing thyroid cancer (see section on symptoms and signs, earlier).

1. Workup of a palpable thyroid nodule

If the nodule is palpable, TSH assay and ultrasonography of the thyroid should be performed. These two modalities will help guide clinical decision making. If the nodule appears suspicious on ultrasound (on the basis of position, shape, size, margins, or echogenic pattern), FNA should be performed irrespective of whether the patient’s TSH level is elevated, normal, or suppressed. For instance, it has been reported that nodules in patients with Graves disease may be malignant in 9% of the cases. If the nodule does not appear suspicious on ultrasound, the clinician can proceed with workup of the abnormal TSH level. For example, if the TSH level is suppressed, the patient may have hyperthyroidism caused by either a single autonomous nodule or a multinodular goiter. The patient would then be evaluated for hyperthyroidism and therapy initiated, as appropriate.

In patients with an elevated TSH level suggestive of hypothyroidism, the next steps would be based on the ultrasound findings. If the nodule does not appear suspicious, thyroid peroxidase antibodies (useful for diagnosing Hashimoto thyroiditis) can be measured and treatment of hypothyroidism initiated (ie, using levothyroxine therapy). If the nodule appears suspicious, FNA should be performed.

2. Workup of an “incidental” thyroid nodule

If the thyroid nodule is found incidentally by ultrasonography, the next step is to obtain a TSH level. If the TSH level is normal, the nodule is <10 mm, the patient does not have risk factors for thyroid malignancy, and the ultrasound findings do not appear suspicious, clinical follow-up is performed. If the nodule is >10 mm or the patient has risk factors for thyroid malignancy, FNA should be performed.

Approximately 70% of FNA specimens are classified as benign, 5% are malignant, 10% are suspicious, and 10–20% are nondiagnostic. If FNA reveals malignant cells, surgical intervention is indicated and further treatment will be based on the characteristics noted at surgery (pathologic findings, positive lymph nodes, etc).

Treatment

Patients with malignant thyroid nodules should be referred to surgical and medical oncologists familiar with the management of these tumors. The remainder of this discussion focuses on follow-up and management of patients with FNA-negative thyroid nodules.

Use of exogenous levothyroxine therapy in a euthyroid patient in an effort to “suppress the TSH” (ie, decrease TSH level to <0.1 IU/mL) and “shrink” the nodule is of benefit in only a few patients with palpable nodules. The side effects of exogenous thyroid therapy (cardiac arrhythmias, osteoporosis, etc) must be considered, especially in older patients and in postmenopausal women; its use in these populations is thus relatively contraindicated.

Patients with very large nodules may require surgery, especially if symptoms secondary to the size (eg, dysphagia) are present. If there is a change in size of the nodule, a repeat FNA should be performed.

Ultrasound-guided percutaneous ethanol injection (PEI) is a therapeutic option for patients with benign nodules that have a large fluid component (thyroid cysts). Aspiration (eg, during FNA) itself may drain a cyst and shrink the size, but recurrences are common. Surgery is sometimes needed if the cyst is very large. Some data show that PEI is more effective in decreasing the size of a nodule than aspiration alone.

ADRENAL INSUFFICIENCY

General Considerations

The most common cause of primary adrenal insufficiency is autoimmune adrenalitis (Addison disease). Other possible causes include AIDS and the antiphospholipid syndrome. Secondary adrenal insufficiency may result from pituitary or hypothalamic disease. Iatrogenic tertiary adrenal insufficiency caused by suppression of hypothalamic-pituitary-adrenal function secondary to glucocorticoid administration is a more common secondary cause of adrenal insufficiency (Table 37-3).

Clinical Findings

A. Symptoms and Signs

Adrenal insufficiency presents with a wide range of symptoms and signs, including weakness, malaise, anorexia, hyperpigmentation (especially of the gingival mucosa, scars, and skin creases), vitiligo, postural hypotension, abdominal pain, nausea and vomiting, diarrhea, constipation, myalgia, and arthralgia. The most specific sign of primary adrenal insufficiency is hyperpigmentation of the skin and mucosal surfaces. Another specific symptom of adrenal insufficiency is a craving for salt. Autoimmune adrenal disease can be accompanied by other autoimmune endocrine deficiencies, such as thyroid disease, diabetes mellitus, pernicious anemia, hypoparathyroidism, and ovarian failure.

In acute adrenal failure, adrenal crisis occurs. Adrenal crisis is characterized by hypotension, bradycardia, fever, hypoglycemia, and a progressive deterioration in mental status. Abdominal pain, vomiting, and diarrhea also may be present. In the patient with spontaneous adrenal insufficiency, acute adrenal hemorrhage and adrenal-vein thrombosis should be considered.

B. Laboratory Findings

Laboratory abnormalities occur in nearly all patients and include hyponatremia, hyperkalemia, acidosis, slightly elevated plasma creatinine concentrations, hypoglycemia, hypercalcemia, mild normocytic anemia, lymphocytosis, and mild eosinophilia. The diagnosis of adrenal insufficiency relies on a finding of inadequate cortisol production. Plasma cortisol concentration fluctuates throughout the day in a diurnal pattern that is normally high in the early morning and low in the late afternoon. Cortisol levels also increase with stress. A low plasma cortisol level of <3 μ/dL (<83 nmol/L) either in the morning or at a time of stress provides presumptive evidence of adrenal insufficiency. Conversely, a level of ≥20 μg/dL (≥550 nmol/L) rules out adrenal insufficiency. An intermediate plasma cortisol level of 3–19 μg/dL (83–525 nmol/L) is not diagnostic.

For most patients in whom adrenal insufficiency is considered, a short adrenocorticotropic hormone (ACTH) stimulation test should be performed. In this test, a low dose of ACTH (1 g or 0.5 g/1.73 m² surface area) is given and the patient’s blood is tested 30 and 60 minutes later to confirm a corresponding increase in plasma cortisol. A rise in plasma cortisol concentration after 30 or 60 minutes to a peak of ≥20 μg/dL (≥55 nmol/L) is considered normal. No increase in serum cortisol or a blunted response after ACTH administration confirms adrenal insufficiency. If the test is slightly abnormal, an insulin or a metyrapone test using 30 mg/kg of metyrapone with a snack at midnight should be performed.

C. Imaging Studies

In patients with adrenal insufficiency, radiologic studies may be indicated. In patients having headaches and visual disturbances, a magnetic resonance imaging (MRI) scan should be performed to investigate for a possible pituitary or hypothalamic tumor. In patients with suspected primary adrenal insufficiency, a computed tomography (CT) scan of the adrenal glands should be performed to rule out hemorrhage, adrenal vein thrombosis, or metastatic disease as the cause of the adrenal dysfunction.

Treatment

For patients with symptomatic adrenal insufficiency, fluid management, correction of other metabolic abnormalities such as hypoglycemia and hyperkalemia, and the administration of corticosteroids are primary concerns. An approach to managing this condition is shown in Table 37-4.

While providing fluid resuscitation and addressing other metabolic emergencies, the practitioner should administer emergency doses of hydrocortisone. Once the patient is stabilized, corticosteroid maintenance should be provided in divided doses early in the morning and afternoon to simulate the diurnal release of cortisol by the adrenal gland. The smallest dose that relieves the patient’s symptoms should be used to minimize weight gain and risk of osteoporosis. During febrile illnesses, acute injury, or other periods of physiologic stress, the dose of hydrocortisone should be doubled or tripled temporarily. Patients with primary adrenal insufficiency should also receive fludrocortisone as a substitute for aldosterone.

CUSHING SYNDROME

General Considerations

Cushing syndrome refers to overproduction of cortisol due to any cause (eg, adrenal hyperplasia, exogenous steroid use). Cushing disease is a more specific term that refers to excessive cortisol resulting from excessive ACTH produced by pituitary corticotrophic tumors. ACTH-producing tumors account for 80% of cases of Cushing syndrome. The remaining 20% are caused by adrenal tumors, such as adenomas, carcinomas, and micronodular and macronodular hyperplasia, associated with autonomous production of glucocorticoids.

Cushing syndrome is rare, with a prevalence estimated at approximately 10 per 1 million persons. Cushing disease is 4–6 times more prevalent in women than in men, whereas ectopic ACTH secretion is more common in men, largely due to the higher incidence in men of bronchogenic lung cancers that produce ACTH.

Clinical Findings

A. Symptoms and Signs

The most common signs of Cushing syndrome are sudden onset of central weight gain, often accompanied by thickening of the facial fat, which rounds the facial contour (“moon facies”), and a florid complexion due to telangiectasia. Other concomitant signs include an enlarged fat pad (“buffalo hump”), hypertension, glucose intolerance, oligomenorrhea or amenorrhea in premenopausal women, decreased libido in men, and spontaneous ecchymoses (Table 37-5).

B. Laboratory Findings

The evaluation of suspected excessive glucocorticoid production includes screening and confirmatory tests for the diagnosis and localization of the source of hormone excess. The Endocrine Society recommends the initial use of one test with high diagnostic accuracy (urine cortisol, late-night salivary cortisol, 1 mg overnight, or 2 mg 48-hour dexamethasone suppression test). Those patients with an abnormal result should undergo a second test, either one of the above or, in some cases, a serum midnight cortisol or dexamethasone-CRH test.

Affective psychiatric disorders (eg, major depression) and alcoholism can be associated with the biochemical features of Cushing syndrome and, therefore, may decrease the reliability of test results.

C. Imaging Studies

Following confirmation of Cushing syndrome, imaging studies should be performed to look for adenomas (MRI scan) or adrenal tumors (CT scan). If both of these studies are negative, chest radiography or CT scanning should be performed to look for ectopic sources of ACTH production.

Treatment

For patients with a pituitary adenoma (Cushing disease) in whom a circumscribed microadenoma can be identified and resected, the treatment of choice is transsphenoidal microadenomectomy. If an adenoma cannot be clearly identified, patients should undergo a subtotal (85–90%) resection of the anterior pituitary gland. Patients who wish to preserve pituitary function (ie, in order to have children) should be treated with pituitary irradiation. If radiation does not decrease exogenous ACTH production, bilateral total adrenalectomy is a final treatment option. For adult patients not cured by transsphenoidal surgery, pituitary irradiation is the most appropriate choice for the next treatment.

Patients who have a nonpituitary tumor that secretes ACTH are cured by resection of the tumor. Unfortunately, nonpituitary tumors that secrete ACTH are seldom amenable to resection. In these cases, cortisol excess can be controlled with adrenal enzyme inhibitors, alone or in combination, with the proper dose determined by measurements of plasma and urinary cortisol.

For patients with adrenal hyperplasia, bilateral total adrenalectomy is required. Patients with an adrenal adenoma or carcinoma can be managed with unilateral adrenalectomy. Patients with hyperplasia or adenomas almost invariably have recurrences that are not amenable to either radiation or chemotherapy.

Patients who are taking corticosteroids for prolonged periods of time may exhibit signs or symptoms of Cushing syndrome. Once the primary problem for which steroids are being prescribed is controlled, patients should be withdrawn from their corticosteroid treatment slowly to avoid symptoms from adrenal suppression. There are few studies evaluating methods of withdrawal from chronic steroid use, however. Clinicians should be guided by the severity of the underlying condition, the duration that steroids have been used, and the dosage of steroids in determining how quickly dosages of steroids should be reduced.

HYPERALDOSTERONISM

General Considerations

Primary hyperaldosteronism accounts for 70–80% of all cases of hyperaldosteronism and is usually caused by a solitary unilateral adrenal adenoma. Other causes of hyperaldosteronism include bilateral adrenal hyperplasia, so-called idiopathic hyperaldosteronism, and glucocorticoid-remediable hyperaldosteronism. Adrenal carcinoma and unilateral adrenal hyperplasia are rare causes.

Clinical Findings

A. Symptoms and Signs

Patients with hyperaldosteronism present with hypertension and hypokalemia. Other complaints include headaches, muscular weakness or flaccid paralysis caused by hypokalemia, or polyuria. Inappropriate hypersecretion of aldosterone is an uncommon cause of hypertension, accounting for <1% of cases. Any patient presenting with hypertension and unprovoked hypokalemia should be considered for the evaluation of hyperaldosteronism. Hypertension may be severe, although malignant hypertension is rare. The peak incidence occurs between 30 and 50 years of age, and most patients are women.

B. Laboratory Findings

Initially, laboratory evaluation is used to document hyperaldosteronemia and suppressed renin activity. Further diagnostic tests, including imaging procedures, are used to determine whether the etiology is amenable to surgical intervention or requires medical management.

Screening aldosterone measurements can be performed on plasma or 24-hour urine collection. Plasma aldosterone is usually measured after 4 hours of upright posture. Plasma renin activity should be measured in the same sample. A ratio of plasma aldosterone concentration to plasma renin activity of >20:25 is very suspicious for hyperaldosteronism.

In the hypertensive patient with hypokalemia or kaliuresis or with an elevated plasma aldosterone/renin ratio, the diagnosis of hyperaldosteronism is confirmed by demonstrating failure of normal suppression of plasma aldosterone. Urine aldosterone excretion of >30 nmol (>14 μg)/d after oral sodium loading over 3 days establishes the diagnosis.

The intravenous saline suppression test is also widely used to confirm hyperaldosteronism. In this test, isotonic saline is infused intravenously at a rate of 300–500 mL/h for 4 hours, after which plasma aldosterone and renin activity are measured. Aldosterone levels normally fall to <0.28 nmol/L (<10 ng/dL), and renin activity is suppressed. Failure to suppress normally identifies patients with aldosterone-producing adenomas, because most patients with secondary forms of hyperaldosteronism suppress normally. False-negative results are most often seen in patients with bilateral hyperplasia.

Once the diagnosis is established, it is necessary to distinguish between aldosterone-producing adrenal adenoma and bilateral adrenal hyperplasia. A widely used test is based on the less complete suppression of renin activity in hyperaldosteronism caused by bilateral hyperplasia. Plasma renin activity rises slightly and aldosterone concentration increases significantly after the stimulation of 2–4 hours of upright posturing in these patients. In contrast, renin remains suppressed and aldosterone does not rise in patients with adenomas, in whom plasma aldosterone level may fall.

C. Imaging Studies

Imaging procedures can assist in differentiating causes of hyperaldosteronism and lateralizing adenomas. The diagnostic accuracy of high-resolution CT scans is only ∼70% for aldosterone-producing adenomas, largely because of the occurrence of nonfunctioning adenomas. MRI is no better than CT in differentiating aldosterone-secreting tumors from other adrenal tumors. Scintigraphic imaging with ¹³¹I-labeled cholesterol derivatives during dexamethasone suppression provides an image based on functional properties of the adrenal gland. Asymmetric uptake after 48 hours indicates an adenoma, whereas symmetric uptake after 72 hours indicates bilateral hyperplasia. Diagnostic accuracy is 72%. However, if the adrenal CT scan is normal, iodocholesterol scanning is unlikely to be helpful.

Treatment

For adrenal adenoma, total unilateral adrenalectomy is the treatment of choice and provides a cure in most cases. Although some patients with primary bilateral hyperplasia may benefit from subtotal adrenalectomy, these patients cannot be accurately identified preoperatively. Following surgery, the electrolyte imbalances usually correct rapidly, whereas blood pressure control may take several weeks to months.

Medical therapy is indicated for most patients with bilateral adrenal hyperplasia or for patients with adrenal adenomas who are unable to undergo adrenalectomy. Spironolactone controls the hyperkalemia, although it is not a very potent antihypertensive agent. Amiloride and calcium channel blockers are often used to control blood pressure.

HYPERPARATHYROIDISM

General Considerations

Hyperparathyroidism refers to excessive production of parathyroid hormone (PTH). Primary hyperparathyroidism is the overproduction of PTH in an inappropriate fashion, usually resulting in hypercalcemia. Primary hyperparathyroidism is more common in postmenopausal women. The most common cause is a benign solitary parathyroid adenoma (80% of all cases). Another 15% of patients have diffuse hyperplasia of the parathyroid glands, a condition that tends to be familial. Carcinoma of the parathyroid occurs in <1% of cases.

In secondary hyperparathyroidism, patients have appropriate additional production of PTH because of hypocalcemia related to other metabolic conditions such as renal failure, calcium absorption problems, or vitamin D deficiency.

Clinical Findings

A. Symptoms and Signs

Most patients have nonspecific complaints that may include aches and pains, constipation, muscle fatigue, generalized weakness, psychiatric disturbances, polydipsia, and polyuria. The hypercalcemia can cause nausea and vomiting, thirst, and anorexia. A history of peptic ulcer disease or hypertension may be present, as well as accompanying constipation, anemia, and weight loss. Precipitation of calcium in the corneas may produce a band keratopathy, and patients may also experience recurrent pancreatitis. Finally, skeletal problems can result in pathologic fractures.

B. Laboratory Findings

Hypercalcemia (serum calcium level >10.5 mg/dL when corrected for serum albumin level) is the most important clue to the diagnosis. In patients who have an elevated calcium level with no apparent cause, serum PTH should be determined using a two-site immunometric assay. An elevated PTH level in the presence of hypercalcemia confirms the diagnosis of primary hyperparathyroidism.

Other findings may include a low serum phosphate level (<2.5 mg/dL) with excessive phosphaturia. Urine calcium excretion may be high or normal. Alkaline phosphatase levels are elevated only in the presence of bone disease, and elevated plasma chloride and uric acid levels may be seen.

C. Imaging Studies

With chronic hyperparathyroidism, diffuse bone demineralization, loss of the dental lamina dura, and subperiosteal resorption of bone (particularly in the radial aspects of the fingers) may be apparent on x-rays. Cysts may be noted throughout the skeleton, and “salt-and-pepper” appearance of the skull may be seen. Pathologic fractures can occur, and renal calculi and soft-tissue calcification may be visualized.

Imaging studies are usually reserved for patients with resistant or recurrent disease. In these cases, ultrasonography, CT scanning, MRI, and thallium-201–technetium-99m (²⁰¹Tl–^99m Tc) scanning may help locate ectopic parathyroid tissue.

Treatment

Treatment of severe hypercalcemia and parathyroidectomy are the mainstays for therapy. When hypercalcemia is severe, treatment includes aggressive hydration. Correction of any underlying hyponatremia and hypokalemia should be initiated, along with administration of a loop diuretic to accelerate calcium clearance. Other medications that can be effective in reducing hypercalcemia include etidronate, plicamycin, and calcitonin. Any medications or other products that increase calcium levels, such as estrogens, thiazides, vitamins A and D, and milk, should be avoided.

In addition to management of acute hypercalcemia, surgical removal of parathyroid tissue should be undertaken. Surgical resection provides the most rapid and effective method of reducing serum calcium in these patients. Hyperplasia of all glands requires removal of three glands along with subtotal resection of the fourth. Surgical success is directly related to the experience and expertise of the operating surgeon.

For mild cases and poor surgical candidates, conservative therapy with adequate hydration and long-term pharmacologic therapy is recommended. Patients should avoid drugs and products that elevate calcium and should have their serum calcium monitored closely.

HYPOPARATHYROIDISM

General Considerations

Hypoparathyroidism results from underproduction of PTH. The most common cause is the removal of the parathyroid glands during a thyroidectomy or following surgery for primary hyperparathyroidism. Less commonly, hypoparathyroidism is idiopathic, familial, or the result of a congenital absence of the parathyroid glands (DiGeorge syndrome). Patients with idiopathic hypoparathyroidism often have antibodies against parathyroid and other tissues, and an autoimmune component may play a role. Other unusual causes of hypoparathyroidism include previous neck irradiation, magnesium deficiency, metastatic cancer, and infiltrative diseases.

Clinical Findings

A. Symptoms and Signs

The lack of PTH results in hypocalcemia, which produces most of the symptoms associated with hypoparathyroidism. Symptoms associated with hypocalcemia include tetany, carpopedal spasms, paresthesias of the lips and hands, and a positive Chvostek sign or Trousseau sign. Patients may also exhibit less specific symptoms such as anxiety, depression, or fatigue. Additionally, hyperventilation, respiratory alkalosis with or without respiratory compromise, laryngospasm, hypotension, and seizures may occur with severe hypocalcemia.

B. Laboratory Findings

On laboratory evaluation, patients with hypoparathyroidism have low serum calcium and elevated serum phosphate levels, with a normal alkaline phosphatase level. Urinary levels of calcium and phosphate are decreased. The key finding is a low to absent PTH value.

Treatment

Acute hypocalcemia with tetany requires aggressive therapy with multiple drugs. Therapy should be started with calcium gluconate administered intravenously in a 10% solution. The infusion is given slowly until tetany resolves. Oral calcium along with vitamin D supplementation should be given after the acute crisis has resolved. Hypomagnesemia should be corrected with intravenous magnesium sulfate administered at a dose of 1–2 g every 6 hours. Chronic replacement of magnesium can be accomplished using 600-mg magnesium oxide tablets once or twice daily.

For the maintenance of normal calcium, vitamin D supplementation along with oral calcium should be given. Calcium in the form of calcium carbonate (40% elemental calcium) is the drug of choice, administered in a dose of 1–2 g of calcium per day. Serial calcium levels should be obtained regularly (every 3–6 months), and “spot” urine calcium levels should be maintained below 30 mg/dL.