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Editors: Torre, Dario M.; Lamb, Geoffrey C.; Van Ruiswyk, Jerome J.; Schapira, Ralph M. Title: Kochar's Clinical Medicine for Students, 5th Edition Copyright 2009 Lippincott Williams & Wilkins
> Table of Contents > Part II - Diseases and Disorders > Endocrinology > Chapter 69 - Diseases of the Adrenal Glands

Chapter 69 Diseases of the Adrenal Glands

Jennifer Zebrack Albert Jochen

Diseases of the Adrenal Cortex

The adrenal glands, located at the superior pole of each kidney, are comprised of two concentric layers: the cortex and the medulla. The adrenal cortex consists of three layers that secrete glucocorticoids, mineralocorticoids, and androgens.

Glucocorticoids
The major regulatory system for cortisol is through hypothalamic corticotropin-releasing hormone (CRH) and pituitary adrenocorticotropic hormone (ACTH). Secretion of ACTH is pulsatile, creating a daily diurnal variation in cortisol secretion with maximal release in the morning.

Mineralocorticoids
The renin-angiotensin system is the principal regulator of aldosterone synthesis and release. Renin is produced by the juxtaglomerular cells of the kidney, which catalyzes the conversion of renin substrate to angiotensin I (A-I). Angiotensin-converting enzyme (ACE) converts A-I to angiotensin II (A-II), which stimulates aldosterone production in the adrenal cortex. Aldosterone promotes renal tubular Na+ reabsorption and K+ and H+ ion excretion. The regulation of renin depends on intravascular volume. For instance, upright posture, hemorrhage, diuretics, sodium restriction, and edematous states increase renin secretion. Hyperkalemia and hyponatremia also strongly stimulate aldosterone production.

Androgens and Estrogens

ACTH is the major stimulator of adrenal androgen secretion. Dehydroepiandrosterone (DHEA) and androstenedione are the major androgens synthesized in the adrenals. DHEA is sulfated in the liver to yield DHEA-sulfate (DHEA-S). Androstenedione is converted to the weak estrogen estrone by peripheral aromatase.

Adrenal Insufficiency
Adrenal insufficiency can result from primary destruction of the adrenal cortices (primary adrenal insufficiency or Addison's disease), insufficient pituitary ACTH (secondary adrenal insufficiency), or decreased hypothalamic CRH (corticotropin-releasing hormone) secretion (tertiary adrenal insufficiency). P.428 Primary adrenal insufficiency results in a deficiency of cortisol and aldosterone with elevated plasma ACTH levels. Secondary and tertiary adrenal insufficiency results in a deficiency of cortisol with preserved aldosterone secretion.

Etiology
Development of the clinical manifestations of primary adrenal insufficiency (Addison's disease) requires loss or destruction of 90% or more of both adrenal cortices. In the United States, the most common cause of Addison's

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disease is the idiopathic type resulting from autoimmune destruction of the cortex. It is more common in women, may be familial, and is usually diagnosed in the third to fifth decades of life. This disease shows a high association with other autoimmune disorders, such as Hashimoto's hypothyroidism, Graves' hyperthyroidism, Type 1 diabetes mellitus, pernicious anemia, autoimmune hepatitis, alopecia, and vitiligo. Tuberculosis is the second most frequent cause in the United States and is a common cause in developing countries. Acute primary adrenal insufficiency occurs most commonly in a patient with underactive glands who requires increased glucocorticoid production after exposure to stress (e.g., sepsis, trauma or surgery). It also can follow acute bilateral destruction of the adrenal glands (e.g., adrenal hemorrhage or infarction) (Table 69.1). The most common secondary cause of adrenal insufficiency is iatrogenic from prolonged use and subsequent withdrawal of prescribed exogenous glucocorticoids such as prednisone (which results in significant ACTH suppression, typically after about 30 days of administration). Other secondary and tertiary causes include any disorder of the pituitary or hypothalamus, such as trauma (infundibular stalk section), postpartum necrosis (Sheehan's syndrome), neoplasms, and inflammatory and granulomatous disorders (Table 69.1).

Clinical Manifestations
The evolution of adrenal insufficiency may be gradual or catastrophically sudden. The symptoms of adrenal insufficiency are often nonspecific and include anorexia, nausea, vomiting, diarrhea, weight loss, hypotension, fatigue, weakness, fever, and confusion. In primary adrenal insufficiency, signs of dehydration due to aldosterone deficiency may be present (i.e., tachycardia, orthostatic hypotension). The characteristic hyperpigmentation of the skin (due to ACTH excess) is absent when the adrenal failure is acute, secondary, or tertiary. Hyponatremia is due primarily to an impaired ability to excrete free water; thus, it is common to any type of adrenal insufficiency. However, hyperkalemia and metabolic acidosis are absent in secondary or tertiary adrenal failure because aldosterone secretion is preserved through the renin-angiotensin system. In acute adrenal crisis, the rapid reduction in intravascular volume, vascular tone, and cardiac output can result in vascular collapse and shock. P.429

Table 69.1 Etiology of adrenal insufficiency

Primary Secondary

Idiopathic/autoimmune Tuberculosis Adrenal hemorrhage Bilateral infarction Fungal infection HIV/AIDS Metastatic cancer Bilateral adrenalectomy Congenital adrenal hyperplasia Drugs: mitotane, ketoconazole, metyrapone

Long-term glucocorticoid steroid use (abrupt withdraw) Neoplasms Inflammatory lesions Granulomatous disease Trauma (infundibular stalk section) Radiation Necrosis (Sheehan's syndrome)

In secondary adrenal insufficiency, patients may also have associated deficits of other pituitary hormones, such as growth hormone, follicle-stimulating hormone, luteinizing hormone, and thyroid-stimulating hormone, manifesting as growth retardation or delayed puberty in children and erectile dysfunction, amenorrhea, or hypothyroidism in adults. If a pituitary tumor is the cause, headache, visual field loss, and/or cranial nerve palsies may be present.

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Diagnosis
Adrenal insufficiency is best diagnosed by a rapid cosyntropin stimulation test. The test is best done between 6 a.m. and 10 a.m. Plasma samples are drawn for cortisol before and 3 to 60 minutes after administering 0.25 mg of cosyntropin intravenous (IV) or intramuscular (IM). Normally, the plasma cortisol should increase 8 g/dL above the baseline, and it should exceed 20 g/dL at 30 to 60 minutes. Therefore a rise of cortisol level <8 /g above baseline is considered abnormal. The plasma ACTH level separates primary from secondary adrenal failure; ACTH is elevated and typically exceeds 250 pg/mL in the primary type, but it is low or inappropriately normal in other types. Patients with secondary adrenal insufficiency should be tested for other pituitary hormone deficiencies as well. In the case of shock and normal adrenal function, a random plasma cortisol level should be at least 20 g/dL; in most cases, the level exceeds 30 g/dL. Computed tomography (CT) scan or magnetic resonance imaging (MRI) of the abdomen may suggest infection, hemorrhage, or other diffuse abnormality of the adrenal glands.

Treatment
If acute adrenal insufficiency is suspected, the patient should be treated immediately without waiting for confirmation of the diagnosis. Once blood specimens have been obtained for diagnosis, therapy includes prompt administration of IV fluids and IV glucocorticoid replacement, as well as treatment of the stress that precipitated the crisis. Because it does not affect plasma cortisol measurement if a cosyntropin test has been initiated, dexamethasone is often given initially. Hydrocortisone is the preferred glucocorticoid in the treatment of adrenal crisis because it exhibits the greatest mineralocorticoid activity. Mineralocorticoid replacement is unnecessary if the total daily hydrocortisone dose exceeds 100 mg. With proper treatment, patients with acute adrenal insufficiency have a very good prognosis. Left untreated, acute adrenal crisis is fatal. Treatment of chronic adrenal insufficiency includes daily, maintenance glucocorticoid (e.g., cortisone acetate, hydrocortisone, or prednisone). Patients with primary adrenal insufficiency also require daily mineralocorticoid (i.e., fludrocortisone) replacement and unrestricted salt intake. Dosages need to be increased during illness and in the perioperative period due to the increased level of stress. Patients should be educated about the adjustment of medication during illness and wear a medical bracelet or necklace.

Complications/Prognosis
Adrenal insufficiency is easily treatable. However, if undiagnosed or improperly treated, the consequences are often fatal, with vascular collapse and shock. In chronic adrenal insufficiency, daily replacement therapy and careful adjustment of medication during illness is necessary to avoid adrenal crisis.

Cushing's Syndrome
Cushing's syndrome is a condition caused by excess amounts of cortisol adenoma or cancer resulting from hypersecretion of the adrenal cortex which may result from a hypersecreting adrenal tumor, ectopic ACTH, or prolonged exposure to high therapeutic doses of glucocorticoids or prolonged exposure to high therapeutic doses of glucocorticoids. P.430

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Figure 69.1 Etiology of hypercortisolemia: Cushing's syndrome.

Cushing's disease refers to a high cortisol state caused by a pituitary ACTH hypersecreting tumor (most common cause), and less frequently pituitary hyperplasia. Cushing's disease is six times more common in women than in men; the mean age at diagnosis is in the fourth decade.

Etiology
Because of the widespread pharmacologic use of glucocorticoids, the most common cause of Cushing's syndrome is iatrogenic or exogenous glucocorticoid use. Endogenous cases (Fig. 69.1) may be either ACTH dependent (e.g., ACTH-secreting pituitary adenoma or ectopic ACTH-secreting neoplasm) or ACTH independent (e.g., adrenal adenoma, adrenal carcinoma). Benign adrenal tumors causing Cushing's syndrome predominantly produce glucocorticoids; adrenal cancers, however, often secrete high levels of adrenal androgens and glucocorticoids. Ectopic ACTH secretion occurs in a few neoplasms (e.g., small cell carcinoma of the lung, carcinoid tumors, pancreatic islet cell tumors), usually in men in the fifth decade and beyond. Functioning benign adrenal adenomas and adrenocortical cancers each give rise to less than 10% of cases of Cushing's syndrome. Benign adenomas are usually small and synthesize cortisol very efficiently. In contrast, functioning

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adrenocortical cancers are very large at diagnosis and often produce adrenal steroids inefficiently. P.431

Table 69.2 Clinical manifestations of hypercortisolemia

Truncal obesity

95%

Menstrual Irregularities

80%

Hypertension

75%

Facial plethora (round face)

75%

Hirsutism/vellus type hair growth

65%

Gonadal dysfunction

50%

Violaceous striae

65%

Diabetes mellitus

65%

Hyperlipidemia

70%

Proximal muscle weakness

60%

Clinical Manifestations
The clinical features of hypercortisolemia are shown in Table 69.2. They include centripetal obesity, which is caused by the accumulation of fat in trunk, face, and neck, hence the description of buffalo hump and moon facies. At times, it is helpful to examine serial photographs of the patient, looking for evidence of progressive physical changes consistent with excessive cortisol exposure. The facial plethora (round face) may be subtle (Fig. 69.3) or quite obvious (Fig. 69.4). Patients may commonly experience proximal muscle wasting and weakness, which are caused by the catabolic effect of high glucocorticoid levels on skeletal muscles. Hypertension, diabetes mellitus, osteoporosis, and depression are often present. Thin skin, easy bruisability, violaceous striae (on breasts and abdomen) and skin atrophy are some of the dermatologic manifestations of Cushing's syndrome. Hyperpigmentation is most commonly found in sun or pressure exposed areas (elbows, knuckles, waist). It occurs most often in patients with ectopic ACTH secreting tumors and less often in patients pituitary disease (Cushing's disease). However, it is absent in high cortisol states caused by adrenal disease (Cushing's syndrome) because lack of

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secretion of ACTH (Table 69.3). In benign adrenal adenomas, the signs of cortisol excess usually begin gradually. In functioning adrenocortical carcinomas, the course tends to be more acute and rapidly progressive, with prominent hyperandrogenic effects (i.e., hirsutism, virilization) and lack of typical Cushingoid features. Patients may also report abdominal, back, and flank pain and a palpable abdominal mass caused by the large tumor size. Cushing's syndrome also can be caused as a paraneoplastic syndrome related to ectopic production of ACTH by certain cancers, classically small cell lung carcinoma. These patients more frequently present with severe proximal weakness, weight loss, and hypokalemia along with rapid development of the florid clinical manifestations of Cushing's syndrome.

Diagnosis
A 24-hour urinary cortisol, or salivary cortisol and a low-dose dexamethasone suppression test, are often initially performed as the screening tests. The evaluation of a patient with suspected Cushing's syndrome is outlined in Figure 69.2. A 24-hour urine collection for free cortisol results in very few false positive results. Elevated salivary cortisol levels, obtained at 11 p.m., can also be used to diagnose glucocorticoid excess and to improve accuracy of low-dose dexamethasone suppression test. A low-dose 1-mg dexamethasone P.432 P.433 P.434 suppression test may produce false-positive results in normal subjects, in patients with obesity or depression.

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Figure 69.2 Diagnosis, workup, and differentiation of hypercortisolemia (Cushing's disease/syndrome). UFC, urine-free cortisol.

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Figure 69.3 These photographs of a young woman with Cushing's syndrome show subtle changes in the facial outlines over a 3-year period.

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Figure 69.4 This photograph of a middle-aged woman with Cushing's syndrome demonstrates the characteristic plethoric facies.

Table 69.3 Frequency of occurrence and potential causes of hypercortisolemia

Hypercortisolemia Ectopic ACTH Pituitary Adrenal

Hyperpigmentation

++

Cause

Ectopic ACTH secreting tumor (+ACTH)

Pituitary tumor (+ACTH)

Adrenal adenoma (ACTH)

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Once hypercortisolemia is established, the distinction between ACTH dependence and ACTH independence should follow, based on measurement of plasma ACTH; levels exceeding 20 pg/mL indicate ACTH-dependent hypercortisolism. Patients with primary adrenal neoplasms have a suppressed or low plasma ACTH (<10 pg/mL) and adrenal mass on CT scan. ACTH-dependent Cushing's syndrome must be further separated into a pituitary tumor or an ectopic ACTH-secreting neoplasm. A high-dose dexamethasone suppression test can be used at this time to differentiate between ectopic ACTH secreting tumor (not suppressible ACTH/cortisol secretion) versus a pituitary or adrenal ACTH secreting mass (suppressible ACTH/cortisol secretion). A normal CT or MRI of the sella cannot make exclude a pituitary-secreting tumor, because only 50% to 60% of patients with Cushing's disease (pituitary) have a sellar abnormality on head MRI or CT. Hypercortisolemia with concomitant ACTH suppression (ACTH <10 pg/mL) and an adrenal mass seen on CT or MRI are diagnostic of a primary adrenal neoplasm.

Treatment
Transsphenoidal resection is the treatment of choice for the ACTH-secreting pituitary neoplasm. Remissions occur in approximately 80% to 90% of patients with Cushing's disease who undergo transsphenoidal adenoma resection. Conventional external radiotherapy is not effective as a primary treatment, but it may be combined with pituitary surgery. Ectopic ACTH production is managed by treating the primary tumor or by using adrenolytic agents such as mitotane, aminoglutethimide, or metyrapone. These agents also are useful in inoperable cases. Adrenalectomy is the preferred treatment in glucocorticoid-producing adrenal neoplasms. Glucocorticoid replacement is required for 1 to 2 years to avoid acute adrenal crisis due to suppression of the hypothalamus, pituitary, and atrophy of the contralateral adrenal. Malignant tumors are usually treated with debulking surgery followed by chemotherapy.

Complications/Prognosis
Patients with Cushing's syndrome are prone to health complications related to excess cortisol production, such as hypertension, diabetes mellitus, and osteoporosis. Benign adrenal adenomas are cured with surgery. The prognosis for most adrenal carcinomas is very poor. Median survival after diagnosis in adults is 14 to 36 months; untreated, survival averages 3 months.

Primary Hyperaldosteronism
Normally, the renin-angiotensin system is the major regulator of aldosterone synthesis and release, and aldosterone promotes renal tubular Na+ reabsorption and K+ and H+ ion excretion. Primary hyperaldosteronism (Conn syndrome) is an abnormal excess of mineralocorticoid production by the adrenal gland. Primary hyperaldosteronism occurs in 1% to 5% of hypertensives. It is seen most often in the third through fifth decades. In hypertensive patients with spontaneous hypokalemia (K+ <3.5 mEq/L), 40% have some variant of primary hyperaldosteronism.

Etiology
Approximately 50% of cases of primary hyperaldosteronism are due to aldosterone-producing adenomas (APAs). Most of the remaining cases are caused by bilateral idiopathic hyperaldosteronism (IHAs). Rarely, it may be due to glucocorticoid-suppressible hyperaldosteronism or an aldosterone-secreting adrenal carcinoma. APAs are typically solitary, unilateral, small (<2 cm in diameter), and benign. In IHA, there is bilateral hyperplasia of the zona glomerulosa, possibly from hyperstimulation by an unidentified aldosterone-releasing factor. P.435

Clinical Manifestations

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In primary hyperaldosteronism, the intravascular volume is typically high. Key manifestations include hypertension, spontaneous hypokalemia, metabolic alkalosis, low plasma renin activity, and an elevated plasma aldosterone level. The hypertension usually is moderate and is due to the sodium-retaining effects of the mineralocorticoid. Rarely, the hypokalemia may evoke easy fatigability, anorexia, muscle weakness, and cramps.

Diagnosis
Screening for primary hyperaldosteronism should be performed in hypertensive patients with spontaneous hypokalemia below 3.5 mEq/L, or a serum K+ below 3.0 mEq/L while taking a diuretic. The first phase of the workup includes screening tests, followed by testing to confirm the diagnosis (Table 69.4). In primary hyperaldosteronism PRA is low, PAC is elevated, and PAC/PRA ratio is >20 (elevated). Testing is optimal when the individual is salt loaded and when the hypokalemia is corrected. Before biochemical testing, the following medications should be discontinued: all antihypertensive agents except peripheral -1 antagonists and central -2 agonists for at least 1 week, diuretics for 4 weeks, and estrogen and spironolactone for 6 weeks. Over 90% of cases of primary hyperaldosteronism are due to either APA or IHA, so the last phase involves differentiating between these two causes. High-resolution CT is performed initially because it localizes the APA in 70% to 80% of cases. Bilateral adrenal vein catheterization is the most definitive means to distinguish between APA and IHA.

Treatment
Patients with an APA who are at low surgical risk should undergo unilateral adrenalectomy. One year following a successful surgery, 80% to 90% of patients remain normotensive and normokalemic. After 5 years, however, 50% develop recurrence of the hypertension while remaining normokalemic; the reason for this is not clear. Factors predicting persistence or recurrence of hypertension after unilateral adrenalectomy include duration of hypertension and family history of hypertension. In patients with IHA, bilateral adrenalectomy is ineffective in controlling hypertension, so medical management is the treatment of choice. Patients should follow a low-sodium diet (<80 mEq/day), exercise regularly, and maintain an ideal body weight. Potassium-sparing diuretics (e.g., spironolactone, amiloride, and triamterene) are the usual pharmaceutical agents for treating the hypokalemia of primary hyperaldosteronism. Spironolactone, the drug of choice, is often combined with nifedipine or an ACE inhibitor. If this therapy does not control the hypertension, the next step is empiric trials of other antihypertensive drugs, which usually are equally effective. P.436

Table 69.4 Diagnostic tests for primary hyperaldosteronism

Screening Level Confirmatory Level Localizing

PRA (ng/mL/hour)

<2

Saline infusion test

>50

CT of the adrenals

PAC (ng/dL)

<14

MRI of adrenals

PAC/PRA (ng/dL)

>30

Adrenal vein catheterization

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24-h urinary potassium (mEq)

>30

CT, computed tomography; PAC, plasma aldosterone concentration; PRA, panel reactive antibody.

Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia (CAH) is a family of autosomal recessive disorders resulting from defects in glucocorticoid, mineralocorticoid, and androgen production. Deficient cortisol biosynthesis causes a compensatory rise in pituitary ACTH, resulting in adrenocortical hyperplasia and overproduction of the steroids that precede the enzymatic defect.

Etiology
CAH can result from any one of five enzyme deficiencies: 21-hydroxylase, 11-hydroxylase, 3-hydroxysteroid dehydrogenase, 17-hydroxylase, or 20,22-desmolase. Classic 21-hydroxylase deficiency, the only human leukocyte antigenlinked type, accounts for more than 90% of cases of CAH. The next most common, 11-hydroxylase deficiency, accounts for almost 5% of cases.

Clinical Manifestations
CAH can take two forms: a classic, congenital form with nearly total enzymatic deficiency or, more often, a lateonset form with a partial enzymatic deficiency and onset after puberty. Clinical features depend on which steroids are deficient or in excess, as well as the absolute degree of deficiency or excess. The manifestations of the most common form, 21-hydroxylase deficiency, usually include virilization in females or ambiguous genitalia, salt-wasting, nephropathy, hyponatremia, and hyperkalemia. 11-Hydroxylase deficiency typically presents with virilization in females or ambiguous genitalia, high blood pressure, and hypokalemic alkalosis.

Diagnosis
In CAH, the steroid precursors to the defective enzymes are elevated; these steroids are used for diagnosis when CAH is suspected. For instance, in 21-hydroxylase and 11-hydroxylase deficiency, plasma 17-OH progesterone and 11deoxycortisol are typically elevated, respectively. In mild or late forms, measurement of the plasma steroid precursor after exogenous cosyntropin stimulation may be necessary for diagnosis.

Treatment
The enzymatic defects that impair cortisol and mineralocorticoid synthesis are treated respectively with glucocorticoids and mineralocorticoids. The consequent reduction in release of pituitary ACTH results in suppression of the overproduced adrenocortical steroids.

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Diseases of the Adrenal Medulla

Derived from embryonic neural crest cells, the adrenal medulla is composed primarily of chromaffin cells that convert the amino acid tyrosine to catecholamines (epinephrine, norepinephrine, dopamine). Released in response to stress, catecholamines are important mediators of the central and autonomic nervous systems. Because the predominant catecholamine, epinephrine, has a slightly higher affinity for -adrenergic receptors, the main hemodynamic effect is cardiac, increasing both heart rate and contractility. Combined with an 1-mediated vasoconstriction, these collective effects significantly raise the blood pressure. Neoplasms are the most significant of all the adrenal medullary disorders, presenting most commonly as pheochromocytomas in adults and neuroblastomas in children (one of the common solid tumors of childhood).

Pheochromocytoma
Pheochromocytomas are autonomously functioning, catecholamine-secreting, chromaffin-cell neoplasms.

Etiology
About 90% are benign solitary nodules found within the adrenal medulla itself. However, because they can arise any P.437 where neural crest tissue has migrated during the course of embryonic development, approximately 10% are located intra-abdominally in close proximity to the celiac or mesenteric sympathetic ganglia. Adrenal medullary pheochromocytomas are almost always (90%) unilateral. Bilateral lesions usually occur as familial neoplasms, as in type IIa (Sipple's syndrome) or type IIb multiple endocrine neoplasia syndrome (Table 69.5). The multiple endocrine neoplasia syndromes are transmitted as autosomal dominant diseases with incomplete penetrance and variable expression.

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Table 69.5 Classification of the multiple endocrine neoplasia (MEN) syndromes

MEN Syndrome Associated disorders

MEN type I (Wermer's syndrome)

Hyperparathyroidism Pituitary adenomas Pancreatic islet cell tumor Gastrinoma VIPoma Insulinoma Glucagonoma

MEN type IIa (Sipples's syndrome)

Medullary carcinoma of thyroid Pheochromocytoma Hyperparathyroidism

MEN type IIb

Marfanoid habitus Pheochromocytoma Medullary carcinoma of thyroid Mucosal and intestinal neuromas

Clinical Manifestations
The hallmark of a pheochromocytoma is hypertension. The clinical triad of episodic headaches, palpitations, and excessive diaphoresis occurring with hypertension provides the best clinical clue for this tumor (Table 69.6). If this triad and hypertension are absent, the diagnosis of a pheochromocytoma P.438 can be set aside confidently. Although 80% or more of these patients are hypertensive on examination, nearly one half exhibit normotensive, symptom-free periods, interspersed with episodic and transient symptoms.

Table 69.6 Clinical manifestations associated with pheochromocytomas

Symptoms Incidence (%) Signs Incidence (%)

Headache

75100

Hypertension

75100

Palpitations

5075

Tachycardia

5075

Diaphoresis

5075

Postural hypotension

5075

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Anxiety

2550

Paroxysmal hypertension

2550

Tremulousness

2550

Weight loss

2550

Chest pain

2550

Tremor

2550

Abdominal pain

2550

Pallor

2550

Nausea/emesis

2550

Weakness/fatigue

2550

Diagnosis
The most commonly used screening test is a 24-hour urine measurement of catecholamines (norepinephrine and epinephrine) or their metabolites (metanephrine and vanillylmandelic acid). Because many medications (levodopa, tricyclic antidepressants, and decongestants) influence the test results, all medications should be withheld for a minimum of 1 to 2 days, if possible, before collecting the urine sample. The sensitivity and specificity of plasma and urinary catecholamines is shown in Table 69.7. In most diagnoses of pheochromocytoma, the total urinary metanephrine and catecholamines (norepinephrine and epinephrine) exceed 1,000 g per 24 hours and 150 g per 24 hours, respectively. Plasma norepinephrine, another useful screening test in pheochromocytomas, typically exceeds 2,000 pg/mL. However, because catecholamine secretion may be intermittent, single plasma catecholamine measurements may be less sensitive than urinary levels. Recently, measurement of plasma metanephrine levels has been shown to have a higher sensitivity and specificity than the level of urinary catecholamine and their metabolites for the diagnosis of both sporadic and familial pheochromocytoma. Once a pheochromocytoma is confirmed biochemically, localization with CT or MRI should follow. Radionuclide tests with 131I-meta-iodobenzylguanidine, a radioactive amine taken up and concentrated by adrenergic chromaffin cells, are useful if extra-adrenal or metastatic pheochromocytomas are suspected.

Treatment
Pheochromocytoma is almost always cured by surgical excision of the tumor. The recent development of laparoscopic surgical techniques has provided a safe alternative to open surgical techniques. An -adrenergic blocking agent (e.g., phenoxybenzamine, 10 mg twice daily, then increase by 10 mg every 2 days until blood pressure is controlled) is administered for at least 14 days prior to surgery in order to avoid an intraoperative hypertensive crisis. Phentolamine (a reversible -blocker) and nitroprusside (a direct-acting arterial vasodilator) usually are used to manage any hypertensive crises that arise during the induction of anesthesia or during surgery. When -blockade fails to control the hypertension metyrosine, a tyrosine hydroxylase inhibitor, which reduces tumor stores of catecholamines, also may be used for preoperative management of pheochromocytoma. Successful preoperative -blockade lowers intraoperative fluid requirements, decreases the need for intraoperative medication to control blood pressure, and attenuates blood loss. Severe hypotension after tumor excision usually is avoided by perioperative plasma volume expansion with normal saline. Following -blockade, -blockers are used

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preoperatively to control tachycardia.

Complications/Prognosis
Unrecognized pheochromocytomas are potentially lethal. Hypertensive crisis or shock may be precipitated by drugs, anesthetic agents, surgery for unrelated conditions, or childbirth. However, with P.439 early diagnosis, these patients have a very high cure rate. Inoperable or malignant pheochromocytomas are managed medically with - and -adrenergic blockade. If these agents fail to provide symptom relief, metyrosine may be added. In these rare patients, the 5-year survival rate is less than 50%.

Table 69.7 Laboratory diagnosis of pheochromocytoma

Plasma Urinary

Sensitivity

Free metanephrine: 99%

Fractionated metanephrine: 97%

Specificity

Free metanephrine: 89%

Total metanephrine: 93% VMA: 95%

VMA, vanylmandelic acid.

Incidental Adrenal Mass

Since the advent of abdominal imaging using CT or MRI, the incidentally discovered adrenal mass (the so-called adrenal incidentaloma) has become a common radiographic finding and clinical dilemma. The incidence of detection of such adrenal masses is common and ranges from 0.5% to 10% of such imaging studies.

Etiology
Common causes of an adrenal mass can be found in Table 69.8 and include both benign adenomas and malignant tumors (primary adrenocortical carcinoma or metastatic lesions). Primary malignancies that most commonly metastasize to the adrenals include breast, lung, lymphoma, melanoma, and colon. The majority of small (<5 cm) masses are benign and nonfunctional (do not secrete hormone). Functioning adrenal tumors include pheochromocytoma and those that cause Cushing's syndrome or primary hyperaldosteronism. Between 50% to 70% of primary adrenocortical carcinomas are functional.

Clinical Manifestations
Patients with small, nonfunctioning, benign adrenal nodules are typically asymptomatic, while patients with primary adrenocortical carcinoma most commonly present with abdominal pain and an easily palpable mass. Other clinical characteristics of adrenal masses depend on their functional nature; excessive cortisol is the most common secretory product for both benign and malignant functioning masses. P.440

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Table 69.8 Differential diagnosis of adrenal mass

Benign nonfunctional adrenal cortical adenoma Benign functional adrenal cortical adenoma Cushing's syndrome Virilizing Feminizing Hyperaldosteronism Primary adrenal cortical carcinoma Nonfunctional Functional Tumors of the adrenal medulla Pheochromocytoma Ganglioneuromas/neuroblastoma Benign adrenal cyst Myelolipoma Intra-adrenal hemorrhage Metastases from other primary malignancies Congenital adrenal hyperplasia

Table 69.9 Screening laboratory assessment for adrenal incidentaloma

Overnight 1-mg dexamethasone suppression test or 24-hour urinary free cortisol Serum dehydroepiandrosterone sulfate Serum potassium Aldosterone: Plasma rennin activity (if serum potassium <3.5 mEq/L) 24-hour urine metanephrine, VMA, and catecholamines

VMA, vanylmandelic acid.

Diagnosis
Initially, the appearance of the CT or MRI scan images taken in context with a thorough history and physical examination may provide clues to the nature of the mass. Evidence is sought for signs of Cushing's syndrome, pheochromocytoma, primary hyperaldosteronism, nonadrenal malignancies, and adrenocortical carcinoma. Initial screening tests shown in Table 69.9 should be performed. Patients who have a primary cancer elsewhere may require needle biopsy to evaluate for adrenal metastasis. A pheochromocytoma should be excluded before needle biopsy is

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performed.

Treatment
For small lesions (<5 cm) associated with normal adrenal function, evaluation typically includes serial CT scans every 3 to 6 months over a period of up to 12 to 18 months. If the lesion is stable in size, it is presumed to be a benign, nonfunctional adrenal adenoma and no further follow-up is needed. Masses 5 cm or larger are usually resected as the risk for adrenocortical carcinoma is greater.

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