Adrenal Gland

Figure 77-1. A: Arterial (dark shaded) and venous (light shaded) anatomy of the adrenal glands. B: Schematic showing outer adrenal cortex (light shaded) and inner adrenal medulla (dark shaded).

The adrenal glands have an extensive vascular supply derived from branches of the inferior phrenic artery superiorly, the aorta medially, and the renal artery inferiorly. Venous return from the right adrenal gland empties directly into the inferior vena cava through a wide but short central vein. Venous drainage from the left adrenal gland empties into a smaller vein that shares a common trunk with the left phrenic vein. Together they join the left renal vein (Fig. 77-1).


Adrenal Cortex

1 Adrenocortical steroid hormones, glucocorticoids, mineralocorticoids, and androgenic steroids are all synthetic derivatives of cholesterol that are either extracted from plasma or synthesized intracellularly (Fig. 77-2). In mitochondria of cells in the adrenal cortex, cholesterol is converted by desmolase (CYP11A1) to delta-5-pregnenolone, the common parent compound for all adrenal cortex steroids. Pregnenolone is then shunted to the three biosynthetic pathways, each compartmentalized within the adrenal according to synthetic capabilities within each zone. In the zonae fasciculata and reticularis, pregnenolone is either converted to progesterone by 3-beta-hydroxysteroid dehydrogenase or is oxidized at position 17 by 17-alpha hydroxylase (CYP17) to form 17-hydroxypregnenolone. In the zona fasciculata, progesterone is hydroxylated by CYP17 at position 17 to form 17-hydroxyprogesterone. Subsequently, 17-hydroxyprogesterone is sequentially hydroxylated at the 21 position by 21-beta hydroxylase (CYP21A2) and at position 11 by 11-beta hydroxylase (CYP11B1) to form cortisol. In the zona reticularis, the androgenic steroids dehydroepiandrostenedione (DHEA) and androstenedione are made from 17-hydroxypregnenolone and 17-hydroxyprogesterone, respectively. Collectively, the glucocorticoid and androgenic steroids are known as 17-hydroxy corticosteroids and 17-hydroxy ketosteroids. In the zona glomerulosa, progesterone is not hydroxylated at the 17 position owing to the lack of enzyme at this location. Instead aldosterone is made from progesterone by a sequential series of hydroxylation steps at position 21 by CYP21A2, position 11 by CYP11B1, and position 18 by aldosterone synthase (CYP11B2 and P450c11as). The zona glomerulosa is well suited to aldosterone biosynthesis because of the relative lack of 17-hydroxylase and the exclusive expression of aldosterone synthase, required for the conversion of corticosterone to aldosterone.

Figure 77-2. Steroid biosynthetic pathways in the adrenal cortex. Steroids and precursors are shown in square boxes. Enzymes are shown in stippled boxes. Enzyme gene symbol designations are: CYP11A1, desmolase; CYP17, 17α-hydroxylase (±17,20 lyase*); 3β-HSD, 3β-hydroxysteroid dehydrogenase; CYP21A2, 21-hydroxylase; CYP11B1, 11β-hydroxylase; CYP11B2, Aldosterone synthase. Inset: Basic steroid ring structure. The four basic carbon rings are designated A, B, C, and D. Individual carbons at sites of steroidegenic enzyme activity are designated numerically.


Cortisol is the predominant glucocorticoid in humans. Production and release of cortisol is tightly regulated by a complex feedback relationship between the hypothalamus, corticotrophs of the anterior pituitary, and cells of the adrenal cortex zonae fasciculata and reticularis. This endocrine system is called the hypothalamic–pituitary–adrenal (HPA) axis. Communication within the HPA axis is mediated by synthesis and secretion of corticotrophin-releasing hormone (CRH) by the hypothalamus and ACTH production by corticotrophs of the anterior pituitary (Fig. 77-3). ACTH is a cleavage product of a precursor polipeptide, proopiomelanocortin (POMC) that is built of 241-amino-acid residues within corticotroph cells of the anterior and intermediate lobes of the pituitary. Several derivatives of POMC are important biologically active substances, including ACTH. Under stimulation of hypothalamic CRH stimulus, POMC can be cleaved into ACTH and β-lipotropic hormone in the anterior lobe. ACTH acts directly on the adrenal to regulate cortisol production by cells within the zonae fasciculata and reticularis. Feedback loops involving cortisol, hypothalamic CRH, and pituitary ACTH keep the concentration of cortisol in plasma within a narrow range of 10 to 15 μg/dL. Typical daily production of cortisol in humans ranges from 10 to 30 mg and can increase to as high as 300 mg per day under conditions of maximal stress.

In circulation, cortisol is protein bound to transcortin and albumin with a small percentage of free cortisol available to target tissues. The half-life of cortisol in circulation is 90 minutes. Cortisol is metabolized in the liver to the inactive metabolites dihydrocortisol and tetrahydrocortisol, which become conjugated to glucuronidate and excreted in the urine. These urinary metabolites, collectively known as 17-hydroxycorticosteroids, as well as free cortisol, can be measured in the urine.

Cortisol binds to specific intracellular cytoplasmic receptors, causing translocation of activated receptor–ligand complexes to the nucleus. Biologic effects result from transcriptional activation of genes and may be grouped into intermediary metabolism, immunomodulation, and regulation of intravascular volume (Table 77-1). Important effects of cortisol on intermediary metabolism center on raising blood glucose directly and indirectly by providing substrate for gluconeogenesis by the liver. These effects include (a) stimulation of glucagon and inhibition of insulin-stimulated glucose uptake by cells; (b) decrease in peripheral protein synthesis and increase in proteolysis, thus delivering gluconeogenic amino acids to the liver; and (c) stimulation of peripheral lipolysis. In effect, cortisol acts anabolically in vital organs to preserve glucose supply and catabolically in peripheral tissues to mobilize gluconeogenic substrates. Cortisol also possesses profound anti-inflammatory and immunosuppressive activities. Impairment of cellular immunity is due to inhibition of interleukin production, impairment of monocyte and neutrophil chemotaxis despite raised leukocyte counts, and reduction of T-cell activation. Humoral immunity is inhibited by inhibition of T-cell stimulation of B cells and by direct inhibition of B-cell proliferation and activation. These immunomodulatory effects may also underlie the impairment of normal wound healing seen in states of cortisol excess. Cortisol also regulates intravascular volume through renal retention of sodium and maintains blood pressure through inotropic and chronotropic effects on the heart as well as by increasing peripheral vascular resistance. In bone, glucocorticoids promote osteopenia by inhibition of bone formation by osteoblasts.

Figure 77-3. Schematic of hypothalamic–pituitary–adrenal axis for cortisol. Regulatory feedback relationships are designated with arrows.

Table 77-1 Systemic Effects of Cortisol

Figure 77-4. Regulatory relationships of renin, the angiotensins, and their sites of production and enzymatic conversion.


Aldosterone is the principle mineralocorticoid in humans. Aldosterone secretion by the cells of the adrenal zona glomerulosa is regulated by the renin–angiotensin system and by plasma potassium (Fig. 77-4). Aldosterone is also regulated to a lesser degree by ACTH and plasma sodium concentration. Juxtaglomerular myoepithelial cells lining afferent arterioles of the kidney sense renal blood flow and pressure, and they secrete renin in response to decreased perfusion. Renin enzymatically activates angiotensinogen to the inactive decapeptide precursor, angiotensin I. Angiotensin I is converted to angiotensin II by angiotensin-converting enzyme in the lung. Angiotensin II has three major effects: (a) arteriolar vasoconstriction; (b) renal sodium retention; and (c) increased aldosterone biosynthesis, each of which results in sodium retention and potassium excretion by the kidney. These effects work together to maintain arterial blood pressure as well as blood volume. Physiologic conditions that stimulate the renin–angiotensin cascade and aldosterone release include dehydration, upright posture, and hemorrhage. Inhibitory factors include volume repletion. Postural changes in renin–angiotensin and aldosterone are mediated by the sympathetic nervous system.

Under normal circumstances, aldosterone secretion is controlled by total body sodium and potassium levels. Excess sodium intake suppresses renin activity and leading to decreased aldosterone levels and increased renal excretion of sodium. Conversely, sodium depletion stimulates the renin–angiotensin system and aldosterone production, which promotes sodium retention by the kidney. Increased potassium intake directly decreases renin release and aldosterone production; decreasing potassium intake increases renin release. Humans with normal sodium intake typically produce 100 to 150 mg of aldosterone per day.

In circulation, aldosterone is bound to albumin and transcortin with a small percentage of free aldosterone available to target tissues. The half-life of aldosterone in plasma is 15 minutes. Aldosterone is metabolized rapidly in the liver and conjugated to glucuronidate, which is excreted in the urine. In liver failure, metabolism of aldosterone is impaired leading to elevated levels and fluid retention.

Aldosterone is the major regulator of extracellular fluid volume and potassium homeostasis (Table 77-2). Aldosterone binds to high-affinity aldosterone receptors in target tissues, including cells of the distal convoluted tubule in the kidney (the major site of action), the salivary glands, and colonic mucosa (minor sites). Stimulation of these cells results in retention of sodium and excretion of potassium. Retention of sodium in the kidney leads to passive reabsorption of water and an increase in extracellular fluid volume. To balance aldosterone-mediated retention of positively charged sodium ions, the kidney epithelium releases intracellular potassium into the distal convoluted tubule for excretion in the urine. Hydrogen ion is also released causing acidification of the urine.

Table 77-2 Effects of Aldosterone Secretion

Adrenal Androgens

Adrenal C-19 androgenic steroids, include DHEA and delta-4-androstenedione, are synthesized in cells of the zona reticularis. These steroids promote secondary sexual characteristics in men and virilization in women. DHEA is the major adrenal androgen, while androstenedione is relatively minor. Both are relatively weak androgens and exert their effects on target tissue after local tissue conversion to testosterone. Unlike gonadal androgens, adrenal androgens are regulated by ACTH, not gonadotropins, and can therefore be inhibited by glucocorticoid administration.

Adrenal Medulla

Figure 77-5. Catecholamine biosynthetic and metabolic pathways. Precursors, catecholamines, and metabolites are shown in square boxes. Enzymes are shown in stippled boxes. Enzyme gene symbol designations are: TH, tyrosine hydroxylase; AADC, aromatic-L-amino acid decarboxylase; DBH, dopamine-β-hydroxylase; PNMT, phenylethanolamine-N-methyltransferase; COMT, catechol-O-methyl-transferase; MAO, monoamine oxidase. VMA, 3-methoxy-4-hydroxy-mandelic acid.

A complex regulatory network governs synthesis and secretion of catecholamines. Factors that increase catecholamine release include splanchnic nerve stimulation, stress, and glucocorticoids. The metabolic milieu within the adrenal medulla also greatly influences catecholamine synthesis by regulating enzymatic activity: glucocorticoids, phospholipids, cyclic adenosine monophosphate, adenosine triphosphate, protein kinase, and magnesium increase activity of PNMT and decrease catecholamine negative feedback. Catecholamines are stored and secreted from granules within cells of the medulla in association with the matrix protein chromogranin. Chromogranin A is measurable in the blood and their measurement may support the biochemical testing for pheochromocytoma, as well as other functional neuroendocrine tumors.

Catecholamines act on target tissues through membrane-bound receptors. Pharmacologic distinction of adrenergic receptors is made based on their relative responsiveness to natural and artificial bioamines. Alpha-adrenergic receptors show highest affinity for norepinephrine, less for epinephrine, and least for isoproterenol. Beta-adrenergic receptors are most responsive to isoproterenol and least to norepinephrine. In addition, specific antagonists recognize each receptor class: alpha-receptors are antagonized by phentolamine and phenoxybenzamine, and beta-receptors are blocked by propranolol and related compounds. Beta-adrenergic receptor subtypes include beta-1, which is present in cardiac muscle, adipose tissue, and small intestine, and beta-2 receptors, which are found in vascular, tracheal, and uterine smooth muscle, skeletal muscle, and liver. Alpha-adrenergic receptors are similarly subdivided: alpha-1 receptors mediate vasoconstriction whereas alpha-2 receptors modulate presynaptic norepinephrine release and platelet aggregation (Table 77-3).

Metabolism of catecholamines occurs through three mechanisms: by specific uptake by sympathetic neurons, by nonspecific uptake and degradation by peripheral tissues, and by excretion in the urine. Catecholamines are metabolized in liver and kidney by two enzymes, monoamine oxidase and catechol-O-methyltransferase (Fig. 77-5). In these tissues, monoamine oxidase and catechol-O-methyltransferase convert epinephrine or norepinephrine to normetanephrine, and metanephrine, 3,4-dihydroxy-mandelic acid, and 3-methoxy-4-hydroxy-mandelic acid. These inactive metabolites are excreted by the kidney and are measurable in the urine either as free compounds or as conjugates of glucuronide or sulfate.

Table 77-3 Catecholamine Effects



The term hypercortisolism refers to the physiologic state of glucocorticoid excess. This disorder is rare, with an estimated incidence of 10 per million population. The most common cause of hypercortisolism is the administration of exogenous steroids as immunosuppressive therapy for inflammatory disorders or after organ transplantation. Endogenous hypercortisolism, or Cushing syndrome, in all cases is caused by increased adrenal production of cortisol, which may be ACTH dependent (ACTH elevated) or independent (ACTH suppressed). Some patients with major depression or chronic alcoholism have abnormally high cortisol secretion and may appear to have clinical and biochemical features of Cushing syndrome. Pseudo-Cushing syndrome responds to treatment of the underlying disorder.

3 Cushing syndrome is ACTH dependent in 80% to 90% of cases. Such ACTH-dependent hypercortisolism is most often (80% to 90% of cases) caused by an ACTH-secreting pituitary adenoma (termed Cushing disease). Ectopic ACTH-producing nonendocrine tumors (mostly non–small-cell lung cancer and bronchial carcinoids) represent 10% to 20% of cases of ACTH-dependent Cushing syndrome. All causes of ACTH-dependent Cushing syndrome involve bilateral adrenal hyperplasia in response to ACTH stimulation.

Of patients with endogenous Cushing syndrome, 10% to 25% have ACTH-independent disease caused by a primary adrenal cause. A solitary adrenal adenoma is present in 80% to 90% of these patients and is often associated with atrophy of both adjacent and contralateral adrenocortical tissue. Nodular cortical hyperplasia of both glands causes the remaining cases of primary adrenal Cushing syndrome. Although nodular hyperplasia represents a diffuse process, one or more distinct nodules may simulate adenomas. Rarely tumors secrete CRH ectopically, leading to ACTH-independent (though ACTH is elevated) Cushing syndrome with secondary adrenal hypertrophy.

Signs and Symptoms

Clinical features of cortisol excess are listed in Table 77-1. Truncal obesity (orange on toothpicks), accumulation of fat around the head and neck (moon facies and buffalo hump), and muscle wasting are present in most patients. Patients often have purple striae and purpura on the abdomen and extremities. Hirsutism may be present in women. High blood pressure is common and is usually moderate, although malignant hypertension has been observed. Bone pain and muscle weakness (caused by proximal muscle wasting and hypokalemia) are also common. Osteoporosis is common and pathologic fractures are observed in advanced cases. Neurologic symptoms, including headache, emotional lability, depression, and even psychosis may be observed. Glucose intolerance is common but can often be managed by alterations in diet alone. The serum potassium level may be low secondary to the weak mineralocorticoid properties of cortisol. Autonomous glucocorticoid production without specific signs and symptoms of Cushing syndrome is termed subclinical Cushing syndrome. This condition is being diagnosed with increased frequency because of the detection of adrenal incidentalomas by routine CT. A substantial percentage of incidentalomas are hormonally active, with 5% to 20% of the tumors producing glucocorticoids. The estimated prevalence of subclinical hypercortisolism is 79 cases per 100,000 persons, substantially higher than classic Cushing syndrome. Depending on the amounts of glucocorticoids secreted by the tumor, the clinical spectrum ranges from slightly attenuated diurnal cortisol rhythm to atrophy of the contralateral adrenal gland. Patients with subclinical Cushing syndrome lack the classical stigmata of hypercortisolism but have a high prevalence of obesity, hypertension, and type 2 diabetes.


The investigation of suspected Cushing syndrome should answer two questions: (a) Does the patient have hypercortisolism? (b) If the answer is yes, then what is the cause? It is worthwhile to emphasize that the diagnosis of Cushing syndrome is biochemical. Radiologic investigations should not be undertaken until Cushing syndrome has been confirmed and its likely etiology characterized biochemically.

Hypercortisolism insensitive to suppression by administration of exogenous glucocorticoid is the sine qua non of Cushing syndrome. The low-dose dexamethasone suppression test is the best test in patients with suspected Cushing syndrome. For this test, 1 mg of dexamethasone is administered orally at 11 PM and plasma cortisol is obtained at 8 AM the following day. Normal individuals suppress cortisol to below 5 μg/dL. Patients with Cushing syndrome fail to suppress below 5 μg/dL. False-positive test results occur in 10% to 15% of cases with the overnight test and occur especially in patients with obesity or alcoholism or in those taking estrogens or phenytoin. Measurement of free cortisol (not metabolites) in three consecutive 24-hour collections of urine is also a good screening test for Cushing syndrome. Collections should include concurrent creatinine measurement to evaluate the completeness of the collection. A 24-hour urinary-free cortisol level greater than 100 μg is diagnostic of Cushing syndrome. This test may be less sensitive than the low-dose dexamethasone suppression test in mild hypercortisolism. Plasma cortisol levels can normally vary considerably during a 24-hour period, so a single random plasma cortisol level is not helpful in establishing a diagnosis of Cushing syndrome.

Once the presence of hypercortisolism is established, the next task is to determine ACTH-dependent (pituitary or ectopic source) from ACTH-independent (primary adrenal) causes. Measurement of basal ACTH by immunoradiometric assay is the best test to make this distinction. Plasma ACTH levels are normally between 10 and 100 pg. Suppression of the absolute level of ACTH below 5 pg/mL is nearly diagnostic of adrenocortical neoplasms, which secrete high levels of cortisol and inhibit ACTH release by the pituitary. Patients with pituitary neoplasms and secondary bilateral adrenocortical hyperplasia have ACTH levels that may range from the upper limits of normal (15 pg/mL) to 500 pg/mL. The highest plasma levels of ACTH (more than 1,000 pg/mL) are in patients with ACTH-producing nonendocrine tumors, such as non–small-cell lung cancer.

Although 80% to 90% of patients with ACTH-dependent Cushing syndrome have Cushing disease, a high dose dexamethasone suppression test may be required to exclude ectopic ACTH syndrome. Hypercortisolism caused by ACTH-secreting pituitary adenomas is suppressed at least partially by high dexamethasone, whereas hypercortisolism caused by adrenal tumors and ectopic ACTH-producing tumors is not suppressed. For this test 2 mg dexamethasone is administered orally every 6 hours for 2 days, and a 24-hour urine collection for free cortisol is taken during the second day. About 90% of patients with pituitary source Cushing disease have a 50% reduction in urine-free cortisol. The specificity of the test can be improved to 100% for diagnosing pituitary disease if more than 90% suppression in urinary-free cortisol is used.

Algorithm 77-1. Diagnosis of hypercortisolism. ACTH, adrenocorticotropic hormone; IRMA, immunoradiometric assay; CT, computed tomography; MRI, magnetic resonance imaging; PET, positron emission tomography.

Biochemical testing of suspected Cushing syndrome is followed by radiologic studies. Pituitary adenomas are best imaged with gadolinium-enhanced magnetic resonance imaging (MRI) of the sella turcica, which has a sensitivity approaching 100%, although small pituitary microadenomas may be missed. Patients with ACTH-independent Cushing syndrome require thin-section CT or MRI of the adrenal, which identifies adrenal abnormalities with more than 95% sensitivity. CT or MRI of the chest may identify a source of ectopic ACTH and should be undertaken in patients with elevated ACTH and hypercortisolism that cannot be suppressed by high-dose dexamethasone.

Despite the accuracy of biochemical testing and radiographic localization, a pituitary versus ectopic source of ACTH sometimes cannot be determined. Bilateral inferior petrosal sinus sampling is the best test to settle this issue. Simultaneous bilateral petrosal sinus and peripheral blood samples are obtained before and after peripheral intravenous injection of 1 μg/kg CRH. An inferior petrosal sinus to peripheral plasma ACTH ratio of 2.0 at basal stimulated or of 3.0 after CRH administration is 100% sensitive and specific for pituitary adenoma. Comparison of right and left inferior petrosal sinus ratios may also lateralize the adenoma.

The laboratory approach to the diagnosis of Cushing syndrome is summarized in Algorithm 77-1. A careful history and physical examination form the basis for suspecting this condition. A low-dose dexamethasone suppression test and/or urinary-free cortisol measurement provide initial evidence for the diagnosis. Plasma ACTH determination and the high-dose dexamethasone suppression test are then used to identify the underlying cause of excess cortisol production by the adrenal cortex. Imaging studies support the cause of Cushing syndrome suggested by biochemical testing and localize the site for subsequent treatment.


ACTH-dependent Cushing syndrome is best treated by removing the source of ACTH excess. In the case of Cushing disease, transsphenoidal resection of the pituitary microadenoma is successful in 80% or more of cases. If a microadenoma is not found, then hemihypophysectomy may be performed with the understanding that fertility may be impaired. Pituitary irradiation is a good treatment option when fertility is desired, when a tumor is not found or is unresectable, or cure is not achieved by transsphenoidal resection of a tumor. Debulking of unresectable primary lesions or recurrences with or without bilateral adrenalectomy may provide palliation in some patients. Treatment of ectopic ACTH syndrome involves removal of the primary lesion. Medical adrenalectomy with metyrapone, aminoglutethimide, and mitotane has been used to suppress production of corticosteroid in inoperable cases for both pituitary and ectopic sources of ACTH. Bilateral adrenalectomy is a good option for patients intolerant of mitotane.

ACTH-independent Cushing syndrome is best treated by removal of the adrenal tumor and affected gland. Small lesions, less than 6 cm in diameter, may be resected laparoscopically. Lesions larger than 6 cm or those suspected of being carcinoma require an anterior open approach. Resection of cortisol-producing benign adrenal adenomas is curative and prognosis is good following resection. Cortisol-producing adrenocortical carcinomas recur frequently following adrenalectomy, heralded by the reemergence of hypercortisolism. Micronodular pigmented hyperplasia and macronodular adrenal hyperplasia may involve both adrenal glands. These conditions are cured only by bilateral adrenalectomy. Medical adrenalectomy with mitotane or agents interfering with cortisol production is not currently recommended.

Whether patients with subclinical Cushing syndrome should undergo adrenalectomy is unclear. Several small series have demonstrated weight loss, an improvement in hypertension and glucose control following adrenalectomy for subclinical Cushing syndrome. Furthermore, patients with subclinical Cushing syndrome may progress to overt Cushing syndrome as frequently as 12.5% at 1 year. Accordingly, adrenalectomy for subclinical Cushing syndrome may be beneficial and is reasonable in young patients, patients with suppressed plasma ACTH, and patients with a recent weight gain, substantial obesity, arterial hypertension, diabetes mellitus, and osteopenia. Truly asymptomatic patients with normal plasma ACTH concentrations and the elderly or unfit may be observed. Demonstration of the benefits of surgery versus conservative treatment in patients with subclinical Cushing syndrome will require a randomized prospective trial.

All patients who undergo adrenalectomy for Cushing syndrome require perioperative and postoperative glucocorticoid replacement, since the contralateral gland is suppressed. Replacement therapy with hydrocortisone, 12 mg/m2 per day, may be required as long as 2 years postoperatively. Adequacy of replacement is monitored clinically. The duration of replacement therapy is guided by normalization of the ACTH stimulation test.


Hyperaldosteronism is a syndrome of hypertension and hypokalemia caused by autonomous adrenal secretion of the mineralocorticoid aldosterone. Hyperaldosteronism may be primary, as a result of an adrenal neoplasm with suppressed plasma renin, or may be secondary, as a result of elevated plasma renin. Primary hyperaldosteronism is twice as common in women as in men, and it usually occurs between the ages of 30 and 50 years. Screening of hypertensive patients with plasma aldosterone and plasma renin activity (PRA) has suggested that primary hyperaldosteronism may be the underlying cause of up to 15% of cases of essential hypertension.

Algorithm 77-2. Diagnosis and management of hyperaldosteronism. PRA, plasma renin activity; PAC, plasma aldosterone concentration; CT, computed tomography; AVS, bilateral adrenal venous sampling.

4 An aldosterone-producing adrenal adenoma (Conn syndrome) is the source of primary hyperaldosteronism in 60% to 70% of cases. Idiopathic bilateral adrenal hyperplasia causes the remaining cases of primary hyperaldosteronism. Adrenocortical carcinoma is a rare cause of primary hyperaldosteronism. Autosomal dominant glucocorticoid-suppressible hyperaldosteronism is a rare cause of hyperaldosteronism resulting from the fusion of the ACTH-responsive 11-beta hydroxylase gene promoter to the aldosterone synthase gene in cells of the adrenal cortex.

Secondary hyperaldosteronism is a physiologic response of the renin–angiotensin system to decreased renal perfusion due to renal artery stenosis, cirrhosis, congestive heart failure, and normal pregnancy. The adrenal cortex functions normally and secretes aldosterone in response to the elevated plasma renin and angiotensin caused by these conditions. Secondary hyperaldosteronism responds to treatment of the underlying cause.

Signs and Symptoms

Clinical manifestations of primary hyperaldosteronism are attributable to hypersecretion of aldosterone by the adrenal gland (Table 77-2). Aldosterone-mediated retention of sodium and excretion of potassium and hydrogen ion by the kidney causes moderate diastolic hypertension. Edema is absent. Hypokalemia occurs spontaneously in 80% to 90% of patients with primary hyperaldosteronism but may be normal. Hypokalemia is easily provocable in the remaining patients. Potassium depletion frequently causes symptoms of muscle weakness and fatigue, polyuria and polydipsia, as well as impaired insulin secretion and fasting hyperglycemia. Primary hyperaldosteronism should be suspected in hypertensive patients with spontaneous hypokalemia (serum concentration <3.5 mEq/L), moderate hypokalemia (serum potassium concentration <3.0) during diuretic therapy despite concomitant use of oral potassium or potassium-sparing diuretics, or refractory hypertension without explanation.


The clinical hallmarks of primary hyperaldosteronism are (a) diastolic hypertension without edema; (b) suppression of plasma renin in the face of volume depletion; and (c) hypersecretion of aldosterone that fails to suppress with intravascular volume expansion. Diagnostic evaluation must establish primary hyperaldosteronism, discern surgically correctable adrenal adenoma from medically treatable idiopathic hyperplasia, and localize an adrenal tumor (Algorithm 77-2).

Demonstration of an elevated plasma aldosterone concentration (PAC) in the setting of suppressed PRA is the best test to establish primary hyperaldosteronism. The ratio in normal subjects and patients with essential hypertension is 4:10 compared with more than 30 in most patients with primary hyperaldosteronism. A PAC of greater than 20 ng/dL and a PAC/PRA ratio of greater than 30 are diagnostic for aldosteronoma with almost 90% sensitivity. A serum potassium value less than 3.5 mEq/L and urinary potassium excretion greater than 30 mEq/day also support a diagnosis of primary hyperaldosteronism. Before biochemical evaluation, patients need to be potassium repleted and have an adequate sodium intake. Medications including ACE inhibitors and spironolactone should be withheld for at least 4 weeks before study.

An elevated PAC/PRA ratio alone does not establish the diagnosis of primary hyperaldosteronism, which must be confirmed by demonstrating inappropriate aldosterone secretion with salt loading. This involves a 24-hour urine collection for sodium and aldosterone after 3 days of a high-sodium diet. The 24-hour urinary excretion of aldosterone should be greater than 14 μg per 24 hours after a high-salt diet for patients with primary hyperaldosteronism. An intravenous saline infusion test or captopril challenge test is also a reliable method to confirm primary hyperaldosteronism. These tests are not usually required.

After the diagnosis of primary hyperaldosteronism is made, distinction must be made between an aldosteronoma and idiopathic adrenal hyperplasia. The first test measures aldosterone in blood collected at 8 AM from a patient who has been supine overnight. Laboratory studies are repeated 4 hours later after the patient has been upright. Aldosterone secretion in patients with an aldosteronoma is unaffected by postural changes (<20 ng/dL), whereas, in patients with idiopathic adrenal hyperplasia, plasma aldosterone levels are elevated 33% (>20 ng/dL) or more by postural changes.

Figure 77-6. Computed tomography scan of right adrenal aldosteronoma. Short arrow shows aldosteronoma. Long arrow shows normal contralateral adrenal gland.

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May 5, 2017 | Posted by in GENERAL SURGERY | Comments Off on Adrenal Gland

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