21: Disorders of the Adrenal Cortex

The adrenal gland is actually two endocrine organs, one wrapped around the other. The outer adrenal cortex secretes many different steroid hormones, including glucocorticoids such as cortisol, mineralocorticoids such as aldosterone, and androgens, chiefly dehydroepiandrosterone (DHEA). The glucocorticoids help to regulate carbohydrate, protein, and fat metabolism. The mineralocorticoids help to regulate Na⁺ and K⁺ balance and extracellular fluid volume. The glucocorticoids and mineralocorticoids are essential for survival, but no essential role of adrenal androgens has been determined. The inner adrenal medulla, discussed in Chapter 12, secretes catecholamines (epinephrine, norepinephrine, and dopamine).

Mainly because of their potent immunosuppressive and anti-inflammatory effects, glucocorticoids are used commonly in pharmacologic doses to treat diseases such as autoimmune disorders. Interestingly, while the deleterious effects of glucocorticoids in states of hypercortisolism and the beneficial effects of their use in pharmacotherapy are rather well understood, the actual role of endogenous glucocorticoids in metabolic homeostasis during times of minimal stress remains somewhat enigmatic.

The major disorders of the adrenal cortex (Table 21–1) are characterized by excessive or deficient secretion of each type of adrenocortical hormone: hypercortisolism (Cushing syndrome), adrenal insufficiency (Addison disease), hyperaldosteronism (aldosteronism), hypoaldosteronism, and androgen excess.

Anatomy

The adrenal glands are paired organs located in the retroperitoneal area near the superior poles of the kidneys (Figure 21–1). They are flattened, crescent-shaped structures, which together normally weigh about 8–10 g. Each is covered by tight fibrous capsules and surrounded by fat. The blood flow to the adrenals is copious.

Grossly, each gland consists of two concentric layers: The yellow peripheral layer is the adrenal cortex, and the reddish brown central layer is the adrenal medulla. Adrenal cortical tissue is sometimes found at other sites, usually near the kidney or along the path taken by the gonads during their embryonic descent (Figure 21–1).

Histology

The adrenal cortex can be subdivided into three concentric layers: zona glomerulosa, zona fasciculata, and zona reticularis (Figure 21–2). The zona glomerulosa is the outermost layer, situated immediately beneath the capsule. Zona glomerulosa cells are columnar or pyramidal in appearance and are arranged in closely packed, rounded, or arched clusters surrounded by capillaries. They secrete mineralocorticoids, primarily aldosterone. The zona fasciculata is the middle layer of the cortex. Zona fasciculata cells are polyhedral in shape and arranged in straight cords or columns, one or two cells thick, running at right angles to the capsule with capillaries between them. The zona reticularis, the innermost layer of the cortex, lies between the zona fasciculata and the adrenal medulla, accounting for only 7% of the mass of the adrenal gland. Zona reticularis cells are smaller than the other two types and are arranged in irregular cords or interlaced in a network. Zona fasciculata and zona reticularis cells secrete both glucocorticoids, primarily cortisol and corticosterone, and androgens such as dehydroepiandrosterone. These steroid hormones are low-molecular-weight lipid-soluble molecules able to diffuse freely across cell membranes.

Physiology of Normal Adrenal Cortex

Glucocorticoids

Glucocorticoid Synthesis, Protein Binding, & Metabolism

Cortisol and corticosterone are referred to as glucocorticoids because they increase hepatic glucose output by stimulating the catabolism of peripheral fat and protein to provide substrate for hepatic gluconeogenesis. The glucocorticoids help regulate the metabolism of carbohydrates, proteins, and fat. They act on virtually all cells of the body.

Synthesis and Binding to Plasma Proteins—

The major glucocorticoids secreted by the adrenal cortex are cortisol and corticosterone. Biosynthetic pathways for these hormones are illustrated in Figure 21–3.

Both cortisol and corticosterone are secreted in an unbound state but circulate bound to plasma proteins. They bind mainly to corticosteroid-binding globulin (CBG) (or transcortin) and to a lesser extent to albumin. Protein binding serves mainly to distribute and deliver the hormones to target tissues, but it also delays their metabolic clearance and prevents marked fluctuations of glucocorticoid levels during episodic secretion by the gland.

Corticosteroid-Binding Globulin—

CBG (molecular weight ~50,000) is an α-globulin synthesized in the liver. Its production is increased by pregnancy, estrogen or oral contraceptive therapy, hyperthyroidism, diabetes mellitus, certain hematologic disorders, and familial CBG excess. When the CBG level rises, more cortisol is bound, and the free cortisol level falls temporarily. This fall stimulates pituitary adrenocorticotropic hormone (ACTH) secretion and more adrenal cortisol production. Eventually, the free cortisol level and the ACTH secretion return to normal but with an elevated level of protein-bound cortisol. Similarly, when the CBG level falls, the free cortisol level rises. CBG production is decreased in cirrhosis, nephrotic syndrome, hypothyroidism, multiple myeloma, and familial CBG deficiency.

Free and Bound Glucocorticoid—

Normally, about 96% of the circulating cortisol is bound to CBG and 4% is free (unbound). The bound hormone is inactive. The free hormone is physiologically active. The normal morning total plasma cortisol level is 5–20 μg/dL (140–550 nmol/L). Because cortisol is protein bound to a greater degree than corticosterone, its half-life in the circulation is longer (~60–90 minutes) than that of corticosterone (~50 minutes).

Metabolism—

Glucocorticoids are metabolized in the liver and conjugated to glucuronide or sulfate groups. The inactive conjugated metabolites are excreted in the urine and stool. The metabolism of cortisol is decreased in infancy, old age, pregnancy, chronic liver disease, hypothyroidism, anorexia nervosa, surgery, starvation, and other major physiologic stress. Catabolism of cortisol is increased in thyrotoxicosis. Because of its avid protein binding and extensive metabolism before excretion, less than 1% of secreted cortisol appears in the urine as free cortisol.

Regulation of Secretion

Adrenocorticotropic Hormone and Corticotropin-Releasing Hormone—

Glucocorticoid secretion is regulated primarily by ACTH, a 39-amino-acid polypeptide secreted by the anterior pituitary. Its half-life in the circulation is very short (~10 minutes). The site of its catabolism is unknown. ACTH regulates both basal secretion of glucocorticoids and increased secretion provoked by stress.

ACTH, in turn, is regulated by hypothalamic corticotropin-releasing hormone (CRH), a 41-amino-acid polypeptide secreted into the median eminence of the hypothalamus. CRH secretion by the hypothalamus is regulated by a variety of neurotransmitters (Figure 21–4) in response to physical and emotional stressors. The hypothalamus is subject to regulatory influences from other parts of the brain, including the limbic system. CRH is transported in the portal-hypophysial vessels to the anterior pituitary (see Chapter 19). There, CRH causes a prompt increase in ACTH secretion. This, in turn, leads to a transient increase in cortisol secretion by the adrenal. Arginine-vasopressin (AVP) is an additional hypothalamic peptide that regulates ACTH release.

The control of ACTH and CRH/AVP secretion involves three components: episodic secretion and diurnal rhythm of ACTH, stress responses of the hypothalamic-pituitary-adrenal axis, and negative feedback inhibition of ACTH secretion by cortisol.

Episodic and Diurnal Rhythm of ACTH Secretion—

ACTH is secreted in episodic bursts throughout the day, after a diurnal (circadian) rhythm, with bursts most frequent in the early morning and least frequent in the evening (Figure 21–5). The peak level of cortisol in the plasma normally occurs between 6:00 and 8:00 AM (during sleep, just before awakening) and the nadir at around 12:00 AM. The diurnal rhythm of ACTH secretion persists in patients with adrenal insufficiency who are receiving maintenance doses of glucocorticoids but is lost in Cushing syndrome. The diurnal rhythm is altered also by changes in patterns of sleep (eg, shift work), light-dark exposure, or food intake; physical stress such as major illness, surgery, trauma, or starvation; psychologic stress, including severe anxiety, depression, and mania; CNS and pituitary disorders; liver disease and other conditions that affect cortisol metabolism; chronic kidney disease; alcoholism; and antiserotonergic drugs such as cyproheptadine.

Normally, the morning plasma ACTH concentration is about 25 pg/mL (5.5 pmol/L). Plasma ACTH and cortisol values in various normal and abnormal states are shown in Figure 21–6.

Stress Response—

Plasma ACTH and cortisol secretion are also triggered by various forms of stress. Emotional stress (such as fear and anxiety) and bodily injury (such as surgery or hypoglycemia) release CRH from the hypothalamus. Similarly, vasopressin is released in response to volume depletion. ACTH secretion induced by these hormones, in turn, stimulates a transient increase in cortisol secretion (Figure 21–7). If the stress is prolonged, it may abolish the normal diurnal rhythm of ACTH and cortisol secretion.

Negative Feedback—

A rising level of plasma cortisol inhibits release of ACTH from the pituitary by both inhibiting CRH release from the hypothalamus and interfering with the stimulatory action of CRH on the pituitary (Figure 21–4). The fall in plasma ACTH leads to a decline in adrenal secretion of cortisol. Conversely, the loss of negative feedback resulting from a drop in plasma cortisol induces a net increase in ACTH secretion. In untreated chronic adrenal insufficiency, there is a marked increase in the rate of ACTH synthesis and secretion.

ACTH and CRH secretion are also inhibited by chronic pharmacologic treatment with exogenous corticosteroids in proportion to their glucocorticoid potency. When prolonged corticosteroid treatment is stopped, the adrenal is atrophic and unresponsive and the patient is at risk for acute adrenal insufficiency. Chronic suppression of the HPA axis by exogenous glucocorticoids also impacts on hypothalamic CRH and pituitary ACTH secretion and it may take some time to recover after cessation of glucocorticoid treatment. Such adrenal insufficiency after abrupt glucocorticoid withdrawal can be life threatening. The time to recovery to full physiological function of the HPA axis is dependent on duration and dose of glucocorticoid treatment. Moreover, there are significant interindividual differences in these parameters. While there are no useful predictors to facilitate determining which patients are at risk for prolonged adrenal insufficiency, there is some evidence that alternate-day glucocorticoid treatment tends to preserve some adrenal function. Another well-accepted method of preventing long-term suppression of the HPA axis following glucocorticoid therapy is to slowly taper the dosage of exogenous glucocorticoids. Tapering exogenous glucocorticoid has a dual function. A short-term taper (days to a few weeks) of pharmacologic doses of glucocorticoids prevents a rebound flare of the underlying treated disease (eg, autoimmune disorder). A slow taper of exogenous glucocorticoid from physiologic replacement doses to complete discontinuation serves the purpose of allowing the endogenous HPA axis to recover. Such tapering only supports the recovery of HPA-axis function if it is done slowly (weeks to months) with doses below the daily physiologic glucocorticoid equivalent (eg, 5.0–7.5 mg of prednisone).

Effects of ACTH on the Adrenal—

Circulating ACTH binds to high-affinity receptors (ACTH receptor or melanocortin MC2 receptor) on adrenocortical cell membranes, activating adenylyl cyclase, increasing intracellular cyclic adenosine monophosphate (cAMP). There is a dual response to ACTH stimulation: a) immediate production and release of cortisol, and b) induction of steroidogenic enzyme synthesis.

Prolonged hypersecretion or administration of ACTH causes initial hypertrophy followed by hyperplasia of the zona fasciculata and zona reticularis. Growth factors such as additional POMC peptides and insulin-like growth factors play important roles in this process. Conversely, prolonged ACTH deficiency results in adrenocortical atrophy.

Mechanism of Action

The physiologic effects of glucocorticoids in various tissues are the result of their binding to the ubiquitous cytosolic glucocorticoid receptors (GRs) (Figure 21–8). The hormone-GR complexes then enter the nucleus and can act by two main mechanisms: a) transactivation, in which the GRs bind to nuclear DNA and promote the transcription of DNA, production of mRNAs, and hence synthesis of proteins; or b) transrepression, in which gene transcription is inhibited through interference with other transcription factors.

Effects

The effects of glucocorticoids on target tissues are summarized in Table 21–2. Under physiologic circumstances, the effects of glucocorticoid are not very well understood but appear to be mainly permissive. The effects of glucocorticoids secreted at supraphysiologic levels, however, are well described. In most tissues, glucocorticoids have a catabolic effect, promoting degradation of protein and fat to provide substrate for intermediary metabolism. In the liver, however, glucocorticoids have a synthetic effect, promoting the uptake and use of carbohydrates (in synthesis of glucose and glycogen), amino acids (in synthesis of RNA and protein enzymes), and fatty acids (as an energy source).

During fasting, glucocorticoids help to maintain plasma glucose levels by several mechanisms (Table 21–2). In peripheral tissues, glucocorticoids antagonize the effects of insulin. Glucocorticoids inhibit glucose uptake in muscle and adipose tissue. The brain and heart are spared from this antagonism, and the extra supply of glucose helps these vital organs to cope with stress. In diabetics, the insulin antagonism may worsen control of blood sugar levels, raise plasma lipid levels, and increase the formation of ketone bodies. However, in nondiabetics, the rise in blood glucose levels stimulates a compensatory increase in insulin secretion that prevents these sequelae.

Small amounts of glucocorticoids must be present for other metabolic processes to occur (permissive action). For example, glucocorticoids must be present for catecholamines to produce their calorigenic, lipolytic, pressor, and bronchodilator effects and for glucagon to increase hepatic gluconeogenesis.

Glucocorticoids are also required to resist various stresses. Indeed, the increased secretion of pituitary ACTH and consequent increase in circulating glucocorticoids after injury are essential to survival. Hypophysectomized or adrenalectomized individuals treated with only maintenance doses of glucocorticoids may die when exposed to such stress. This underscores the crucial role of glucocorticoids as stress hormones.

Mineralocorticoids

Synthesis, Protein Binding, & Metabolism

The primary function of mineralocorticoids is to regulate Na⁺ excretion and maintain a normal intra-vascular volume. However, other factors affect Na⁺ excretion besides the mineralocorticoids, such as the glomerular filtration rate, atrial natriuretic peptide, presence of an osmotic diuretic, and changes in tubular reabsorption of Na⁺ that are not regulated by mineralocorticoid.

Synthesis—

Aldosterone is the principal mineralocorticoid secreted by the adrenal. Deoxycorticosterone also has minor mineralocorticoid activity, as does corticosterone.

Protein Binding—

Aldosterone is bound to plasma proteins (albumin and corticosteroid-binding globulin) to a lesser extent than glucocorticoids. The amount of aldosterone secreted under normal circumstances is small (~0.15 mg/24 h). The normal average plasma concentration of (free and bound) aldosterone is 0.006 μg/dL (0.17 nmol/L). Free (unbound) aldosterone comprises 30–40% of the total.

Metabolism—

The half-life of aldosterone is short (~20– 30 minutes). Aldosterone is catabolized principally in the liver, and its metabolites are excreted in the urine. Less than 1% of secreted aldosterone is excreted in urine in the free form.

Regulation

Aldosterone secretion is regulated primarily by the renin-angiotensin system but also by pituitary ACTH and by the plasma electrolytes, K⁺ and, to a lesser extent, Na⁺.

Regulation by Renin-Angiotensin System—

The renin-angiotensin system regulates aldosterone secretion in a feedback fashion (Figure 21–9). Renin is a proteolytic enzyme produced from a larger protein, prorenin. Renin is excreted by the juxtaglomerular cells of the kidney in response to decreases in renal perfusion pressure and reflex increases in renal nerve discharge. Once in the circulation, renin acts on angiotensinogen, to form angiotensin I, a decapeptide. In the lung and elsewhere, angiotensin I is converted by angiotensin-converting enzyme (ACE) to angiotensin II, an octapeptide. Angiotensin II binds to zona glomerulosa cell membrane receptors and stimulates synthesis and secretion of aldosterone. Aldosterone promotes Na⁺ and water retention, causing plasma volume expansion, which then shuts off renin secretion. In the supine state, there is a diurnal rhythm of aldosterone and renin secretion; the highest values are in the early morning before awakening.

The physiologic stimuli for the renin-angiotensin system to increase aldosterone secretion include factors that reduce renal perfusion such as extracellular fluid volume depletion, dietary Na⁺ restriction, and decreases in intra-arterial vascular pressure (eg, resulting from hemorrhage or upright posture). Other disease states that cause reduced renal perfusion include renal artery stenosis, salt-losing disorders, heart failure, and hypoproteinemic states (cirrhosis of the liver, or nephrotic syndrome). These disorders increase renin secretion, producing secondary hyperaldosteronism.

Regulation by ACTH—

ACTH also stimulates mineralocorticoid output. More ACTH is needed to stimulate mineralocorticoid than glucocorticoid secretion, but the amount required is still within the range of normal ACTH secretion. The effect of ACTH on aldosterone secretion is transient, however. Even if ACTH secretion remains elevated, aldosterone production declines to normal within 48 hours, perhaps because renin secretion decreases in response to hypervolemia.

Regulation by Plasma Electrolytes—

An increase in plasma K⁺ concentration—or a fall in plasma Na⁺—stimulates aldosterone release. Although minor changes of plasma K⁺ (≤1 mEq/L) have an effect, major changes in plasma Na⁺ (drops of about 20 mEq/L) are needed to stimulate aldosterone secretion. Na⁺ depletion increases the affinity and number of angiotensin II receptors on adrenocortical cells.

Mechanism of Action

Aldosterone, like other steroid hormones, acts by binding to a mineralocorticoid receptor (MR) in the cytosol. The expression of the MR is restricted to a small number of tissues, such as the kidney. Interestingly, glucocorticoids also have a high affinity to the MR, but usually do not exert mineralocorticoid effects because mineralocorticoid-sensitive tissues express the enzyme 11-hydroxysteroid dehydrogenase type 2, which metabolizes and inactivates glucocorticoids before it can bind to the MR. The aldosterone-MR complex moves into the nucleus of the target cell and increases transcription of DNA, induction of mRNA, and stimulation of protein synthesis by ribosomes. The aldosterone-stimulated proteins have two effects: a rapid effect to increase the activity of epithelial sodium channels (ENaCs) by increasing the insertion of ENaCs into the cell membrane from a cytosolic pool, and a slower effect to increase the synthesis of ENaCs. One of the genes activated by aldosterone is the gene for serum- and glucocorticoid-regulated kinase (sgk), a serine-threonine protein kinase. The sgk gene product increases ENaC activity (Figure 21–10). Aldosterone also increases the mRNAs for the three subunits that comprise the ENaCs.

The fact that the principal effect of aldosterone on Na⁺ transport takes 10–30 minutes to develop and even longer to peak indicates that it depends on the synthesis of new proteins by the genomic mechanism. However, aldosterone also binds directly to distinct membrane receptors with a high affinity for aldosterone, and, by a rapid nongenomic action, increases the activity of membrane Na⁺-K⁺ exchangers to increase intracellular Na⁺.

Effects

The target organs for the mineralocorticoids include the kidney, colon, duodenum, salivary glands, and sweat glands. In the distal renal tubules and collecting ducts, aldosterone acts to promote the exchange of Na⁺ for K⁺ and H⁺, causing Na⁺ retention, K⁺ diuresis, and increased urine acidity. Elsewhere, it acts to increase the reabsorption of Na⁺ from the colonic fluid, saliva, and sweat. The mineralocorticoids may also increase K⁺ and decrease Na⁺ concentrations in muscle and brain cells. Aldosterone action on epithelial cells of the choroid plexus alters the composition of cerebrospinal fluid in a fashion thought to contribute to blood-pressure regulation. In the heart, aldosterone has been shown to induce heart remodeling and interstitial and perivascular fibrosis of the myocardium.

Characteristic syndromes are produced by excessive or deficient secretion of each type of adrenal hormone. Excessive glucocorticoid secretion (Cushing syndrome) results in a moon-faced, plethoric appearance, with truncal obesity, purple abdominal striae, hypertension, osteoporosis, mental aberrations, protein depletion, and glucose intolerance or frank diabetes mellitus.

Excessive mineralocorticoid secretion in hyperaldosteronism leads to Na⁺ retention, usually without edema, and K⁺ depletion, resulting in hypertension, muscle weakness, polyuria, hypokalemia, metabolic alkalosis, and sometimes hypocalcemia and tetany.

Excessive androgen secretion causes virilization or hirsutism and precocious pseudopuberty or a disorder of sexual development (46,XX DSD [disorder of sexual development], formerly known as female pseudohermaphroditism).

Deficient glucocorticoid secretion resulting from autoimmune or other destruction of the adrenal glands (Addison disease) causes symptoms of weakness, fatigue, malaise, anorexia, nausea and vomiting, weight loss, hypotension, hypoglycemia, and marked intolerance of physiologic stress (eg, infection). Elevation of plasma ACTH may produce hyperpigmentation.

Associated mineralocorticoid deficiency leads to renal Na⁺ wasting and K⁺ retention and can produce manifestations of severe dehydration, hypotension, decreased cardiac size, hyponatremia, hyperkalemia, and metabolic acidosis. Deficient mineralocorticoid secretion also occurs in patients with renal disease and low circulating renin levels (hyporeninemic hypoaldosteronism).

Cushing Syndrome

Cushing syndrome is the clinical condition resulting from chronic exposure to excessive circulating levels of glucocorticoids (Figure 21–11). It is also called hypercortisolism. The most common cause of the syndrome is excess secretion of ACTH from the anterior pituitary gland (Cushing disease).

Etiology

Cushing syndrome may occur either spontaneously or as the result of chronic glucocorticoid administration (iatrogenic Cushing syndrome). The overall incidence of spontaneous Cushing syndrome is approximately two to four cases per million population. It is nine times more common in women than in men. The major causes of Cushing syndrome are summarized in Table 21–3.

Hypothalamic CRH Hypersecretion

Uncommonly, patients with Cushing syndrome have diffuse hyperplasia of pituitary corticotroph cells responsible for ACTH hypersecretion. The hyperplasia is probably due to hypersecretion of CRH by the hypothalamus or nonhypothalamic tumors that secret ectopic CRH. Chronic CRH hypersecretion does not cause pituitary adenomas.

Pituitary Cushing Disease

Cushing disease is the most common cause of noniatrogenic hypercortisolism. It is four to six times more prevalent in women than in men. Patients with Cushing disease have a pituitary adenoma causing excessive secretion of ACTH (Figure 21–12). Such adenomas are located in the anterior pituitary, are usually less than 10 mm in diameter (microadenomas), and are composed of basophilic corticotroph cells containing ACTH in secretory granules. Macroadenomas are less common and carcinomas extremely rare. Pituitary adenomas are common, found in 10–25% of unselected autopsy series, and in about 10% of asymptomatic individuals subjected to magnetic resonance imaging (MRI). Use of molecular biology techniques to determine the clonal origin of corticotroph tumors has shown that ACTH-secreting pituitary adenomas are monoclonal, arising from a single progenitor cell. Presumably, somatic mutations are required for tumorigenesis.

In Cushing disease, the chronic ACTH hypersecretion causes bilateral hyperplasia of the adrenal cortex. Combined adrenal weights (normal: 8–10 g) range from 12 g to 24 g. The adrenal hyperplasia is most typically micronodular, but in some patients, particularly those with long-standing Cushing disease, macronodular hyperplasia develops.

Ectopic ACTH Syndrome

In the ectopic ACTH syndrome, a nonpituitary tumor synthesizes and hypersecretes biologically active ACTH or an ACTH-like peptide (Figure 21–12). The neoplasms most frequently responsible are small cell carcinomas of the lung and bronchial carcinoid tumors. Ectopic ACTH hypersecretion is more common in men, largely owing to the more frequent occurrence of these lung tumors in men. Other associated tumors are listed in Table 21–3. Chronic ACTH hypersecretion causes marked bilateral adrenocortical hyperplasia, with combined adrenal weights ranging from 24–50 g or more. The ACTH secreted by the nonpituitary tumor causes adrenal hyperfunction, and the high circulating cortisol levels suppress hypothalamic secretion of CRH and the pituitary secretion of ACTH. Pituitary corticotroph cells have a decreased ACTH content.

Ectopic CRH Syndrome

The ectopic CRH syndrome is a rare cause of Cushing syndrome (see Figure 21–12). Most cases have been associated with bronchial carcinoid tumors.

Functioning Adrenocortical Tumors

Both adrenocortical adenomas and carcinomas may cause Cushing syndrome by elaborating cortisol autonomously (Figure 21–12). Adenomas are usually 3–6 cm in diameter, weigh 10–70 g, are encapsulated, and consist predominantly of zona fasciculata cells. They are relatively inefficient in cortisol synthesis. Adrenocortical carcinomas are usually large, weighing 100 g to several kilograms, and are often palpable as an abdominal mass by the time Cushing syndrome becomes clinically manifest. Grossly, they are highly vascular, with areas of necrosis, hemorrhage, cystic degeneration, and calcification. They are highly malignant lesions, tending to invade the adrenal capsule, neighboring organs and blood vessels and metastasize to the liver and lungs.

Adrenal Micronodular Hyperplasia

ACTH-independent adrenal micronodular hyperplasia is a rare cause of Cushing syndrome (also termed primary pigmented nodular adrenocortical disease). Pathologically, it is characterized by multiple small, pigmented, usually bilateral cortisol-secreting nodules. About half of cases occur sporadically in children and young adults. The remainder occur as an autosomal dominant disorder in association with blue nevi; pigmented lentigines (freckles) of the skin and mucosal surfaces of the head and face; cutaneous, mammary, and atrial myxomas; pituitary somatotroph adenomas; and tumors of peripheral nerves, testes, and other endocrine glands (Carney complex).

Adrenal Macronodular Hyperplasia

Another rare cause of Cushing syndrome is bilateral adrenal macronodular hyperplasia. In this condition, both glands are markedly enlarged, with bulging nodules found at cut section. Microscopically, the nodules reveal a variegated histologic pattern characterized by trabecular, adenoid, and zona glomerulosa–like structures. Occasionally, the hyperplasia may be unilateral. Some patients with macronodular hyperplasia do not show typical cushingoid features. In these cases, the macronodular hyperplasia is most often discovered incidentally on ultrasound or computed tomography (CT) examination of the abdomen and can be considered benign.

Pathophysiology

The various causes of Cushing syndrome can be divided into two categories: ACTH dependent and ACTH independent. The causes of ACTH-dependent Cushing syndrome include Cushing disease (95% of ACTH-dependent cases), ectopic ACTH hypersecretion (5%), and ectopic CRH secretion (rare), all of which are characterized by chronic ACTH hypersecretion and increased secretion of cortisol. Causes of ACTH-independent Cushing syndrome include glucocorticoid-secreting adrenocortical adenomas and carcinomas and adrenal micronodular and macronodular hyperplasia, all of which are characterized by autonomous secretion of cortisol and suppression of pituitary ACTH (Figures 21–12 and 21–13).

Cushing Disease

In Cushing disease, there is a persistent overproduction of ACTH by the pituitary adenoma. The ACTH hypersecretion is disorderly, episodic, and random; the normal diurnal rhythm of ACTH and cortisol secretion is usually absent, and midnight values of cortisol are elevated and can be used in diagnostic procedures. Plasma levels of ACTH and cortisol vary and may at times be within the normal range (Figure 21–13). However, a 24-hour urine free cortisol measurement confirms hypercortisolism. The excessive cortisol does not suppress ACTH secretion by the pituitary adenoma.

Most (90%) patients with Cushing disease have exaggerated plasma ACTH and cortisol responses to CRH stimulation and incompletely suppressed secretion of ACTH and cortisol by exogenous glucocorticoids (eg, 1-mg dexamethasone suppression test). Although these findings suggest that the pituitary adenoma cells are unusually sensitive to CRH and relatively resistant to glucocorticoids, the findings may simply be due to the increased number of ACTH-secreting cells. About 10% of patients with pituitary microadenomas do not exhibit major increases in plasma ACTH in response to CRH. Presumably, the clonal cells of such patients have a receptor or postreceptor defect.

Despite ACTH hypersecretion, the pituitary and adrenals fail to respond normally to stress. Stimuli such as hypoglycemia or surgery fail to increase ACTH and cortisol secretion, probably because chronic hypercortisolism has suppressed CRH secretion by the hypothalamus. Hypercortisolism also inhibits other normal pituitary and hypothalamic functions, affecting thyrotropin, growth hormone, and gonadotropin release. Surgical removal of the ACTH-producing pituitary adenoma reverses these abnormalities.

Ectopic ACTH Syndrome

In the ectopic ACTH syndrome, hypersecretion of ACTH and cortisol is random and episodic and quantitatively greater than in patients with Cushing disease (Figure 21–13). Indeed, plasma levels and urinary excretion of cortisol, adrenal androgens, and other steroids are often markedly elevated. Ectopic ACTH secretion by tumors is usually not suppressible by exogenous glucocorticoids such as dexamethasone (Figure 21–14).

Ectopic CRH Syndrome

Clinically, the ectopic CRH syndrome is indistinguishable from the ectopic ACTH syndrome. Biochemically, however, plasma CRH concentrations are elevated (not suppressed), and CRH-stimulated secretion of ACTH is suppressible with high doses of dexamethasone (not so in the ectopic ACTH syndrome). Sometimes, nonpituitary tumors produce both CRH and ACTH ectopically.

Adrenal Tumors

Primary adrenal adenomas and carcinomas are not under hypothalamic-pituitary control and thus autonomously hypersecrete cortisol. The hypercortisolism suppresses pituitary ACTH production, resulting in atrophy of the uninvolved adrenal cortex (Figure 21–12). Steroid secretion is random and episodic and not usually suppressible by dexamethasone. With adrenocortical carcinomas, overproduction of androgenic precursors is common, resulting in hirsutism or virilization of female patients or precocious puberty in children. On the other hand, with adrenal adenomas, production of androgenic precursors is relatively limited. Thus, their clinical manifestations are chiefly those of cortisol excess.

Bilateral Micronodular Hyperplasia

ACTH levels are low, and cortisol is not suppressed by high doses of dexamethasone. This is different from classic primary pigmented nodular adrenocortical disease, where a paradoxical increase in cortisol levels can be observed.

Bilateral Macronodular Hyperplasia

Again, hypercortisolism, low plasma ACTH, loss of diurnal rhythm of ACTH, and lack of suppression with high doses of dexamethasone are found. A subset of patients with bilateral ACTH-independent macronodular adrenal hyperplasia have been found to have abnormal adrenal receptors, including those for gastric inhibitory polypeptide (food-induced hypercortisolism), vasopressin, β-adrenergic agonists, LH/hCG (hypertension during pregnancy and after menopause), or serotonin (5-HT).

Subclinical Cushing Syndrome

With routine use of ultrasound and CT imaging studies, adrenal masses are being detected with increased frequency in asymptomatic patients. Termed “incidentalomas” (see later discussion), a substantial percentage are hormonally active. From 5% to 20% produce glucocorticoids. Such autonomous glucocorticoid production without specific symptoms and signs of Cushing syndrome is termed subclinical Cushing syndrome. With an estimated prevalence of 79 cases per 100,000 persons, subclinical Cushing syndrome is much more common than classic Cushing syndrome. Depending on the amount of glucocorticoid secreted by the tumor, the clinical spectrum ranges from slightly attenuated diurnal cortisol rhythm to complete atrophy of the contralateral adrenal gland with lasting adrenal insufficiency after unilateral adrenalectomy.

Clinical Manifestations

Glucocorticoid excess leads to glucose intolerance in several ways. First, cortisol excess promotes synthesis of glucose in the liver from amino acids liberated by protein catabolism. The increased hepatic gluconeogenesis occurs via stimulation of the enzymes glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. Second, there is an increase in hepatic synthesis of glycogen and ketone bodies. Third, cortisol antagonizes the action of insulin in peripheral glucose utilization, perhaps by inhibiting glucose phosphorylation. The glucose intolerance and hyperglycemia clinically manifest as thirst and polyuria. Overt diabetes mellitus occurs in 10–15% of patients with Cushing syndrome. The diabetes is characterized by insulin resistance, ketosis, and hyperlipidemia, but acidosis and microvascular complications are rare.

With chronic cortisol excess, muscle wasting occurs as a result of excess protein catabolism, decreased muscle protein synthesis, and induction of insulin resistance in muscle via a postinsulin receptor defect. Proximal muscle weakness occurs in about 60% of cases. It is usually manifested by difficulty in climbing stairs or rising from a chair or bed without use of the arms. Fatigue when combing or drying the hair is also seen.

Obesity and redistribution of body fat are probably the most recognizable features of Cushing syndrome. Weight gain is often the initial symptom. The obesity is centralized, with relative sparing of the extremities. The redistribution of adipose tissue affects mainly the face, neck, trunk, and abdomen. Thickening of facial fat rounds the facial contour, producing the “moon facies.” An enlarged dorsocervical fat pad (“buffalo hump”) can occur with weight gain from any cause; increased fat pads that fill and bulge above the supraclavicular fossae are more specific for Cushing syndrome. Abdominal fat deposition results in centripetal obesity, with an elevated waist-to-hip circumference ratio (>1.0 in men and >0.8 in women) in 50% of patients with Cushing syndrome. This fat deposition occurs both subcutaneously and intra-abdominally, most prominently around the viscera, perhaps because intra-abdominal fat appears to have a higher density of glucocorticoid receptors than other fat tissue.

The reason for the abnormal fat distribution is unknown. However, plasma leptin levels are significantly elevated in patients with Cushing syndrome compared with both nonobese healthy individuals and obese individuals with a similar percentage of body fat but no endocrine or metabolic disorder. Leptin is an adipocyte-derived satiety factor that helps to regulate appetite and body weight. The elevated leptin in patients with Cushing syndrome is probably a result of visceral obesity. Glucocorticoids may act, at least in part directly, on adipose tissue to increase leptin synthesis and secretion. Chronic hypercortisolism may also have an indirect effect via the associated hyperinsulinemia or insulin resistance.

Given the known lipolytic effects of glucocorticoids, the increased fat deposition caused by glucocorticoid excess seems paradoxical. It may be explained by the increase in appetite or by the lipogenic effects of the hyperinsulinemia that the cortisol excess causes.

Glucocorticoid excess inhibits fibroblasts, leading to loss of collagen and connective tissue. Thinning of the skin, abdominal striae, easy bruisability, poor wound healing, and frequent skin infections are the result. Atrophy leads to a translucent appearance of the skin. Cutaneous atrophy is best appreciated as a fine “cigarette paper” wrinkling or tenting of the skin over the dorsum of the hand or over the elbow.

On the face, corticosteroid excess causes perioral dermatitis, characterized by small follicular papules on an erythematous base around the mouth, and a rosacea-like eruption, characterized by central facial erythema. Facial telangiectases and plethora over the cheeks may result from loss of subcutaneous tissue with hypercortisolism. Steroid acne, characterized by numerous pustular lesions reflecting androgenic effects or papular lesions reflecting glucocorticoid effects, sometimes occurs on the face, chest, or back. Acanthosis nigricans, a dark, soft, velvety skin with fine folds and papillae, may occur in intertriginous areas, such as under the breasts and in the groin, or at sites of friction, such as the neck or belt line. Acanthosis nigricans is thought to result from two changes in the skin’s extracellular matrix: decreased viscosity caused by altered glycosaminoglycan formation and abnormal deposition of the extracellular matrix in papillae that protrude from the dermis.

Prominent reddish purple striae occur in 50–70% of patients, most commonly over the abdominal wall, breasts, hips, buttocks, thighs, and axillae. The striae result from increased subcutaneous fat deposition, which stretches the thin skin and ruptures the subdermal tissues. These striae are depressed below the skin surface because of loss of underlying connective tissue and are wider (not infrequently 0.5–2.0 cm) than the pinkish-white striae of pregnancy or rapid weight gain. Easy bruisability occurs in about 40% of cases. Ecchymoses occur after minimal trauma, resulting in purpura. Wound healing is delayed, and surgical incisions sometimes undergo dehiscence. Fungal infections of the skin and mucous membranes are frequent, including tinea versicolor, seborrheic dermatitis, onychomycosis, and oral candidiasis.

In the ectopic ACTH syndrome, hyperpigmentation of the skin may occur owing to the markedly elevated level of circulating ACTH, which has some melanocyte-stimulating hormone (MSH)-like activity. However, hyperpigmentation is rare in Cushing disease and is absent in adrenal tumors except after total adrenalectomy (Nelson syndrome).

In about 80% of female patients, hirsutism from increased secretion of adrenal androgens occurs over the face, abdomen, breasts, chest, and upper thighs. Acne often accompanies the hirsutism.

Although the physiologic role of glucocorticoids in bone and Ca²⁺ metabolism is not well understood, excessive glucocorticoid production inhibits bone formation and accelerates bone resorption (see Chapter 17). Glucocorticoids exert direct effects on the main cell types that regulate bone metabolism. They inhibit osteoblast differentiation, inducing osteoblast and osteocyte apoptosis while at the same time prolonging osteoclast survival. As mentioned earlier, hypercortisolism also leads to a state of hypogonadism (due to inhibition of hypothalamic GnRH) in both males and females and therefore reduces the beneficial effect of sex hormones on bone strength.

Furthermore, glucocorticoid excess decreases intestinal Ca²⁺ absorption and increases urinary Ca²⁺ excretion (hypercalciuria), resulting in a negative Ca²⁺ balance. Glucocorticoids impair intestinal absorption and renal tubular reabsorption of Ca²⁺ by inhibiting the effects of vitamin D on the intestine and renal tubules as well as hydroxylation of vitamin D in the liver. There is a secondary increase in PTH secretion, accelerating bone resorption.

As a result of the hypercalciuria, kidney stones occur in about 15% of patients. Such patients may present with renal colic. Glucocorticoids also reduce the renal tubular reabsorption of phosphate, leading to phosphaturia and reduced serum phosphorus concentrations.

The combination of decreased bone formation and increased bone resorption ultimately leads to a generalized loss in bone mass (osteoporosis) and an increased risk of bony fracture. The fracture risk is potentiated by accompanying myopathy that predisposes to falls. Osteoporosis is present in most patients; back pain is an initial complaint in 58% of cases. X-ray films frequently reveal vertebral compression fractures (16–22% of cases), rib fractures, and sometimes multiple stress fractures. For unknown reasons, avascular (aseptic) necrosis of bone (usually of the femur or humerus) occurs sometimes with exogenous (iatrogenic) corticosteroids but is rare with endogenous hypercortisolemia.

Glucocorticoid excess alters the normal inflammatory response to infection or injury by several mechanisms. On the molecular level, glucocorticoids exert their effect by activating the GR which in turn interferes with other transcription factors (eg, nuclear factor kappa-B [NFκB], activator protein [AP1]) necessary for transcription of proinflammatory genes and immune mediators. Generally glucocorticoids decrease the number of CD₄ T lymphocytes and more potently inhibit T_H1-associated cytokines (eg, interleukin 2). They also inhibit fibroblastic activity, preventing the walling off of bacterial and other infections. Therefore, patients with hypercortisolism are more prone to diseases that require a cell-mediated immune response, such as tuberculosis, fungal or Pneumocystis infections.

Glucocorticoid excess also suppresses manifestations of allergic disorders that are due to the release of histamine from tissues.

Hypertension occurs in 75–85% of patients with spontaneous Cushing syndrome. The exact pathogenesis of the hypertension is unclear. It may be related to salt and water retention from the mineralocorticoid effects of the excess glucocorticoid which in high concentrations escape the inactivation by 11β-hydroxysteroid dehydrogenase type 2. Alternatively, it may be due to increased secretion of angiotensinogen. Whereas plasma renin activity and concentrations are generally normal or suppressed in Cushing syndrome, angiotensinogen levels are elevated to approximately twice normal because of a direct effect of glucocorticoids on its hepatic synthesis, and angiotensin II levels are increased by about 40%. Administration of the angiotensin II antagonist saralasin to patients with Cushing syndrome causes a prompt 8- to 10-mm Hg drop in systolic and diastolic blood pressure. Studies in experimental animals have demonstrated that glucocorticoids exert permissive effects on vascular tone by a variety of mechanisms. Some involve vascular smooth muscle cells, including an increased secretion of the vasoconstrictor endothelin, an increase in Ca²⁺ uptake and Ca²⁺ channel antagonist binding, and an increase of α_1B-adrenergic receptors. In addition, glucocorticoids cause a decrease in atrial natriuretic peptide (ANP)-mediated cyclic guanosine monophosphate formation, leading to decreased vasodilation by ANP. Glucocorticoids inhibit nitric oxide synthase in vascular endothelial cells, predisposing to vasoconstriction. Glucocorticoids also sensitize arterioles to the pressor effects of catecholamines.

Gonadal dysfunction occurs commonly in Cushing syndrome and is the result of increased secretion of adrenal androgens (in females) and cortisol (in males and females) from the adrenal cortex. In premenopausal women, the androgens may cause hirsutism, acne, amenorrhea, and infertility. Hypercortisolism appears to affect the hypothalamic gonadotropin-releasing hormone (GnRH) pulse generator to inhibit normal LH and follicle-stimulating hormone (FSH) pulsatility and pituitary responsiveness to GnRH. The high levels of cortisol can thus suppress pituitary LH secretion. In women, this results in menstrual irregularities, including amenorrhea, oligomenorrhea, and polymenorrhea. In men, this results in decreased testosterone secretion by the testis, for which the increased adrenal secretion of weak androgens does not compensate. Decreased libido, loss of body hair, small and soft testes, and impotence ensue.

Excess glucocorticoids frequently produce mental symptoms, including euphoria, increased appetite, irritability, emotional lability, and decreased libido. Many patients experience impaired cognitive function, with poor concentration and poor memory, and disordered sleep, with decreased rapid eye movement sleep and early morning awakening. Glucocorticoid excess also accelerates the basic electroencephalographic rhythm. Significant psychiatric illness—mainly depression but also anxiety, psychosis with delusions or hallucinations, paranoia, or hyperkinetic (even manic) behavior—occurs in 51–81% of patients with Cushing syndrome. The pathogenesis of these CNS effects is not well understood.

Glucocorticoid excess inhibits growth in children, in part by directly inhibiting bone cells and by decreasing growth hormone and thyroid-stimulating hormone (TSH) secretion and somatomedin generation. Glucocorticoids suppress growth also by exerting direct effects on the growth plate, including inhibition of mucopolysaccharide production, resulting in reduced cartilaginous bone matrix and epiphyseal proliferation.

With long-standing hypercortisolism, there may be mild to moderate elevations of intraocular pressure and glaucoma, perhaps related to swelling of collagen strands in the trabecular meshwork, which interferes with aqueous humor drainage. Posterior subcapsular cataracts may develop. About half of patients will develop exophthalmos, which is often asymptomatic. Visual field defects occur in 40% of patients with pituitary macroadenomas related to pressure on the optic chiasm; field defects do not occur with microadenomas.

Routine laboratory tests in Cushing syndrome usually demonstrate a high normal hemoglobin, hematocrit, and red blood cell number. Polycythemia occurs rarely, secondary to androgen excess. The total white blood cell count is usually normal; however, the percentages of lymphocytes and eosinophils and the total lymphocyte and eosinophil counts are frequently subnormal.

Serum electrolytes are usually normal. Hypokalemic metabolic alkalosis sometimes occurs as a result of mineralocorticoid hypersecretion in patients with ectopic ACTH syndrome or adrenocortical carcinoma. Fasting hyperglycemia occurs in about 10–15% of patients; postprandial hyperglycemia and glucosuria are more common. Most patients with Cushing syndrome have secondary hyperinsulinemia and abnormal glucose tolerance tests. The serum Ca²⁺ is generally normal; the serum phosphorus is low normal or slightly low. Hypercalciuria can be demonstrated in 40% of cases.

Patients with subclinical Cushing syndrome lack the classic stigmas of hypercortisolism but frequently have obesity, hypertension, and type 2 diabetes mellitus.

Diagnosis

Suspected hypercortisolism can be investigated by several approaches (see Figure 21–14). Current recommendations involve a stepwise approach to diagnostic evaluation. The first step is to demonstrate pathologic hypercortisolemia and confirm the diagnosis of Cushing syndrome. The second step is to distinguish ACTH-independent disease from ACTH-dependent disease, followed by either adrenal or pituitary imaging. For patients with ACTH-dependent disease, the final step is to determine the anatomic localization of the ACTH source, by MRI or, if equivocal, by inferior petrosal sinus sampling (IPSS) or cavernous sinus sampling (CSS).

Measurement of free cortisol in a 24-hour urine specimen collected on an outpatient basis demonstrates excessive excretion of cortisol (24-hour urinary free cortisol levels >100 μg/24 h). Urinary free cortisol values are rarely normal in Cushing syndrome. Urinary free cortisol measurement is the most specific test to screen for and confirm the presence of Cushing syndrome.

Performance of an overnight 1-mg dexamethasone suppression test will demonstrate lack of the normal suppression of adrenal cortisol production by exogenous corticosteroid (dexamethasone). The overnight dexamethasone suppression test is accomplished by prescribing 1 mg of dexamethasone at 11:00 PM, and then obtaining a plasma cortisol level the next morning at 8:00 AM. In normal individuals, the dexamethasone suppresses the early morning surge in cortisol, resulting in plasma cortisol levels of less than 1.8 μg/dL (50 nmol/L). This cut-off provides high test sensitivity. In Cushing syndrome, cortisol secretion is not suppressed to as great a degree, and values are often more than 10 μg/dL (280 nmol/L).

If the overnight dexamethasone suppression test is normal, the diagnosis is very unlikely; if the urine free cortisol is also normal, Cushing syndrome is excluded. If the results of both tests are abnormal, hypercortisolism is present and the diagnosis of Cushing syndrome can be considered established if conditions causing false-positive results (pseudo-Cushing syndrome) are excluded (acute or chronic illness, obesity, high-estrogen states, drugs, alcoholism, and depression). The CRH test is a useful adjunct in patients with borderline elevated urinary cortisol levels resulting from probable pseudo-Cushing state.

In patients with equivocal or borderline results, a 2-day low-dose dexamethasone suppression test is often performed (0.5 mg every 6 hours for eight doses). Normal responses to this test exclude the diagnosis of Cushing syndrome. Normal responses are an 8:00 AM plasma cortisol level of less than 2 μg/dL (56 nmol/L); a 24-hour urinary free cortisol level of less than 10 μg/24 h (<28 μmol/24 h); and a 24-hour urinary 17-hydroxycorticosteroid level of less than 2.5 mg/24 h (6.9 μmol/24 h) or 1 mg/g creatinine (0.3 mmol/mol creatinine).

Confirmation of the diagnosis of Cushing syndrome entails measurement of plasma ACTH level (Figure 21–14). Assay of the plasma ACTH level helps to differentiate ACTH-dependent from ACTH-independent causes of Cushing syndrome. These tests are then followed by imaging procedures (eg, thin-section CT scan or MRI) to determine the location of a suspected pituitary, adrenal, lung, or other tumor.

With adrenal carcinomas, CT typically demonstrates an inhomogeneous large adrenal mass with irregular margins and variable contrast enhancement of solid components. MRI can also detect these tumors and can assess invasion into large vessels.

Clinically Inapparent Adrenal Mass (Incidentaloma)

Adrenal masses are common. Routine autopsy studies find an adrenal mass in at least 3% of persons older than 50 years. Most of these pose no threat to health, but a small proportion cause endocrinologic problems. Approximately 1 in 4000 adrenal tumors is malignant.

Incidentalomas are clinically inapparent masses discovered incidentally in the course of diagnostic testing or treatment for other clinical conditions. Estimated prevalence of incidentaloma is about 1–2% in patients undergoing routine ultrasonography for nonendocrinologic complaints to 4.3% of patients with a previous diagnosis of cancer. The prevalence rises with age from less than 1% for persons younger than 30 years to 7% for those 70 years or older.

Pathologically, clinically inapparent adrenal masses can be either benign (adenomas, some pheochromocytomas, myelolipomas, ganglioneuromas, adrenal cysts, hematomas) or malignant (adrenocortical carcinomas, some pheochromocytomas, metastases from other cancers). Adrenocortical carcinoma occurs with an estimated incidence of 1–2 per 1 million persons per year. Adrenocortical carcinoma is more likely if the adrenal tumor is large (>4 cm).

Diagnostic evaluation is typically performed to determine whether the lesion is hormonally active or nonfunctioning and whether it is likely to be malignant or benign.

In unselected patients and those without endocrinologic symptoms, most adrenal incidentalomas (>70%) are nonfunctioning tumors. However, up to 20% of patients have subclinical hormonal overproduction; such patients may be at risk for metabolic or cardiovascular disorders. Most common (~5–10%) is cortisol overproduction, sometimes termed subclinical Cushing syndrome. Less common are catecholamine excess from pheochromocytomas and aldosterone excess from adrenal adenomas. Sex hormone excess from virilizing or feminizing tumors is only very rarely observed in benign adenomas. Experts recommend that all patients have a 1-mg dexamethasone suppression test and measurement of plasma (or urinary) free metanephrines, and hypertensive patients should have determinations of serum potassium and plasma aldosterone concentration and plasma renin activity.

Patients with subclinical autonomous glucocorticoid hypersecretion may progress to develop metabolic disorders, such as insulin resistance, or full-blown Cushing syndrome.

The size and appearance of the mass on CT or MRI can help in distinguishing malignant from benign tumors. For example, more than 60% of incidentalomas smaller than 4 cm are benign adenomas and less than 1% are adrenocortical carcinomas. By contrast, for lesions larger than 6 cm, up to 25% are carcinomas and less than 15% are benign adenomas. In addition, if a CT scan reveals a smooth-bordered, homogeneous mass with a low value on a standardized measure of x-ray absorption (CT attenuation value of <10 Hounsfield units), the mass is likely a benign adenoma. Utility of radionuclide scintigraphy and positron emission tomography scanning is unclear. CT-guided fine-needle aspiration biopsy can be helpful in the diagnosis of patients with a history of cancer and a heterogeneous adrenal mass with a high CT attenuation value of more than 20 Hounsfield units.

Surgery is usually recommended for patients with unilateral incidentalomas found on history, physical examination, and laboratory studies to have symptoms, signs, and biochemical evidence of any adrenal hormone excess. Surgery is also recommended for all patients with biochemical evidence of pheochromocytomas, whether symptomatic or not. Management of patients with subclinical hyperfunctioning adrenal cortical adenomas is more controversial; both surgical and nonsurgical approaches are used.

Recommended monitoring consists of a second imaging study 6–12 months later and follow-up endocrinologic studies to exclude hormonal hypersecretion. No further monitoring is recommended for patients with nonsecreting tumors that remain stable in size. Follow-up of patients with nonfunctioning masses shows that the vast majority of incidentalomas remain stable in size: about 5–25% increase in size by 1 cm or more, and 3–4% decrease in size. Overall, 20% or less of nonfunctioning tumors develop hormone overproduction (usually cortisol, rarely catecholamine or aldosterone, hypersecretion) when monitored for up to 10 years. Tumors 3 cm or larger are more likely to develop hyperfunction than smaller masses.

Adrenocortical Insufficiency

Adrenocortical insufficiency generally occurs because of either destruction or dysfunction of the adrenal cortex (primary adrenocortical insufficiency) or deficient pituitary ACTH or hypothalamic CRH secretion (secondary adrenocortical insufficiency). However, congenital defects in any one of several enzymes occurring as “inborn errors of metabolism” can lead to deficient cortisol secretion. Enzyme deficiencies can also result from treatment with various drugs, such as metyrapone, amphenone, and mitotane.

The causes of adrenocortical insufficiency are shown in Table 21–4. No matter what the origin, the clinical manifestations of primary adrenocortical insufficiency are a consequence of deficiencies of cortisol, aldosterone, and androgenic steroids. Secondary adrenal insufficiency results in a selective cortisol (and androgen) deficiency.

Etiology

Primary Adrenocortical Insufficiency

Primary adrenocortical insufficiency (Addison disease) is most often due to autoimmune destruction of the adrenal cortex (~80% of cases). In the past, tuberculosis involving the adrenals was the most common cause, but it has now become uncommon. Other less common causes include histoplasmosis, adrenal hemorrhage or infarction, genetic diseases, metastatic carcinoma, and AIDS-related (cytomegalovirus) adrenalitis.

Primary adrenal insufficiency is rare, with reported prevalence rates of 39–60 cases per 1 million population. Addison disease is somewhat more common in women, with a female-to-male ratio of 1.25:1. It usually occurs in the third to fifth decades.

Autoimmune Adrenocortical Insufficiency—

Autoimmune destruction of the adrenal glands is thought to be related to generation of antiadrenal antibodies. Circulating adrenal autoantibodies can be detected in more than 80% of patients with autoimmune adrenal insufficiency, either isolated or associated with autoimmune polyglandular syndrome type 1 or type 2 (see later discussion). These adrenal autoantibodies are of at least two types: adrenal cortex antibodies (ACA) and antibodies to the steroid 21-hydroxylase enzyme (cytochrome P450c21). The 21-hydroxylase antibodies are highly specific for Addison disease. In asymptomatic patients, these antibodies may also be important predictors for the subsequent development of adrenal insufficiency. When adrenal autoantibodies are present, 41% of patients develop adrenal insufficiency within 3 years. In adults with other organ-specific autoimmune disorders (eg, premature ovarian failure), detection of adrenal cortex or 21-hydroxylase antibodies was associated with progression to overt Addison disease in 21% and to subclinical hypoadrenalism in 29%. In children, the risk was even higher: In those with other organ-specific autoimmune diseases (eg, hypoparathyroidism), detection of adrenal autoantibodies was associated with a 90% risk of overt Addison disease and a 10% risk of subclinical hypoadrenalism. In patients with subclinical adrenal insufficiency and positive ACA and 21-hydroxylase autoantibodies, corticosteroid treatment can lead to disappearance of autoantibodies and recovery of normal adrenocortical function.

Autoantibodies to other tissue antigens are frequently found in patients with autoimmune adrenocortical insufficiency as well. Thyroid antibodies have been found in 45%, gastric parietal cell antibodies in 30%, intrinsic factor antibodies in 9%, parathyroid antibodies in 26%, gonadal antibodies in 17%, and islet cell antibodies in 8%.

It is not surprising, therefore, that autoimmune adrenal insufficiency is frequently associated with other autoimmune endocrine disorders. Two distinct polyglandular syndromes involving the adrenal glands have been described. Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare autosomal recessive disorder caused by a mutation in the autoimmune regulator (AIRE) with onset in childhood. The diagnosis requires at least two of the following: adrenal insufficiency, hypoparathyroidism, and mucocutaneous candidiasis. Other endocrine disorders are sometimes associated, including gonadal failure and type 1 diabetes mellitus. There is also an increased incidence of other nonendocrine immunologic disorders, including alopecia, vitiligo, pernicious anemia, chronic hepatitis, and GI malabsorption. The autoimmune pathogenesis of this condition involves antibody formation against cytochrome P450 cholesterol–side chain cleavage enzyme (P450scc). This enzyme converts cholesterol to pregnenolone, an initial step in cortisol synthesis (see Figure 21–3). P450scc is found in both the adrenal glands and gonads but not in other tissues involved in APS-1.

Autoimmune polyendocrine syndrome type 2 (APS-2) consists of adrenal insufficiency, Hashimoto thyroiditis, and type 1 diabetes mellitus. It is associated with the haplotypes HLA-B8 (DW3) and -DR3. Its pathogenesis involves antibody formation against the 21-OH enzyme mentioned previously. Other autoimmune complications such as vitiligo (4–17%), pernicious anemia, celiac disease, and myasthenia gravis are present in a subset of patients.

Pathologically, the adrenal glands are small and atrophic, and the capsule is thickened. There is an intense lymphocytic infiltration of the adrenal cortex. Cortical cells are absent or degenerating, surrounded by fibrous stroma and lymphocytes. The adrenal medulla is preserved.

Adrenal Tuberculosis—

Tuberculosis causes adrenal failure by total or near-total destruction of both glands. Such destruction usually occurs gradually and produces a picture of chronic adrenal insufficiency. Adrenal tuberculosis usually results from hematogenous spread of systemic tuberculous infection (lung, GI tract, or kidney) to the adrenal cortex. Pathologically, the adrenal is enlarged in the acute phase and is later replaced with caseous necrosis; both cortical and medullary tissue is destroyed. Calcification of the adrenals can be detected radiographically in about 50% of cases.

Bilateral Adrenal Hemorrhage—

Bilateral adrenal hemorrhage leads to rapid destruction of the adrenals and precipitates acute adrenal insufficiency. In children, hemorrhage is usually related to fulminant meningococcal septicemia (Waterhouse-Friderichsen syndrome) or pseudomonas septicemia. In adults, hemorrhage is related to anticoagulant therapy of other disorders in one third of cases. Other causes in adults include sepsis, coagulation disorders (eg, antiphospholipid syndrome), adrenal vein thrombosis, adrenal metastases, traumatic shock, severe burns, abdominal surgery, and obstetric complications.

Pathologically, the adrenal glands are often massively enlarged. The inner cortex and medulla are almost entirely replaced by hematomas. There is ischemic necrosis of the outer cortex, and only a thin rim of subcapsular cortical cells survives. There is often thrombosis of the adrenal veins.

The pathogenesis of such acute adrenal insufficiency is thought to be related to a stress-induced increase in ACTH levels, which markedly increases adrenal blood flow to such a degree that it exceeds the capacity for adrenal venous drainage. Thrombosis may then lead to hemorrhage. In surviving patients, the hematomas may later calcify.

Adrenal Metastases—

Metastases to the adrenals occur frequently from lung, breast, and stomach carcinomas, melanoma, lymphoma, and many other malignancies. However, metastatic disease seldom produces adrenal insufficiency because more than 90% of both adrenals must be destroyed before overt adrenal insufficiency develops. On pathologic examination, the adrenal glands are often massively enlarged.

AIDS-Related Adrenal Insufficiency—

Adrenal insufficiency in AIDS usually occurs in the late stages of HIV infection. The adrenal gland is commonly affected by opportunistic infection (especially cytomegalovirus, disseminated Mycobacterium avium-intracellulare, M tuberculosis, Cryptococcus neoformans, Pneumocystis jirovecii, and Toxoplasma gondii) or by neoplasms such as Kaposi sarcoma. Although pathologic involvement of the adrenal glands is frequent, clinical adrenal insufficiency is uncommon. More than half of patients with AIDS have necrotizing adrenalitis (most commonly resulting from cytomegalovirus infection), but it is usually limited in extent to less than 50–70% of the gland. Because adrenal insufficiency does not occur until more than 90% of the gland is destroyed, clinical adrenal insufficiency occurs in less than 5% of patients with AIDS. Since antiretroviral therapy has improved and fewer patients progress to AIDS, adrenal insufficiency is less often encountered in HIV-positive patients.

However, medications used by AIDS patients can alter steroid secretion and metabolism. Ketoconazole interferes with steroid synthesis by the adrenals and gonads. Rifampin, phenytoin, and opioids increase steroid metabolism.

Genetic Disorders of Adrenal Insufficiency—

These disorders can be subclassified into four categories: 1) congenital adrenal hyperplasia (see disorders of adrenal androgen synthesis below), 2) adrenal hypoplasia congenita with cytomegaly, 3) adrenal hypoplasia congenita without cytomegaly, and 4) degenerative and metabolic diseases affecting adrenal function.

Mutation of the DAX1 gene causes X-linked adrenal hypoplasia congenita with delayed-onset adrenal insufficiency and hypogonadotropic hypogonadism. The adrenal cortex in this disorder consists of peculiarly shaped, large adrenal cells with large nuclei, which leads to the name, cytomegaly.

Adrenal hypoplasia congenita without cytomegaly mainly comprises the ACTH insensitivity syndromes, a group of rare diseases in which resistance to ACTH is either the sole feature or associated with other symptoms. In familial glucocorticoid deficiency (FGD), adrenocortical unresponsiveness to ACTH causes both decreased adrenal secretion of glucocorticoids and androgens and increased pituitary secretion of ACTH. Responsiveness to angiotensin II is normal. Affected infants and young children come to medical attention because of symptoms of cortisol deficiency, especially cutaneous hyperpigmentation, growth retardation, recurrent hypoglycemia, and recurrent infections. Older children may later manifest tall stature related to advanced bone age. The diagnosis is suggested when cortisol secretion does not respond to either endogenous or exogenous ACTH stimulation. On histologic examination, there is preservation of the zona glomerulosa but degeneration of the zona fasciculata and zona reticularis.

To date, there are three genes known to cause the classical disorder of FGD. In FGD-1, the resistance to ACTH is caused by one of several missense mutations within the coding region of the ACTH receptor (MC2R). In FGD-2, the ACTH receptor accessory protein (MRAP), which ensures localization of the ACTH receptor in the plasma membrane has been shown to be mutated and dysfunctional. FGD-4 is caused by mutations in nicotinamide nucleotide transhydrogenase.

Adrenal insufficiency also occurs both in the alacrima, achalasia, and adrenal insufficiency (“triple A”) syndrome and in adrenoleukodystrophy. In both cases, adrenal insufficiency results from progressive destruction of the gland, resulting in deficiencies of androgens, glucocorticoids, and mineralocorticoids (usually in this order).

Secondary Adrenocortical Insufficiency

Secondary adrenocortical insufficiency most commonly results from ACTH deficiency caused by chronic exogenous glucocorticoid therapy. Rarely, ACTH deficiency results from pituitary or hypothalamic tumors or from isolated CRH deficiency. Genetic disorders leading to secondary adrenal insufficiency have also been described (eg, TPIT, POMC mutations, see Chapter 19).

Pathophysiology

Primary Adrenocortical Insufficiency

Gradual adrenocortical destruction, such as occurs in the autoimmune, tuberculous, and other infiltrative diseases, results initially in a decreased adrenal glucocorticoid reserve. Basal glucocorticoid secretion is normal but does not increase in response to stress and surgery; trauma or infection can precipitate acute adrenal crisis. With further loss of cortical tissue, even basal secretion of glucocorticoids and mineralocorticoids becomes deficient, leading to the clinical manifestations of chronic adrenal insufficiency. The fall in plasma cortisol reduces the feedback inhibition of pituitary ACTH secretion (Figure 21–12), and the plasma level of ACTH rises (Figure 21–15).

Rapid adrenocortical destruction such as occurs in septicemia or adrenal hemorrhage results in sudden loss of both glucocorticoid and mineralocorticoid secretion, leading to acute adrenal crisis.

Secondary Adrenocortical Insufficiency

Secondary adrenocortical insufficiency occurs when large doses of glucocorticoids are given for their anti-inflammatory and immunosuppressive effects in treatment of asthma, rheumatoid arthritis, ulcerative colitis, and other diseases. If such treatment is extended beyond 4–5 weeks, it produces prolonged suppression of CRH, ACTH, and endogenous cortisol secretion (Figure 21–12). Should the exogenous steroid treatment be abruptly discontinued, the hypothalamus and pituitary are unable to respond normally to the reduction in level of circulating glucocorticoid. The patient may develop symptoms and signs of chronic adrenocortical insufficiency or, if subjected to stress, acute adrenal crisis. Prolonged suppression of the hypothalamic-pituitary-adrenal axis can be avoided by using alternate-day steroid regimens whenever possible.

ACTH deficiency is the primary problem in secondary adrenocortical insufficiency. The ACTH deficiency leads to diminished cortisol and adrenal androgen secretion, but aldosterone secretion generally remains normal. In the early stages, there is a decreased pituitary ACTH reserve. Basal ACTH and cortisol secretion may be normal but does not increase in response to stress. With progression, there is further loss of ACTH secretion, atrophy of the adrenal cortex, and decreased basal cortisol secretion. At this stage, there is decreased responsiveness not only of pituitary ACTH to stress but also of adrenal cortisol to stimulation with exogenous ACTH.

Clinical Manifestations

The clinical manifestations of glucocorticoid deficiency are nonspecific symptoms: weakness, lethargy, easy fatigability, anorexia, nausea, joint pain, and abdominal pain. Hypoglycemia occurs occasionally. In primary adrenal insufficiency, hyperpigmentation of skin and mucous membranes also occurs. In secondary adrenal insufficiency, hyperpigmentation does not occur, but arthralgias and myalgias may occur. Other clinical features of adrenocortical insufficiency are listed in Table 21–5 and detailed next.

Impaired gluconeogenesis predisposes to hypoglycemia. Severe hypoglycemia may occur spontaneously in children. In adults, the blood glucose level is normal provided there is adequate intake of calories, but fasting causes severe (and potentially fatal) hypoglycemia. In acute adrenal crisis, hypoglycemia may also be provoked by fever, infection, or nausea and vomiting.

In primary adrenal insufficiency, the persistently low or absent plasma cortisol level results in marked hypersecretion of ACTH by the pituitary. Because ACTH has intrinsic MSH activity, a variety of pigmentary changes can occur. These include generalized hyperpigmentation (diffuse darkening of the skin); increased pigmentation of skin creases, nail beds, nipples, areolae, pressure points (such as the knuckles, toes, elbows, and knees), and scars formed after the onset of ACTH excess; increased tanning and freckling of sun-exposed areas; and hyperpigmentation of the buccal mucosa, gums, and perivaginal and perianal areas. These changes do not occur in secondary adrenal insufficiency because ACTH secretion is low, not high, in this condition.

In primary adrenal insufficiency, aldosterone deficiency results in renal loss of Na⁺ and retention of K⁺, causing hypovolemia and hyperkalemia. The hypovolemia, in turn, leads to prerenal azotemia and hypotension. Salt craving has been documented in about 20% of patients with adrenal insufficiency.

Patients may also be unable to excrete a water load. Hyponatremia may develop, reflecting retention of water in excess of Na⁺. The defective water excretion is probably related to increases in posterior pituitary vasopressin secretion, disinhibited by low cortisol levels and increased by the perception of nausea; these can be reduced by glucocorticoid administration. In addition, the glomerular filtration rate (GFR) is low. Treatment with mineralocorticoids raises the GFR by restoring plasma volume, and treatment with glucocorticoids improves the GFR even further.

The inability to excrete a water load may predispose to water intoxication. A dramatic example of this sometimes occurs when untreated patients with adrenal insufficiency are given a glucose infusion and subsequently develop high fever (“glucose fever”), collapse, and die. The pathogenesis of this condition is related to metabolism of the glucose, leaving free water to dilute the extracellular fluid. This dilution results in an osmotic gradient between the interstitial fluid and cells of the hypothalamic thermoregulatory center, which causes cells to swell and malfunction.

In secondary adrenal insufficiency, aldosterone secretion by the zona glomerulosa is preserved. Thus, clinical manifestations of mineralocorticoid deficiency, such as volume depletion, dehydration, hypotension, and electrolyte abnormalities, generally do not occur. Hyponatremia may occur as a result of inability to excrete a water load and increased vasopressin release due to nausea but is not accompanied by hyperkalemia.

Hypotension occurs in about 90% of patients. It frequently causes orthostatic symptoms and occasionally syncope or recumbent hypotension. Hyperkalemia may cause cardiac arrhythmias, which are sometimes lethal. Refractory shock may occur in glucocorticoid-deficient individuals who are subjected to stress. Vascular smooth muscle becomes less responsive to circulating catecholamines, and capillaries dilate and become permeable. These effects impair vascular compensation for hypovolemia and promote vascular collapse. A reversible cardiomyopathy has been described.

Cortisol deficiency commonly results in loss of appetite, weight loss, and GI disturbances. Weight loss is common and, in chronic cases, may be profound (15 kg or more). Nausea and vomiting occur in most patients; diarrhea is less frequent. Such GI symptoms often intensify during acute adrenal crisis.

In women with adrenal insufficiency, loss of pubic and axillary hair may occur as a result of decreased secretion of adrenal androgens. Amenorrhea occurs commonly, in most cases related to weight loss and chronic illness but sometimes as a result of ovarian failure.

CNS consequences of adrenal insufficiency include personality changes (irritability, apprehension, inability to concentrate, and emotional lability), increased sensitivity to olfactory and gustatory stimuli, and the appearance of electroencephalographic waves slower than the normal alpha rhythm.

Patients with acute adrenal crisis have symptoms of fever, weakness, apathy, and confusion. Anorexia, nausea, and vomiting may lead to volume depletion and dehydration. Abdominal pain may mimic that of an acute abdominal process. Evidence suggests that the symptoms of acute glucocorticoid deficiency are mediated by significantly elevated plasma levels of cytokines, particularly IL-6 and, to a lesser extent, IL-1 and TNF. Hyponatremia, hyperkalemia, lymphocytosis, eosinophilia, and hypoglycemia occur frequently. Acute adrenal crisis can occur in patients with undiagnosed ACTH deficiency and in patients receiving corticosteroids who are not given increased steroid dosage during periods of stress. Precipitants include infection, trauma, surgery, and dehydration. Gastrointestinal infections are particularly challenging because of the associated inability to ingest or absorb oral hydrocortisone replacement, which can lead to adrenal crisis despite other treatments. If unrecognized and untreated, coma, severe hypotension, or shock unresponsive to vasopressors may rapidly lead to death.

Laboratory findings in primary adrenocortical insufficiency include hyponatremia, hyperkalemia, occasional hypoglycemia, and mild azotemia (Table 21–6). The hyponatremia and hyperkalemia are manifestations of mineralocorticoid deficiency. The azotemia, with elevations of blood urea nitrogen (BUN) and serum creatinine, is due to volume depletion and dehydration. Mild acidosis is frequently present. Hypercalcemia of mild to moderate degree occurs infrequently.

Hematologic manifestations of adrenal insufficiency include normocytic, normochromic anemia, neutropenia, lymphocytosis, monocytosis, and eosinophilia. Hyperprolactinemia occurs when serum cortisol levels are low. Abdominal x-ray films demonstrate adrenal calcification in about 50% of patients with Addison disease caused by adrenal tuberculosis and in a smaller percentage of patients with bilateral adrenal hemorrhage. CT scans detect adrenal calcification even more frequently in such cases and may also reveal bilateral adrenal enlargement in cases of adrenal hemorrhage; tuberculous, fungal, or cytomegalovirus infection; metastases; and other infiltrative diseases. Electrocardiographic findings include low voltage, a vertical QRS axis, and nonspecific ST wave changes related to electrolyte abnormalities (eg, peak T waves from hyperkalemia).

Diagnosis

Primary Adrenal Insufficiency

To establish the diagnosis of fully developed primary adrenal insufficiency, the physician must demonstrate an inability of the adrenal glands to respond normally to ACTH stimulation. This is usually done by performing an ACTH stimulation test (Figure 21–16). To do so, the physician obtains an 8:00 AM plasma cortisol, then administers 250 μg of synthetic ACTH (cosyntropin) intravenously or intramuscularly. Repeat plasma cortisol levels are obtained 30 and 60 minutes later. Normal individuals demonstrate a rise in plasma cortisol levels to more than 18 μg/dL. Patients with Addison disease have a low 8:00 AM plasma cortisol (and high ACTH) and virtually no increase in plasma cortisol after cosyntropin.

Secondary Adrenocortical Insufficiency

The diagnosis of ACTH deficiency from exogenous glucocorticoids is suggested by obtaining a history of chronic glucocorticoid therapy or by finding cushingoid features on physical examination. Hypothalamic or pituitary tumors leading to ACTH deficiency usually produce symptoms and signs of other endocrinopathies. Deficient secretion of other pituitary hormones such as LH and FSH or TSH may produce hypogonadism or hypothyroidism (see Chapter 19). Excessive secretion of growth hormone or prolactin from a pituitary adenoma may produce acromegaly or amenorrhea and galactorrhea. Unfortunately, the conventional ACTH stimulation test uses a dose (250 μg ACTH) that is supraphysiologic and capable of transiently stimulating the adrenal cortex in some patients with secondary (pituitary or hypothalamic) adrenal insufficiency. The “gold standard” test for diagnosis of secondary adrenal insufficiency is the insulin tolerance test. Injection of insulin leads to hypoglycemia, which is detected by the hypothalamus, subsequently activating the entire hypothalamic-pituitary-adrenal cortex axis, provided that all axis components are intact. A rise of cortisol to more than 18 μg/dL as a response to symptomatic hypoglycemia excludes the diagnosis of secondary adrenal insufficiency.

Hyperaldosteronism (Excessive Production of Mineralocorticoids)

Primary aldosteronism occurs because of excessive unregulated secretion of aldosterone by the adrenal cortex. It is now thought to be the most common potentially curable and specifically treatable cause of hypertension. Secondary hyperaldosteronism occurs because aldosterone secretion is stimulated by excessive secretion of renin by the juxtaglomerular apparatus of the kidney.

The clinical features of hyperaldosteronism may also be due to non-aldosterone-mediated mineralocorticoid excess. Causes include Cushing syndrome; congenital adrenal hyperplasia resulting from 11β-hydroxylase deficiency or 17α-hydroxylase deficiency; the syndrome of apparent mineralocorticoid excess resulting from 11β-hydroxysteroid dehydrogenase (11β-HSD) deficiency; primary glucocorticoid resistance; and Liddle syndrome resulting from activating mutations of the gene encoding for β- and γ-subunits of the renal epithelial sodium channel.

Etiology

The causes of hyperaldosteronism are listed in Table 21–7.

Primary Aldosteronism

Primary aldosteronism usually results from an aldosterone-secreting adenoma of the adrenal cortex (Figure 21–17) or bilateral hyperplasia of its zona glomerulosa. Adenomas are readily identified by their characteristic golden yellow color. The adjacent adrenal cortex may be compressed. Adenomas producing excessive aldosterone are indistinguishable from those producing excessive cortisol except that they tend to be smaller (usually <2 cm in diameter). Primary hyperaldosteronism was traditionally regarded as a rare cause of hypertension and not worth looking for in the absence of hypokalemia. However, the development and application of the ratio of plasma aldosterone concentration to plasma renin activity as a screening test to the population of hypertensives has resulted in a marked increase in detection rate, suggesting that primary aldosteronism is actually quite common in patients with hypertension; most have normal serum potassium levels. Up to 15% of patients diagnosed as having essential hypertension have primary aldosteronism.

Bilateral adrenal hyperplasia accounts for 70% of cases of idiopathic (non-adenoma–related) primary aldosteronism. Affected patients have bilateral nonadenomatous hyperplasia of the zona glomerulosa. Selective adrenal vein sampling looking for lateralized aldosterone secretion is the most reliable means of differentiating a unilateral aldosterone-producing adenoma from bilateral adrenal hyperplasia.

Unilateral adrenal hyperplasia is a rare cause of primary aldosteronism. Selective adrenal-vein sampling to determine plasma aldosterone concentrations can help to define unilaterality of disease.

Adrenocortical carcinomas producing only aldosterone are extremely rare. Such tumors are generally large.

Three different forms of genetic primary aldosteronism have been described. All are inherited in an autosomal dominant fashion.

Type 1 primary aldosteronism is glucocorticoid-remediable aldosteronism. As noted in Chapter 11, affected patients have a “hybrid” 11β-hydroxylase-aldosterone synthase gene in which the 11β-hydroxylase gene’s regulatory elements are fused to the coding region of the aldosterone synthase gene. Therefore, ACTH stimulates aldosterone synthase activity. The hybrid CYP11B1/CYP11B2 gene arises from an unequal crossing over between the two CYP11B genes during meiosis. The hybrid gene can be detected in peripheral blood leukocyte DNA. The clinical phenotype varies from severe early-onset hypertension to much milder blood pressure elevation; hypokalemia is usually mild. Affected individuals apparently have an increased risk of premature stroke. Because expression of the hybrid gene is stimulated by ACTH, leading to increased production of aldosterone and other steroids, the hyperaldosteronism is glucocorticoid suppressible. Treatment with low doses of dexamethasone inhibits ACTH. Type 2 primary aldosteronism has been linked to a locus on chromosome 7p22, but the underlying defect has not been elucidated. Type 3 primary aldosteronism is caused by mutations in KCNJ5, an inward rectifying potassium channel, leading to a loss of cation specificity.

Secondary Hyperaldosteronism

Secondary hyperaldosteronism is common. It results from excessive renin production by the juxtaglomerular apparatus of the kidney. The high renin output occurs in response to (1) renal ischemia (eg, renal artery stenosis or malignant hypertension), (2) decreased intravascular volume (eg, heart failure, cirrhosis, nephrotic syndrome, laxative or diuretic abuse), (3) Na⁺-wasting disorders (eg, chronic kidney disease or renal tubular acidosis), (4) hyperplasia of the juxtaglomerular apparatus (Bartter syndrome), or (5) renin-secreting tumors. In these states, stimulation of the zona glomerulosa by the renin-angiotensin system leads to increased aldosterone production.

Pathologically, in secondary hyperaldosteronism, the adrenals may appear grossly normal, but microscopically there may be hyperplasia of the zona glomerulosa.

Pathophysiology

In primary aldosteronism, there is a primary (autonomous) increase in aldosterone production by the abnormal zona glomerulosa tissue (adenoma or hyperplasia). However, circulating levels of aldosterone are still modulated to some extent by variations in ACTH secretion. The chronic aldosterone excess results in expansion of the extracellular fluid volume and plasma volume. In turn, this expansion is registered by stretch receptors of the juxtaglomerular apparatus and Na⁺ flux at the macula densa, leading to suppression of renin production and low circulating plasma renin activity.

Patients with secondary hyperaldosteronism also produce excessively large amounts of aldosterone but, in contrast to patients with primary hyperaldosteronism, have non-suppressed plasma renin activity.

Clinical Consequences of Mineralocorticoid Excess

The major consequences of chronic aldosterone excess are Na⁺ retention and K⁺ and H⁺ wasting by the kidney.

The excess aldosterone initially stimulates Na⁺ reabsorption by the renal collecting and distal tubules, causing the extracellular fluid volume to expand and the blood pressure to rise. When the extracellular fluid expansion reaches a certain point, however, Na⁺ excretion resumes despite the continued action of aldosterone on the renal tubule. This “escape” phenomenon is probably due to increased secretion of atrial natriuretic peptide. Because the escape phenomenon causes the excretion of excess salt, affected patients are not edematous. Such escape from the action of aldosterone does not occur in the distal tubules. There, the elevated aldosterone levels promote continued exchange of Na⁺ for K⁺ and H⁺, causing K⁺ depletion and alkalosis. Affected patients are not markedly hypernatremic because water is retained along with the Na⁺.

The chronic aldosterone excess also produces a prolonged K⁺ diuresis. Total body K⁺ stores are depleted, and hypokalemia develops. Patients may complain of tiredness, loss of stamina, weakness, nocturia, and lassitude, all symptoms of K⁺ depletion. Prolonged K⁺ depletion damages the kidneys (hypokalemic nephropathy), causing resistance to ADH (vasopressin). The resultant loss of concentrating ability causes thirst and polyuria (especially nocturnal).

When the K⁺ loss is marked, intracellular K⁺ is replaced by Na⁺ and H⁺. The intracellular movement of H⁺, along with increased renal secretion of H⁺, causes metabolic alkalosis to develop.

Hypertension—related to Na⁺ retention and expansion of plasma volume—is a characteristic finding. Hypertension can range from borderline to severe but is usually mild or moderate. Accelerated (malignant) hypertension is extremely rare. Because the hypertension is sustained, however, it may produce retinopathy, renal damage, or left ventricular hypertrophy. For example, patients with primary aldosteronism resulting from aldosterone-producing adenomas have increased wall thickness and mass and decreased early diastolic filling of the left ventricle compared with patients who have essential hypertension. Thus, the chance of curing hypertension with resection of an adrenal adenoma is less predictable than the likelihood of correcting the related biochemical abnormalities. Only 50% of patients with adenomas are normotensive 5 years after adrenalectomy; old patients in particular are more likely to require postoperative antihypertensive medications. Patients with no family history of hypertension and who required two or fewer antihypertensive agents preoperatively are more likely to resolve their hypertension after removal of an adrenal tumor.

The heart may be mildly enlarged as a result of plasma volume expansion and left ventricular hypertrophy. Severely K⁺-depleted patients may develop blunting of baroreceptor function, manifested by postural falls in blood pressure without reflex tachycardia, or even malignant arrhythmias and sudden cardiac death.

The K⁺ depletion causes a minor but detectable degree of carbohydrate intolerance (demonstrated by an abnormal glucose tolerance test). This may be due to impaired pancreatic insulin release and reduction in insulin sensitivity related to the hypokalemia. The decrease in glucose tolerance is corrected after K⁺ repletion.

In addition, the alkalosis accompanying severe K⁺ depletion may lower the plasma Ca²⁺ to the point at which latent or frank tetany occurs (see Chapter 17). The hypokalemia may cause severe muscle weakness, muscle cramps, and intestinal atony. Paresthesias may develop as a result of the hypokalemia and alkalosis. A positive Trousseau or Chvostek sign is suggestive of alkalosis and hypocalcemia (see Chapter 17).

Laboratory findings in hyperaldosteronism include hypokalemia and alkalosis (Table 21–6). Typically, the serum K⁺ is below 3.6 mEq/L (3.6 mmol/L), serum Na⁺ is normal or slightly elevated, serum HCO₃ ⁻ is increased, and serum Cl⁻ is decreased (hypokalemic, hypochloremic metabolic alkalosis). There is an inappropriately large amount of K⁺ in the urine.

The hematocrit may be reduced because of hemodilution by the expanded plasma volume. Affected patients may fail to concentrate urine and may have abnormal glucose tolerance tests.

The plasma renin level is suppressed in primary aldosteronism and elevated in secondary hyperaldosteronism. Adrenal cortisol production is usually unaffected.

The ECG may show changes of modest left ventricular hypertrophy and K⁺ depletion (flattening of T waves and appearance of U waves).

Diagnosis of Hyperaldosteronism

Primary Aldosteronism

In the past, the diagnosis of primary aldosteronism was usually suggested by finding hypokalemia in an untreated patient with hypertension (ie, one not taking diuretics) (Table 21–6). However, a low-Na⁺ intake, by diminishing renal K⁺ loss, may mask total body K⁺ depletion. In patients with normal renal function, dietary salt loading will unmask hypokalemia as a manifestation of total body K⁺ depletion. Thus, finding a low serum K⁺ in a hypertensive patient on a high-salt intake and not receiving diuretics warrants further evaluation for hyperaldosteronism. Currently, the best screening test for primary aldosteronism involves determinations of plasma aldosterone concentration (normal: 1–16 ng/dL) and plasma renin activity (normal: 1–2.5 ng/mL/h), and calculation of the plasma aldosterone-renin ratio (normal: <30). Patients with aldosterone-renin ratios of 30 or more require further evaluation. However, a prerequisite for hyperaldosteronism is an increased aldosterone level of at least 14 ng/dL.

Subsequent workup entails measuring the 24-hour urinary aldosterone excretion and the plasma aldosterone level with the patient on a diet containing more than 120 mEq of Na⁺ per day. On a high-sodium diet, the urinary aldosterone excretion exceeds 14 μg/24 h, and the supine plasma aldosterone is usually greater than 14 ng/dL in primary aldosteronism.

High-resolution CT or MRI of the adrenal glands may help to differentiate between adrenal adenoma and bilateral adrenal hyperplasia. The gold standard for diagnosis is bilateral adrenal venous sampling, which is more sensitive and specific than imaging, to identify a unilateral cause of primary aldosteronism.

Secondary Hyperaldosteronism

Patients with secondary hyperaldosteronism due to malignant hypertension, renal artery stenosis, or chronic renal disease also excrete large amounts of aldosterone but, in contrast to primary aldosteronism, have elevated plasma renin activity.

Hypoaldosteronism: Deficient Mineralocorticoid Production or Action

Primary mineralocorticoid deficiency (hypoaldosteronism) may result from destruction of adrenocortical tissue, which invariably results in both androgen and glucocorticoid deficiency. It can also be caused by defects in adrenal synthesis of aldosterone or inadequate stimulation of aldosterone secretion (hyporeninemic hypoaldosteronism). Resistance to the ion downstream effectors of aldosterone, such as are seen in pseudohypoaldosteronism, cause increased aldosterone levels, but decreased aldosterone action. Hypoaldosteronism is characterized by Na⁺ loss, with hyponatremia, hypovolemia, and hypotension, and impaired secretion of both K⁺ and H⁺ in the renal tubules, resulting in hyperkalemia and metabolic acidosis. Renin activity is typically increased.

A secondary deficiency of endogenous mineralocorticoids may occur when renin production is suppressed or deficient. Renin production may be suppressed by the Na⁺ retention and volume expansion resulting from exogenous mineralocorticoids (fludrocortisone acetate) or substances causing mineralocorticoid-like effects (licorice or carbenoxolone). When this happens, hypertension, hypokalemia, and metabolic alkalosis result. When renin production is deficient and unable to stimulate mineralocorticoid production, Na⁺ loss, hyperkalemia, and metabolic acidosis occur.

Etiology

Acute and chronic adrenocortical insufficiency were discussed previously. In long-standing hypopituitarism, some atrophy of the zona glomerulosa may occur, and the increase in aldosterone secretion normally produced by surgery or other stress is absent. Hyporeninemic hypoaldosteronism (type IV renal tubular acidosis) is a disorder characterized by hyperkalemia and acidosis in association with (usually mild) chronic renal insufficiency. Typically, affected individuals are men in the fifth to seventh decades of life who have underlying pyelonephritis, diabetes mellitus, gout, or nephrotic syndrome. The chronic renal insufficiency is usually not severe enough to account for the hyperkalemia. Plasma and urinary aldosterone levels and plasma renin activity are consistently low and unresponsive to stimulation by upright posture, dietary Na⁺ restriction, or furosemide administration. The syndrome is thought to be due to impairment of the juxtaglomerular apparatus associated with the underlying renal disease. Hyporeninemic hypoaldosteronism also has been described transiently in critically ill patients, such as those with septic shock.

Two genetic disorders may produce the symptoms and signs of hypoaldosteronism. In congenital adrenal hyperplasia, there are enzymatic abnormalities in mineralocorticoid biosynthesis (see below). Mutations in the CYP11B2 gene for 11-hydroxylase cause aldosterone synthase deficiency, an isolated defect of aldosterone biosynthesis. Aldosterone levels are low. In pseudohypoaldosteronism, there is renal tubular resistance to mineralocorticoid hormones. Affected patients manifest symptoms and signs of hypoaldosteronism, but aldosterone levels are high. Pseudohypoaldosteronism type 1 is frequently due to mutations involving the amiloride-sensitive epithelial sodium channel. Gordon syndrome (pseudohypoaldosteronism type 2), characterized by hypertension, hyperchloremic acidemia, hyperkalemia, and intact renal function, is due to resistance to the kaliuretic but not sodium reabsorptive effects of aldosterone. The genetic basis of this condition is still unknown.

Clinical Consequences of Mineralocorticoid Deficiency

Patients undergoing bilateral adrenalectomy, if not given mineralocorticoid replacement therapy, will develop profound urinary Na⁺ losses resulting in hypovolemia, hypotension, and, eventually, shock and death. In adrenal insufficiency, these changes can be delayed by increasing the dietary salt intake. However, the amount of dietary salt needed to prevent them entirely is so large that collapse and death are inevitable unless mineralocorticoid treatment with fludrocortisone acetate is also initiated. Secretion of both K⁺ and H⁺ is impaired in the renal tubule, resulting in hyperkalemia and metabolic acidosis.

Congenital Adrenal Hyperplasia

The adrenal cortex also secretes androgens, principally androstenedione, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEAS). In general, the secretion of adrenal androgens parallels that of cortisol. ACTH is the major factor regulating androgen production by the adrenal cortex. The adrenal androgens are secreted in an unbound state but circulate weakly bound to plasma proteins, chiefly albumin. They are metabolized either by degradation and inactivation or by peripheral conversion to the more potent androgens testosterone and dihydrotestosterone. The androgen metabolites are conjugated either as glucuronides or sulfates and excreted in the urine.

DHEA has both masculinizing and anabolic effects. However, it is less than one fifth as potent as the androgens produced by the testis. Consequently, it has very little physiologic effect under normal conditions. In women, the androgenic steroids (adrenal and ovarian) are thought to be required for the maintenance of libido and the capacity to achieve orgasm.

In congenital adrenal hyperplasia, excessive secretion of adrenal androgens results from one of several enzymatic defects in steroid metabolism. This disorder occurs in both sexes and it is the most common cause of ambiguous genitalia. It is a relatively common disease, occurring in 1 in 5000 to 1 in 15,000 births.

Congenital adrenal hyperplasia is actually a group of autosomal recessive disorders, in each of which, because of an enzyme defect, the bulk of steroid hormone production by the adrenal cortex shifts from corticosteroids to androgens. Congenital adrenal hyperplasia is caused by mutations in the CYP21, CYP11B1, CYP17, and 3βHSD genes that encode steroidogenic enzymes and by mutations in the gene encoding the intracellular cholesterol transport protein, steroidogenic acute regulatory protein (StAR). Each of these defects causes different biochemical and clinical consequences. The name of the syndrome derives from the fact that all of the biochemical defects lead to impaired cortisol secretion, resulting in compensatory hypersecretion of ACTH and consequent hyperplasia of the adrenal cortex. By far, the most frequent cause of congenital adrenal hyperplasia is 21β-hydroxylase deficiency, followed by 11β-hydroxylase deficiency (Figure 21–3). More than 90% of cases are due to deficiency of the enzyme steroid 21β-hydroxylase. The 21β-hydroxylase enzyme (cytochrome P450c21) is encoded by the gene CYP21A2. More than 50 different CYP21A2 mutations have been reported, perhaps accounting for a wide range of congenital adrenal hyperplasia phenotypes. The 15 most common mutations, which constitute 90–95% of alleles, derive from intergenic recombination of DNA sequences between the CYP21A2 gene and a neighboring pseudogene (an inactive gene that is transcribed but not translated). These intergenic CYP21A2 mutations are caused by conversion of a portion of the active CYP21A2 gene sequence into a pseudogene sequence, resulting in a less active or inactive gene (gene conversion).

Other cases of congenital adrenal hyperplasia are related to steroid 11β-hydroxylase (cytochrome P450c11) deficiency. Deletion hybrid genes, because of unequal crossing over between CYP11B1 (11β-hydroxylase) and CYP11B2 (aldosterone synthase), are associated with this form of congenital adrenal hyperplasia. CYP11B1, the gene encoding 11β-hydroxylase, is expressed in high levels in the zona fasciculata and is regulated by ACTH. CYP11B2, the gene encoding aldosterone synthase, is expressed in the zona glomerulosa and is primarily regulated by the renin-angiotensin system.

Impaired CYP21A2 or CYP11B1 activity causes deficient production of both cortisol and aldosterone. The low serum cortisol stimulates ACTH production; adrenal hyperplasia occurs, and precursor steroids—in particular 17-hydroxyprogesterone—accumulate. The accumulated precursors cannot enter the cortisol synthesis pathway and thus spill over into the androgen synthesis pathway, forming androstenedione and DHEA/DHEAS. Prenatal exposure to excessive androgens results in masculinization of the female fetus, leading to ambiguous genitalia at birth. Newborn males have normal genitalia.

During the newborn period, there are two classic presentations of congenital adrenal hyperplasia resulting from classic 21β-hydroxylase deficiency: salt wasting and non-salt wasting (also called “simple virilizing”). Neonates with the salt-wasting form have severe cortisol and aldosterone deficiencies and, if undiagnosed and untreated, will develop potentially lethal adrenal crisis and salt wasting at 2–3 weeks of age. Those with the simple virilizing form have sufficient cortisol and aldosterone production to avoid both adrenal crisis and salt wasting and are usually diagnosed because of virilization between birth and 5 years of age. Postnatally, both sexes present with virilization, reflecting the continuing androgen excess. The excess androgens during childhood can produce pseudoprecocious puberty, premature growth acceleration, early epiphyseal fusion, and adult short stature. Variability in the phenotype occurs, depending on the severity of the 21β-hydroxylase deficiency.

The diagnosis of 21β-hydroxylase-deficient nonclassic adrenal hyperplasia is suggested by finding a morning plasma level of the cortisol precursor 17-hydroxyprogesterone more than 200 ng/dL (12.0 nmol/L) (obtained in women during the follicular phase) or more than 10,000 ng/dL (30.3 nmol/L) after ACTH stimulation (see Figure 21–3). Diagnosis of specific defects is confirmed by genotyping of the relevant genes.

Analysis of DNA obtained by chorionic villus sampling in early pregnancy permits prenatal diagnosis. Administration of dexamethasone to the mother of an affected female fetus may prevent genital ambiguity. Postnatally, lifelong hormonal replacement with hydrocortisone (glucocorticoid) and fludrocortisone (mineralocorticoid) can ensure normal puberty and fertility. Antiandrogen therapy (with flutamide) permits reduction in the dose of hydrocortisone sometimes required to suppress androgen levels.

Yeong Kwok, MD

Case 104

Cushing Syndrome

A 35-year-old woman has hypertension of recent onset. Review of systems reveals several months of weight gain and menstrual irregularity. On examination she is obese, with a plethoric appearance. The blood pressure is 165/98 mm Hg. There are prominent purplish striae over the abdomen and multiple bruises over both lower legs. The patient’s physician entertains a diagnosis of hypercortisolism (Cushing syndrome).

Questions

A. What other features of the history and physical examination should be sought?

Additional features of Cushing syndrome include hirsutism (82%), muscular weakness (58%) and muscular atrophy (70%), back pain (58%), acne (40%), psychologic symptoms (40%), edema (18%), headache (14%), polyuria and polydipsia (10%), and hyperpigmentation (6%).

B. Assuming that the diagnosis of hypercortisolism is correct, what is the underlying pathogenesis of this patient’s hypertension, weight gain, and skin striae?

The exact cause of hypertension in hypercortisolism remains unclear. It may be related to salt and water retention from the mineralocorticoid effects of the excess glucocorticoid, to increased secretion of angiotensinogen or deoxycorticosterone, or to a direct effect of glucocorticoids on blood vessels.

The cause of the obesity and redistribution of body fat seen in Cushing syndrome is also somewhat unclear. It may be explained by the increase in appetite or by the lipogenic effects of hyperinsulinemia caused by cortisol excess. The striae result from increased subcutaneous fat deposition, which stretches the thin skin and ruptures the subdermal tissues. These striae are depressed below the skin surface because of loss of underlying connective tissue.

C. List four causes of Cushing syndrome and discuss the relationships among the hypothalamus, pituitary, and adrenal in each case. Which is the most likely cause in this patient?

Major causes of Cushing syndrome include Cushing disease (ACTH-secreting pituitary adenoma), ectopic ACTH syndrome, functioning adrenocortical adenoma or carcinoma, and long-term high-dose exogenous glucocorticoid intake (iatrogenic Cushing syndrome).

In Cushing disease and in ectopic ACTH syndrome, production of both ACTH and cortisol is excessive. Adrenocortical adenomas or carcinomas are characterized by autonomous secretion of cortisol and suppression of pituitary ACTH. The most likely cause in this patient, a 38-year-old woman with gradual onset of symptoms, is Cushing disease (ACTH-secreting pituitary adenoma).

D. How can the diagnosis of hypercortisolism be established in this patient?

Current recommendations involve a stepwise approach to diagnostic evaluation. The first step is to demonstrate pathologic hypercortisolemia and confirm the diagnosis of Cushing syndrome. Measurement of free cortisol in a 24-hour urine specimen collected on an outpatient basis demonstrates excessive excretion of cortisol (24-hour urinary free cortisol levels >150 μg/24 h) and is the most sensitive and specific screening test for Cushing syndrome. Urinary free cortisol values are rarely normal in Cushing syndrome. Performance of an overnight 1-mg dexamethasone suppression test will demonstrate lack of the normal suppression by exogenous corticosteroid (dexamethasone) of adrenal cortisol production. The overnight dexamethasone suppression test is accomplished by prescribing 1 mg of dexamethasone at 11:00 PM and then obtaining a plasma cortisol level the following morning at 8:00 AM. In normal individuals, the dexamethasone suppresses the early morning surge in cortisol, resulting in plasma cortisol levels of less than 5 μg/dL (0.14 μmol/L); in Cushing syndrome, cortisol secretion is not suppressed to as great a degree, and values are more than 10 μg/dL (0.28 μmol/ L). If the overnight dexamethasone suppression test result is normal, the diagnosis is very unlikely; if the urine free cortisol level is also normal, Cushing syndrome is excluded. If both test results are abnormal, hypercortisolism is present and the diagnosis of Cushing syndrome can be considered established provided that conditions causing false-positive results (pseudo-Cushing syndrome) are excluded (acute or chronic illness, obesity, high-estrogen states, drugs, alcoholism, and depression). The CRH test is a useful adjunct in patients with borderline elevated urinary cortisol levels resulting from probable pseudo-Cushing state. In patients with equivocal or borderline results, a 2-day low-dose dexamethasone suppression test is often performed (0.5 mg every 6 hours for eight doses). Normal responses to this test exclude the diagnosis of Cushing syndrome. Normal responses are an 8:00 AM plasma cortisol less than 5 μg/dL (138 nmol/L); a 24-hour urinary free cortisol less than 10 μg/24 h (<28 μmol/24 h); and a 24-hour urinary 17-hydroxycorticosteroid level less than 2.5 mg/24 h (6.9 μmol/24 h) or 1 mg/g creatinine (0.3 mmol/mol creatinine).

The second step is to distinguish ACTH-independent disease from ACTH-dependent disease (Figure 21–14) with assay of the plasma ACTH level. The high-dose dexamethasone suppression test is useful for differentiating pituitary from ectopic ACTH secretion.

The final step for patients with ACTH-dependent disease is to determine the anatomic localization of the ACTH source by MRI or thin-section CT (pituitary, adrenal, lung, or other) or, if equivocal, by inferior petrosal sinus sampling (IPSS) or cavernous sinus sampling (CSS).

Case 105

Adrenal “Incidentaloma”

A 56-year-old man undergoes an abdominal computed tomography (CT) scan in the evaluation of abdominal pain. The scan is unremarkable except for the finding of a 3-cm mass in the right adrenal gland. The mass is homogeneous and smooth, and it has low x-ray absorption on the CT scan. The patient has a normal examination and feels well otherwise.

Questions

A. What other features of the history and physical examination should be sought?

An incidentally found adrenal mass is often referred to as an adrenal incidentaloma. The mass could be an adrenal adenoma or a non-adenoma, which could be a malignancy (primary adrenocortical carcinoma, pheochromocytoma, or a metastatic cancer from a different source), infiltrating process, hemorrhage, or cyst. The evaluation of an adrenal mass requires both a functional and an anatomic workup. The functional evaluation is to determine whether the mass is producing excess adrenal hormone by performing a dexamethasone suppression test (or 24-hour urine free cortisol) to exclude hypercortisolism, by measuring the plasma or urinary metanephrines to exclude pheochromocytoma, and by measuring the serum potassium and aldosterone-to-renin ratio to exclude hyperaldosteronism.

B. What follow-up needs to be pursued and why?

Anatomically, the lesion needs to be evaluated to determine level of concern for malignancy. Lesions like the one in this patient that are small (<3 cm) and homogenous and low in signal intensity (<10 HU) are likely benign, lipid-rich adenomas. Lesions that are large (>6 cm), heterogenous, and not low in signal intensity can be malignant. Lesions that are functional and those that do not fulfill the criteria for benignity are usually removed. A mass that is not removed is followed up with one surveillance CT scan 6–12 months later to ensure that it is not enlarging, which would suggest malignancy. Clinical and/or hormonal reevaluation can be repeated periodically if the patient develops symptoms consistent with a hyperfunctional adrenal tumor since nonfunctioning adenomas may (rarely) develop hormone overproduction at a later time.

Case 106

Adrenocortical Insufficiency

A 38-year-old woman presents for annual follow-up of previously diagnosed Hashimoto thyroiditis, for which she has been receiving thyroid replacement therapy (levothyroxine, 0.15 mg/d). She reports a gradual onset of weakness, lethargy, and easy fatigability over the last 3 months. Review of systems reveals only recent menstrual irregularity, with no menses in 2.5 months. Blood pressure is 90/50 mm Hg (compared with previous readings of 110/75 and 120/80 mm Hg), and her weight is down 13 pounds since her last visit 11 months ago. The skin appears to be tanned, but the patient denies sun exposure. The physician seeing her wonders whether she has now developed adrenal insufficiency (Addison disease).

Questions

A. What other features of the history and physical examination should be sought?

Other symptoms of chronic adrenal insufficiency include anorexia, nausea, vomiting, hypoglycemia, and personality changes. The examiner should look also for orthostatic changes in blood pressure and pulse, hyperpigmentation of the mucous membranes and other areas, vitiligo, and loss of axillary and pubic hair.

B. If Addison disease has developed, what should the serum electrolytes show, and why?

The serum sodium is typically low and the serum potassium high. In Addison disease, the deficiency of cortisol is associated with a deficiency of aldosterone, resulting in unregulated renal loss of sodium and retention of potassium. Additional blood chemistry findings suggesting Addison disease include mild acidosis, azotemia, and hypoglycemia.

C. How can the diagnosis of adrenal insufficiency be established in this patient?

The diagnosis of hypoadrenocorticism can be established by performing an ACTH stimulation test. In Addison disease, there is a low 8:00 AM plasma cortisol and virtually no increase in plasma cortisol 30 minutes and 60 minutes after administration of 250 μg of synthetic ACTH (cosyntropin) intravenously or intramuscularly. At a specificity of 95%, the sensitivity of the 250-μg cosyntropin stimulation test is 97% for primary adrenal insufficiency.

D. What is the pathogenesis of the hypotension, weight loss, and skin hyperpigmentation?

Hypotension, including recumbent hypotension, occurs in about 90% of patients with Addison disease and may cause orthostatic symptoms and syncope. These symptoms are related to the volume contraction resulting from unregulated renal losses of sodium.

Cortisol deficiency commonly results in loss of appetite and in GI disturbances, including nausea and vomiting. Weight loss is common and, in chronic cases, may be profound (≥15 kg).

In primary adrenal insufficiency, the persistently low or absent plasma cortisol level results in marked hypersecretion of ACTH by the pituitary. ACTH has intrinsic melanocyte-stimulating hormone activity, causing a variety of pigmentary changes in the skin, including generalized hyperpigmentation.

Case 107

Hyperaldosteronism (Primary Aldosteronism)

A 42-year-old man presents for evaluation of newly diagnosed hypertension. He is currently taking no medications and offers no complaints. A careful review of systems reveals symptoms of fatigue, loss of stamina, and frequent urination, particularly at night. Physical examination is normal except for a blood pressure of 168/100 mm Hg. Serum electrolytes are reported as follows: sodium, 152 mEq/L; potassium, 3.2 mEq/L; bicarbonate, 32 mEq/L; chloride, 112 mEq/L. The clinical picture is consistent with a diagnosis of primary aldosteronism.

Questions

A. What is the mechanism by which primary aldosteronism causes the history, physical examination, and laboratory findings in this patient?

The major consequences of chronic aldosterone excess are sodium retention and potassium and hydrogen ion wasting by the kidney. Aldosterone binds to a mineralocorticoid receptor in the cytosol. The steroid-receptor complex then moves into the nucleus of the target cell and increases transcription of DNA, induction of mRNA, and stimulation of protein synthesis by ribosomes. The aldosterone-stimulated proteins have two effects: a rapid effect, to increase the activity of epithelial sodium channels (ENaCs) by increasing the insertion of ENaCs into the cell membrane from a cytosolic pool, and a slower effect to increase the synthesis of ENaCs. One of the genes activated by aldosterone is the gene for serum- and glucocorticoid-regulated kinase (sgk), a serine-threonine protein kinase. The sgk gene product increases ENaC activity (Figure 21–10). Aldosterone also increases the mRNAs for the three subunits that comprise the ENaCs. Aldosterone also binds directly to distinct membrane receptors with a high affinity for aldosterone and, by a rapid, nongenomic action, increases the activity of membrane Na⁺-K⁺ exchangers to increase intracellular Na⁺. In the distal renal tubules and collecting ducts, aldosterone acts to promote the exchange of Na⁺ for K⁺ and H⁺, causing Na⁺ retention, K⁺ diuresis, and increased urine acidity. Elsewhere, it acts to increase the reabsorption of Na⁺ from the colonic fluid, saliva, and sweat. Increased sodium is associated with fluid retention, blunting the hypernatremia. The net effect in primary aldosteronism is the mild hypernatremia, hypokalemia, and acidosis seen in this patient.

Hypertension results from this underlying sodium retention and subsequent expansion of plasma volume. The prolonged potassium diuresis produces symptoms of potassium depletion, including muscle weakness, muscle cramps, nocturia (frequent nighttime urination), and lassitude. Blunting of baroreceptor function, manifested by postural falls in blood pressure without reflex tachycardia, may develop.

B. What should the urinalysis and measurement of urine electrolytes show, and why?

Prolonged potassium depletion damages the kidney (hypokalemic nephropathy), causing resistance to antidiuretic hormone (vasopressin). Patients may be unable to concentrate urine (nephrogenic diabetes insipidus), resulting in symptoms of thirst and polyuria and the finding of a low urine specific gravity (<1.010). Urinary electrolytes show an inappropriately large amount of potassium in the urine.

C. How can the diagnosis of primary aldosteronism be established in this patient?

The diagnosis of primary aldosteronism is already suggested by finding hypokalemia in an untreated patient with hypertension. Currently, the best screening test for primary aldosteronism involves determinations of plasma aldosterone concentration (normal: 1–16 ng/dL) and plasma renin activity (normal: 1–2.5 ng/mL/h), and calculation of the plasma aldosterone-renin ratio (normal: <25). Patients with aldosterone-renin ratios of 25 or more require further evaluation.

Subsequent workup entails measuring the 24-hour urinary aldosterone excretion and the plasma aldosterone level with the patient on a diet containing more than 120 mEq of Na⁺ per day. The urinary aldosterone excretion exceeds 14 μg/d, and the plasma aldosterone is usually more than 90 pg/mL in primary aldosteronism. High-resolution CT or MRI of the adrenal glands can also help to differentiate between adrenal adenoma and bilateral adrenal hyperplasia. The gold standard for diagnosis is bilateral adrenal venous sampling, which is more sensitive and specific than imaging, to identify a unilateral cause, namely, an adrenal adenoma causing the primary aldosteronism.

Case 108

Type 4 Hyporeninemic Hypoaldosteronism

A 64-year-old man with a long history of gout and type 2 diabetes mellitus comes in for a routine checkup. Serum chemistries are as follows: sodium, 140 mEq/L; potassium, 6.3 mEq/L; bicarbonate, 18 mEq/L; BUN, 43 mg/dL; creatinine, 2.9 mg/dL; glucose, 198 mg/dL. Chart review shows previous potassium values of 5.3 mEq/L and 5.7 mEq/L. The patient is currently taking only colchicine, 0.5 mg daily, and glyburide, 5 mg twice daily.

Questions

A. What is the most likely cause of this patient’s hyperkalemia, and what is its pathogenesis?

This patient probably has hyporeninemic hypoaldosteronism (type IV renal tubular acidosis), a disorder characterized by hyperkalemia and acidosis in association with (usually mild) chronic kidney disease. The syndrome is thought to be due to impairment of renin production by the juxtaglomerular apparatus, associated with underlying renal disease. Chronic kidney disease is usually not severe enough by itself to account for the hyperkalemia. Impaired secretion of both potassium and hydrogen ion in the renal tubule causes the observed hyperkalemia and metabolic acidosis.

B. What are other possible causes of hypoaldosteronism?

Other causes of hypoaldosteronism include (1) bilateral adrenalectomy; (2) acute or chronic adrenocortical insufficiency; (3) ingestion of exogenous mineralocorticoids (fludrocortisone) or inhibitors of the 11β-hydroxysteroid dehydrogenase type 2 enzyme (licorice), leading to sodium retention, volume expansion, and suppression of renin production; (4) long-standing hypopituitarism, resulting in atrophy of the zona glomerulosa; (5) congenital adrenal hypoplasia, caused by one or more enzymatic abnormalities in mineralocorticoid biosynthesis; and (6) pseudohypoaldosteronism, in which there is renal tubular resistance to mineralocorticoid hormones, presumably because of a deficiency of mineralocorticoid hormone receptors.

C. Plasma renin activity and aldosterone levels are sent to the laboratory. What results should be anticipated?

Plasma and urinary aldosterone levels and plasma renin activity are consistently low and unresponsive to stimulation by ACTH administration, upright posture, dietary sodium restriction, or furosemide administration.

Case 109

Congenital Adrenal Hyperplasia

A newborn full-term male infant is screened for 21-hydroxylase deficiency at birth and is noted to have a high 17-hydroxyprogesterone level on a heel stick blood sample. Both parents are healthy, and there is no history of hormonal problems in the family. The baby appears normal with normal vital signs and physical examination. He is brought back for a repeat examination at 2 weeks, and repeat blood tests show a still elevated 17-hydroxyprogesterone level, a sodium of 125 mEq/L, a potassium of 5.6 mEq/L, and a glucose of 60 mg/dL. He is suspected of having the salt wasting form of congenital adrenal hyperplasia.

Questions

A. Why do most newborns undergo screening for this condition?

Congenital adrenal hyperplasia is a relatively common disease, occurring in 1 in 5000–1 in 15,000 births. By far, the most frequent cause of congenital adrenal hyperplasia is 21β-hydroxylase deficiency. During the newborn period, there are two classic presentations of congenital adrenal hyperplasia resulting from classic 21β-hydroxylase deficiency: salt wasting and non-salt wasting (also called “simple virilizing”). Neonates with the salt-wasting form have severe cortisol and aldosterone deficiencies and, if undiagnosed and untreated, will develop potentially lethal adrenal crisis and salt wasting at 2–3 weeks of age. Since this is a serious condition that is relatively common with a known treatment, it is sensible to screen newborns for this condition.

B. What are the genetic abnormalities in this condition?

More than 90% of cases are due to deficiency of the enzyme steroid 21β-hydroxylase. The 21β-hydroxylase enzyme (cytochrome P450c21) is encoded by the gene CYP21A2. More than 50 different CYP21A2 mutations have been reported, perhaps accounting for a wide range of congenital adrenal hyperplasia phenotypes. The 15 most common mutations, which constitute 90–95% of alleles, derive from intergenic recombination of DNA sequences between the CYP21A2 gene and a neighboring pseudogene (an inactive gene that is transcribed but not translated). These intergenic CYP21A2 mutations are caused by conversion of a portion of the active CYP21A2 gene sequence into a pseudogene sequence, resulting in a less active or inactive gene (gene conversion).

C. How does this disorder lead to ambiguous genitalia in female infants?

Impaired CYP21A2 or CYP11B1 activity causes deficient production of both cortisol and aldosterone. The low serum cortisol stimulates ACTH production; adrenal hyperplasia occurs, and precursor steroids—in particular 17-hydroxyprogesterone—accumulate. The accumulated precursors cannot enter the cortisol synthesis pathway and thus spill over into the androgen synthesis pathway, forming androstenedione and DHEA/DHEAS. Prenatal exposure to excessive androgens results in masculinization of the female fetus, leading to ambiguous genitalia at birth. Newborn males have normal genitalia.