Figure 49.1. Feedback Regulation of the HPA System. The hypothalamic-pituitary-adrenal Axis. The main sites for feedback control for plasma cortisol are the pituitary gland, hypothalamus, and higher centers of the brain. There is a short feedback loop involving the inhibition of CRH by ACTH. There is a negative feedback control of cortisol over the pituitary and hypothalamus. Inflammatory cytokines in response to stress lead to increased cortisol via the hypothalamus and the cortisol produced in turn suppress the proinflammatory cytokines. NOTES: (–) suppression; (+) stimulation; ACTH, adrenocorticotropic hormone; CRH, corticotropin releasing hormone; DHEA, dehydroepiandrostenedione; POMC, proopiomelanocortin; IL, interleukin; TNF, tumor necrosis factor. SOURCE: Reproduced from Adrenal Imaging, 2009, Adrenal Cortical Dysfunction, Trikudanathan S, Dluhy RG, Fig 2.2. With kind permission of Humana Press part of Springer Science and Business media.

    Several factors influence ACTH release—CRH, arginine vasopressin (AVP), circadian rhythm, stress, and free cortisol levels. ACTH has a pulsatile secretion pattern and follows a circadian rhythm, with the peak levels prior to waking and nadir values in the late evening. The sleep–wake pattern, which is disturbed by long-distance travel across time zones or by night-shift working, takes about 2 weeks to reset. Stress such as fever, surgery, hypoglycemia, exercise, and acute emotions trigger the release of CRH, AVP, and subsequently ACTH; the sympathetic nervous system is also activated. Immune–endocrine interaction occurs when proinflammatory cytokines (particularly interleukin-1, interleukin-6, and tumor necrosis factor-α) augment the effects of CRH and AVP on ACTH secretion. Finally, negative feedback control of ACTH secretion is exerted by free plasma cortisol, whereby cortisol inhibits POMC gene transcription in the anterior pituitary gland and CRH and AVP secretion in the hypothalamus. Cortisol also stimulates the higher brain centers (such as the hippocampus and reticular system) and inhibits the locus coeruleus/sympathetic system. Chronic administration of corticosteroids suppresses the hypothalamic-pituitary-adrenal (HPA) axis, which persists for months after cessation of treatment.

PHYSIOLOGICAL ACTIONS OF GLUCOCORTICOIDS

Glucocorticoids play a pivotal role in the intermediary metabolism of carbohydrate, protein, and fat. Glucocorticoids increase the blood glucose concentration by increasing hepatic glycogen synthesis and stimulating gluconeogenesis. Glucocorticoids also exert an anti-insulin action in the peripheral tissues by reducing glucose uptake. Consequently, increased glucocorticoid actions result in insulin resistance and an increase in blood glucose concentrations in the setting of increased protein and lipid catabolism.

    Excess cortisol leads to increased deposition of adipose tissue centrally in the viscera as opposed to the periphery. Excess glucocorticoids cause muscle atrophy by catabolic actions as well as by reducing the protein synthesis in muscle. In the skeleton, osteoblastic activity is inhibited leading to osteoporosis in glucocorticoid excess. Glucocorticoids suppress the inflammatory cytokines and impair cell-mediated immunity. Glucocorticoids increase neutrophil counts by demargination of neutrophils with depletion of the eosinophils. Changes in cortisol levels affect mood, implicating the brain as an important target of this hormone.

CUSHING SYNDROME

Cushing syndrome results from prolonged and inappropriate exposure to elevated levels of glucocorticoids. Endogenous hypercortisolism or Cushing syndrome is caused by excessive secretion of ACTH secretion from either the pituitary (Cushing disease—70%), or from ectopic nonpituitary source/tumors (15%), or from excessive cortisol secretion by adrenal tumors (15%). However, the most common cause of Cushing syndrome is iatrogenic from medical prescription of steroids. Box 49.1 enumerates the causes of Cushing syndrome. Rare causes of ACTH-independent Cushing syndrome include macronodular hyperplasia and PPNAD (micronodular hyperplasia). PPNAD can be sporadic or, most often, a part of Carney’s complex. Carney’s complex is an autosomal dominant disorder characterized by skin pigmentation, endocrine tumors (most prominently PPNAD) and non-endocrine tumors such as cutaneous myxomas, cardiac myxoma, and schwannomas.

Box 49.1 CAUSES OF CUSHING SYNDROME

Clinical Features of Cushing Syndrome

The prominent features of Cushing syndrome include central or truncal obesity with increased fat depots in distinctive sites such as the dorsocervical area (buffalo hump), supraclavicular fat pads, and the mesenteric bed. The extremities are depleted of fat and appear thin. Patients develop moon face, hirsutism, and facial plethora. Signs of protein wasting are characteristically seen with thin skin, easy bruisability, broad violaceous cutaneous striae, and proximal myopathy. Osteoporosis may occur with vertebral fractures. Glucose intolerance occurs owing to insulin resistance, with overt diabetes mellitus in about 20% of the patients. Imaging studies show hepatic steatosis and increased visceral fat. Cortisol excess predisposes to hypertension and thereby increases the cardiovascular risk. In women increased levels of adrenal androgens can lead to acne, hirsutism, and menstrual abnormalities such as oligomenorrhea and amenorrhea. Emotional dysfunction ranging from irritability to depression or even frank psychosis may occur. Wound infections are common and contribute to poor wound healing. The spectrum of clinical presentation is broad and overlaps with many common conditions such as simple obesity, and hence the diagnosis can be challenging. The morbidity and mortality from Cushing syndrome occur mostly from cardiovascular complications, followed by infectious causes.

Screening for Cushing Syndrome

Initial testing for Cushing syndrome should be done in patients with clinical features suggestive of Cushing syndrome or in patients with adrenal incidentaloma. It is reasonable to screen patients with unusual features for their age that could reflect hypercortisolism such as osteoporosis, hypertension, or easy bruising. Studies have shown that Cushing syndrome is prevalent in 2–5% of poorly controlled diabetic patients.

    Initial screening for Cushing syndrome should demonstrate increased cortisol production and/or failure to suppress cortisol secretion when exogenous glucocorticoid (dexamethasone) is administered. Once the diagnosis of hypercortisolism is ascertained, the etiology should be sought. The following tests are useful and complementary as initial diagnostic studies for Cushing syndrome: measurement of urinary free cortisol levels, late-night salivary cortisol, overnight dexamethasone suppression test (DST), and low-dose DST.

    Measurement of 24-hour urinary free cortisol (along with urinary creatinine to ascertain the completeness of collection) is useful to diagnose hypercortisolism. It measures the cortisol that is not bound to CBG, which is filtered by the kidney unchanged and not reabsorbed. Urinary free cortisol (UFC) should not be measured in patients with moderate to severe renal impairment. UFC can also be normal if a patient has cyclic disease or mild Cushing syndrome. False-positive results are seen in any physiological state that increases cortisol production; hence, two measurements done on separate occasions may be needed. Normal values are <80–120 μg/24 hour depending on the assay. The normal circadian rhythm is lost in Cushing syndrome; values of plasma midnight cortisol >2 µg/dL are diagnostic. Although this is a sensitive test and specific, patients require hospitalization for this investigation to avoid any patient influence of stress on cortisol levels; hence it is not a widely used screening test. Salivary cortisol also reflects the amount of free circulating cortisol; a midnight level or a late-night salivary sample collected between 23:00 and 24:00 hours can be a valuable test and obviates hospitalization. Alteration of sleep–wake cycles (e.g., shift work) can produce false-positive results.

    A simple outpatient screening test is the overnight DST (1 mg of dexamethasone at bedtime). Currently, to enhance the sensitivity of this test, a cortisol level >1.8 µg/dL the next morning between 8 and 9 a.m. supports the diagnosis of Cushing syndrome. This may be followed by the low-dose DST (0.5 mg every 6 hours for 48 hours), which has greater specificity. Failure of urinary cortisol to fall <9 μg/day or of plasma cortisol to fall <1.8 µg/dL establishes the diagnosis of autonomous cortisol production.

Investigations to Identify the Cause of Cushing Syndrome

Once a diagnosis of hypercortisolism is confirmed, the next step is to confirm the etiology. Measurement of plasma ACTH level would help distinguish between the ACTH-dependent and ACTH-independent causes. A low or undetectable ACTH level (<9 pg/mL) diagnoses primary adrenal disorders. In pituitary ACTH-secreting microadenomas (Cushing disease) the ACTH levels are inappropriately normal or modestly elevated (27–136 pg/mL), whereas in pituitary macroadenomas and ectopic ACTH syndrome, ACTH values will be two- or threefold elevated.

    In cortisol-producing adrenal adenomas the ACTH level is suppressed or undetectable. There is also suppression in plasma dehydroepiandrosterone sulfate (DHEAS) as adrenal androgen production is reduced as a result of ACTH suppression. In adrenal carcinomas hypercortisolism is often accompanied by increased androgen secretion. The steroid production in adrenal carcinoma is usually resistant to ACTH stimulation and dexamethasone suppression. Patients with primary adrenal disorders should undergo high-resolution computed tomography (CT) scanning of the abdomen.

    To distinguish the etiologies of ACTH-dependent Cushing syndrome, high-dose dexamethasone suppression testing (HDDST) (2 mg every 6 hours for 2 days) may be used. Pituitary macroadenoma and ectopic ACTH production show no suppression, whereas there is usually suppression of 50% or greater of plasma cortisol in ACTH-secreting pituitary microadenomas.

    Imaging study of the pituitary (usually magnetic resonance imaging [MRI] with gadolinium) is the initial imaging study in ACTH-dependent Cushing syndrome; however, it may not always demonstrate a pituitary lesion in patients with Cushing disease. It is also important to keep in mind that 10–20% of normal patients have nonfunctioning pituitary “incidentalomas.” In most circumstances inferior petrosal sinus sampling (IPSS) is needed to prove pituitary hypersecretion of ACTH. Blood from each half of the pituitary drains into the cavernous sinus and then into ipsilateral inferior petrosal sinus. Catheterization and venous sampling for measurement of ACTH from both the sinuses simultaneously compared to a peripheral sample would differentiate a pituitary source from an ectopic source. In pituitary ACTH-secreting tumor the ratio of ACTH concentrations from the inferior petrosal sinus to simultaneously drawn peripheral blood would be greater than twofold basally and greater than threefold after CRH injection. Thus, IPSS is a highly sensitive and specific test to distinguish between pituitary and nonpituitary sources of ACTH excess. However, IPSS is technically demanding, and complications such as thrombosis can occur; therefore, this test should be performed in an experienced center.

    To locate sources for ectopic ACTH production, it would be reasonable to start with a CT scan of the chest and abdomen searching for a mass. Positron emission tomography (PET) scanning would be a second test if CT scanning is negative. Octreotide scanning can also be useful to image ACTH-producing neuroendocrine tumors such as carcinoids. In spite of meticulous investigations, the ectopic ACTH cause for Cushing syndrome can remain occult in about 5–15% of patients; such patients need periodic radiographic reassessment.

DIFFERENTIAL DIAGNOSIS

Pseudo-Cushing Syndrome

Obesity, chronic alcoholism, and depression can mimic the biochemical abnormalities seen in Cushing syndrome. For example, chronic excessive alcohol intake and depression may cause mild elevation in urinary free cortisol, blunted circadian rhythmicity, and resistance to suppression with dexamethasone. However, these patients usually do not have the more reliable clinical features of Cushing syndrome such as proximal myopathy and easy bruisability. Following discontinuation of alcohol or with relief of depression, steroid testing returns to normal.

Management

Surgical resection of the pituitary adenoma using the transsphenoidal approach is the first line of therapy for Cushing disease. Remission in the hands of an experienced surgeon is in the range of 65–90% for microadenomas and 50% for macroadenomas. After removal of the ACTH-producing pituitary adenoma, the normal corticotropes are suppressed; hence, patients need glucocorticoid treatment postoperatively until the HPA axis recovers. A postoperative morning serum cortisol level of <2 µg/dL the day after surgery is suggestive of remission and possible surgical cure. In the past, bilateral adrenalectomy was performed for Cushing disease; that led to the subsequent development of Nelson syndrome in 10–20% of patients—an aggressive ACTH-secreting pituitary macroadenoma. Presumably the ACTH-secreting pituitary tumor escaped feedback inhibition of the hypercortisolism. Pituitary irradiation may be used for patients with postoperative recurrence and in Nelson syndrome. In other centers, gamma knife and stereotactic techniques have been used to treat pituitary adenomas.

    In ectopic ACTH syndrome, tumor-directed therapy involving resection of the primary tumor (e.g., bronchial carcinoid) can lead to cure. However, the prognosis remains poor for small cell lung tumors, and medical therapy inhibiting steroidogenesis is indicated for symptoms of cortisol excess.

    Laparoscopic adrenalectomy is preferred for adrenal adenomas. Adrenal carcinomas carry a poor prognosis with dismal 5-year survival rates. Adrenal carcinomas are neither radiosensitive nor chemosensitive, although mitotane has been shown to improve disease-free survival if administered adjunctively following surgical resection of the neoplasm. The best predictor of outcome is the ability to do a complete surgical resection. A recent clinical trial showed significantly better response rate and progression-free survival with etoposide and mitotane based combination therapies.

Medical Therapies for Cushing Syndrome

Drugs can be used to treat hypercortisolism by inhibiting steroidogenesis: metyrapone, ketoconazole, and mitotane. Metyrapone inhibits 11β-hydroxylase while ketoconazole blocks cytochrome P450-dependent enzymes. These drugs can be used preoperatively or as adjunctive treatment following surgery or radiotherapy. Mitotane inhibits steroidogenesis but in some patients is also cytotoxic to the adrenal gland. Its use is primarily for adrenal carcinoma because of its potential cytotoxicity.

    Pasireotide, a novel somatostatin analogue with high affinity to somatostatin-receptor subtype 5 has been recently approved by FDA for Cushing disease. As ACTH-producing adenomas highly express somatostatin- receptor subtype 5, activation of this receptor inhibits the secretion of ACTH. In clinical trials, pasireotide reduced urinary free cortisol and improved clinical features of hypercortisolism. Of note, a high frequency of hyperglycemia was noted.

ADRENAL INSUFFICIENCY

Primary adrenal insufficiency (Addison disease) results from the destruction of the adrenal cortex and further results in a deficiency in aldosterone, cortisol, and adrenal androgen production. Secondary hypoadrenalism results from decreased ACTH production leading to reduced cortisol and adrenal androgen secretion; aldosterone production is normal, as the renin-angiotensin axis remains intact in such patients. Although Addison disease is uncommon, it carries significant morbidity and mortality if left untreated.

ETIOLOGY

In the Western world the most common cause of Addison disease is autoimmune adrenalitis, with the majority of the patients having autoantibodies directed toward 21-hydroxylase and side-chain cleavage enzymes. Primary adrenal insufficiency can occur as a part of autoimmune polyendocrine syndromes (APS) І and ІІ.

    In the developing world primary adrenal insufficiency is mainly due to infections, especially tuberculosis. Other causes of adrenal insufficiency are listed in box 49.2.

Box 49.2 CAUSES OF ADRENAL INSUFFICIENCY

CLINICAL FEATURES

Symptoms of chronic adrenal insufficiency are nonspecific and include fatigue, weakness, listlessness, anorexia, and weight loss. Gastrointestinal symptoms such as nausea, vomiting, diarrhea, and abdominal cramps can occasionally be the only presenting complaint. A specific sign of primary adrenal insufficiency is cutaneous and mucous hyperpigmentation, which occurs due to elevated ACTH from the absence of negative cortisol feedback. Darkening of the skin is typically seen in the sun-exposed areas, recent scars, palmar creases, and buccal mucosa. Orthostatic hypotension may be marked in primary adrenal insufficiency due to aldosterone deficiency; salt craving is a frequent complaint. Women may note loss of axillary and pubic hair, as a result of the adrenal androgen deficiency. Biochemical abnormalities include hyponatremia (frequent), hyperkalemia, hypoglycemia, elevation of blood urea, mild hypercalcemia, mild normocytic anemia, lymphocytosis, and eosinophilia. In primary adrenal insufficiency hyponatremia occurs due to aldosterone deficiency and sodium wasting, whereas in secondary hypoadrenalism it is dilutional due to cortisol deficiency, which is associated with increased antidiuretic hormone levels and ineffective free water clearance.

    Acute adrenal insufficiency, when caused by adrenal hemorrhage or precipitated by acute infection, presents as hypotension, acute circulatory failure, confusion, abdominal pain, and fever, and prompt recognition is extremely important. In secondary adrenal insufficiency, pallor, scanty axillary and pubic hair with headache and visual symptoms may point toward hypothalamic-pituitary disease. Hyperkalemia is not seen, as there is normal aldosterone secretion.

DIAGNOSIS

A morning plasma cortisol level of ≤3 µg/dL is diagnostic of adrenal insufficiency and precludes the need for further testing; levels ≥19 µg/dL rule out the disorder.

    The most commonly used diagnostic test for adrenal insufficiency is the ACTH stimulation test wherein 250 µg of cosyntropin is given intramuscularly or intravenously, and the cortisol response is measured at 0, 30, and 60 minutes. The normal response is a basal or peak cortisol response >18 µg/dL. This test is useful in diagnosing primary destruction of tissue and longstanding secondary adrenal insufficiency. This test may be normal in patients with mild or recent-onset secondary adrenal insufficiency. In early morning plasma, ACTH level is useful to distinguish primary from secondary adrenal insufficiency if the cortisol levels are abnormal. The plasma ACTH values are usually elevated (above 100 pg/mL) in primary adrenal insufficiency as opposed to secondary hypoadrenalism, where the plasma ACTH values may be low or “inappropriately” normal. Other tests such as the insulin tolerance test, metyrapone test, and CRH test are uncommonly used to diagnose secondary adrenal insufficiency.

    Adrenal autoantibodies (e.g., 21-hydroxylase) can be measured by radioimmunoassay to diagnose autoimmune adrenalitis. CT scan of the adrenal glands may show enlargement (e.g., hemorrhage) or calcification depending on the etiology of the adrenal failure. In secondary adrenal insufficiency there is normal aldosterone secretion, and hyperkalemia is not seen. Pituitary MRI scans and assessment of anterior pituitary functions are usually needed in these patients for concomitant deficiencies of other pituitary hormones.

    Individuals receiving long-term high-dose steroid therapy will develop prolonged HPA suppression leading to adrenal atrophy. Recovery takes months to over 1 year after glucocorticoid withdrawal. Early morning cortisol levels and ACTH stimulation testing should be used to assess adrenal recovery.

DIFFERENTIAL DIAGNOSIS

Chronic nonspecific symptoms such as fatigue, weakness, and malaise should make the possibility of a diagnosis of adrenal insufficiency. When insidious in onset, adrenal insufficiency is frequently mistaken for chronic fatigue syndrome. Occasionally such patients have been misdiagnosed with anorexia nervosa or depression. However, hyperpigmentation, weight loss, and gastrointestinal symptoms should alert the clinician to consider adrenal insufficiency. It is also reasonable to look for other organ-specific autoimmune diseases in the context of polyglandular syndromes.

MANAGEMENT

In the setting of adrenal crisis, parenteral treatment with high doses of hydrocortisone should be immediately initiated along with fluid resuscitation with normal saline. In nonacute situations, replacement doses of oral hydrocortisone at a dosage of 8–10 mg/m²/day should be started in divided doses. To mimic the diurnal pattern of steroid secretion, two-thirds of the total dose is given in the morning and one-third is given in late afternoon with mealtime or snack. In secondary adrenal insufficiency, only glucocorticoid therapy is needed.

    In primary adrenal insufficiency, mineralocorticoid insufficiency is replaced with fludrocortisone, administered at a daily dose of 0.05–0.1 mg orally. Plasma renin activity, blood pressure, and serum electrolytes are useful parameters to titrate the dose of fludrocortisone. In female patients some studies have suggested the benefit of androgen treatment with 25–50 mg/day of DHEA orally to improve sexual function and general well-being.

    Patient education and daily replacement therapy form a cornerstone in the management of primary adrenal insufficiency. Patients are advised to double the dose of hydrocortisone during periods of intercurrent illness or surgery. All patients should wear a medical alert bracelet and should be instructed in self-injection of steroids if they cannot take their dosing orally.

REGULATION OF RENIN-ANGIOTENSIN- ALDOSTERONE AXIS

Renin is formed in the juxtaglomerular cells (JG), located in the renal afferent arteriole of the glomerulus. Renin acts on the substrate angiotensinogen (hepatic origin) to form the angiotensin І. Angiotensin І is converted to angiotensin ІІ by angiotensin-converting enzyme (ACE). Angiotensin ІІ is a potent vasoconstrictor and also stimulates the zona glomerulosa of the adrenal cortex to increase aldosterone secretion. The hexapeptide angiotensin ІІІ also acts as a potent secretagogue of aldosterone secretion (see Figure 49.2). The control of adrenal aldosterone secretion includes the renin-angiotensin system, potassium, and ACTH. Aldosterone serves two important functions: regulation of extracellular fluid volume and potassium homeostasis. Chronic exposure to aldosterone over 3–5 days leads to an “escape” from mineralocorticoid action; after an initial period of sodium retention and a gain of several kilograms, sodium balance is reestablished. Therefore edema does not develop. An increase in atrial natriuretic peptide and interplay of renal hemodynamic factors play a role in the “escape” from the sodium-retaining action of aldosterone. However, it is important to realize that there is no “escape” from the potassium-losing effects of chronic mineralocorticoid exposure.

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