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Hypoglycemia

Hypotension

Occasionally, hyperpigmentation of the skin

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Aldosterone deficiency occurs only in the primary form because aldosterone production is not primarily under feedback control via ACTH. It causes a tendency for:

Volume depletion

Hyponatremia and hyperkalemia

Azotemia and acidosis

Preparation for surgery

A patient who has taken steroids regularly for any period during the past year is assumed to have inadequate adrenal reserve.

Perioperative steroid replacement is handled on an individual basis and depends on how long the patient was taking steroids, the dosage that was taken, and the magnitude of the planned procedure. The following is a general guideline for a patient undergoing a major operation who is a chronic steroid user:

The target is 100–150 mg of hydrocortisone intravenously daily for 2–3 days.

The steroid dosage is then returned to the preoperative oral dosage.

E Hyperadrenocorticalism (Cushing's syndrome)

Types. Cushing's syndrome results from the effects of chronically increased cortisol levels. Different mechanisms cause two types of Cushing's syndrome.

ACTH dependent

Pituitary Cushing's syndrome , or Cushing's disease , accounts for approximately 70% of the cases of Cushing's syndrome and is more common in middle -aged women.

It results from an overproduction of ACTH by the pituitary, which results in bilateral adrenal hyperplasia.

The source of the excess ACTH has been debated.

Pituitary tumors, either chromophobic or basophilic adenomas, probably account for the majority of cases. Some autopsy series have shown pituitary tumors in at least 90% of patients who have Cushing's disease.

However, in the remaining patients no tumor was found. This raises the possibility of an abnormality in the hypothalamic-pituitary axis, resulting in increased ACTH secretion.

Ectopic Cushing's syndrome also represents approximately 15% of the cases and is more common in older men.

In this form, ACTH is produced by an extra-adrenal, extrapituitary neoplasm. The result is a hyperplasia of the adrenocortical tissue with consequent hypercortisolism.

The cause is most commonly a small cell carcinoma of the lung, but the syndrome can also occur with bronchial carcinoids, thymomas, and tumors of the pancreas and liver.

ACTH independent. Adrenal Cushing's syndrome accounts for approximately 15% of the cases.

It is caused by an excess of cortisol that is produced autonomously by the adrenal cortex. This can be due to an adenoma, a carcinoma, or bilateral nodular dysplasia and ectopic cortisol - producing tumors.

The remaining adrenocortical tissue atrophies, and ACTH levels are low because of suppression by the excess cortisol.

Clinical presentation. The presentation of Cushing's syndrome is extremely variable and consists of any combination of various features. The most common manifestations are listed in Table 16 -2.

Diagnosis. No one test is conclusive for Cushing's syndrome. However, the normal diurnal rhythm of cortisol secretion is usually lost in Cushing's syndrome. The laboratory test results and the clinical presentation must be considered together to make an accurate diagnosis (Table 16 -3).

Plasma total cortisol is the most direct measurement, since Cushing's syndrome is a state of hypercortisolism.

The accuracy of this determination is increased by measuring morning and afternoon samples as well as a morning sample after a suppressing dose of dexamethasone the night before.

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TABLE 16-2 Common Manifestations of Cushing's Syndrome

Plasma cortisol levels are suggestive of Cushing's syndrome if they exceed 30 µg/dL at 8:00 A.M. and 15 µg/dL at 5:00 P.M., or 10 µg/dL at 8:00 A.M., following a midnight dose of 1 mg dexamethasone, especially if these results are reproducible on several different days.

The overnight dexamethasone suppression test is not fully reliable, as both false -positive and false -negative results occur. Adjusting the dose of dexamethasone on the basis of the patient's weight may reduce the number of false -positive and false -negative results.

24 -Hour urinary free cortisol is the most reliable urinary index of hypercortisolism due to the increased renal clearance of unmetabolized cortisol, if further confirmation is needed.

Pathogenesis. Once the diagnosis of Cushing's syndrome has been made, the underlying pathophysiologic mechanism (see II E 1) must be identified.

The plasma ACTH level gives a good indication of the type of Cushing's syndrome.

Extremely low values are found with adrenal Cushing's syndrome due to the suppressive effects of cortisol.

Very high levels occur with ectopic Cushing's syndrome due to the autonomous ACTH production.

In pituitary Cushing's syndrome, the values are normal in 50% of the cases but are increased in the other 50%.

Differentiating ectopic from pituitary Cushing's syndrome when the ACTH level is in the intermediate range can be difficult. Four methods are helpful in making this distinction:

High-dose dexamethasone suppression test. After the diagnosis of Cushing's syndrome has been made, the patient is given dexamethasoiie, 8 mg/day for 2 days, and the urine is collected for measurement of 17 -hydroxycorticosteroids. In pituitary Cushing's syndrome, the 17 - hydroxycorticosteroid levels will usually decrease to less than 50% of normal, whereas they will show no suppression in the ectopic syndrome. However, there have been enough recorded exceptions in both cases to make this test of questionable value.

Corticotropin -releasing hormone (CRH) test. Response to CRH stimulation can be used instead of high-dose dexamethasone suppression (Table 16 -4).

Jugular versus peripheral ACTH levels. Samples of venous blood are drawn from a peripheral site and, by catheterization, from the inferior petrosal sinus. Ratios of petrosal to peripheral ACTH greater than 2.0 have correlated with a pituitary source for the Cushing's syndrome and ratios less than 1.5 with an ectopic source.

TABLE 16-3 ACTH Determinations for Sources of Cushing's Syndrome

ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone.

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TABLE 16-4 Corticotropin-releasing Hormone Stimulation Test Response

CRH, corticotropin-releasing hormone; ACTH, adrenocorticotropic hormone.

Plasma lipotropic hormone (LPH, lipotropin) concentration. This tends to be higher than the ACTH concentration with ectopic Cushing's syndrome, while the opposite holds true for pituitary Cushing's syndrome.

Localization of the tumor

Pituitary Cushing's syndrome. Polytomography of the sella turcica has localized some pituitary tumors, but computed tomography (CT) and magnetic resonance imaging (MRI) are more sensitive and are specific for detecting small adenomas.

Ectopic Cushing's syndrome. A chest film usually shows the offending neoplasm; however, a technique such as CT or MRI may be needed to detect pancreatic or hepatic tumors.

Adrenal Cushing's syndrome. Several techniques are available.

CT or MRI can correctly identify more than 90% of adrenal lesions, including adenomas larger than 1 cm in diameter, carcinomas, and bilateral hyperplasia.

Radioisotope scanning. A radiocholesterol analogue, NP-59 (iodomethylnorcholesterol), can successfully localize functioning adrenocortical tumors in 70%–75% of these patients.

Arteriography can localize adrenal tumors and is helpful in assessing the arterial supply of a neoplasm before its surgical removal.

Retrograde adrenal venography can also localize adrenal tumors and allows for bilateral

cortisol measurements. However, there is a 5% risk of adrenal hemorrhage and possible infarction.

Venacavography is helpful if a malignancy is suspected to assess the intravenous extension of the tumor.

Treatment

Curative therapy

Pituitary Cushing's syndrome. Treatment depends on the cause.

Trans-sphenoidal resection of the tumor is the procedure of choice if a pituitary adenoma is localized.

Pituitary irradiation from an external source has been effective in up to 80% of children. However, the cure rate is only about 15%–20% for adults.

Implantation of yttrium-90 may improve results, but this requires a separate operation for implantation and may cause progressive hypopituitarism.

There is a lag period with radiation therapy of up to 18 months before effects are seen.

Bilateral total adrenalectomy

With the advent of effective trans-sphenoidal removal of pituitary adenomas, bilateral adrenalectomy is now reserved for cases in which no pituitary adenoma is found, radiation has failed, or when the patient is too sick to tolerate the prolonged radiation process or to await its ultimate effect.

The advantage of bilateral adrenalectomy is its immediate and complete control of the cushingoid state.

The disadvantages are the increased morbidity and mortality secondary to the operative procedure. It produces a permanent addisonian state, and in at least 15% of the cases, an ACTH-secreting pituitary tumor develops (Nelson's syndrome). Therefore, all patients treated for Cushing's disease with bilateral total adrenalectomy must be monitored yearly with visual field examination and sellar tomography or head CT scans.

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Ectopic Cushing's syndrome. Treatment is directed toward the underlying neoplasm secreting ACTH. Removal of the tumor is curative. However, because of the diffuse nature of small cell lung cancers, often only palliative therapy can be offered.

Adrenal Cushing's syndrome. Treatment involves total adrenalectomy via laparopscopic or open techniques.

Laparoscopic adrenalectomy has become the preferred approach for most benign adenomas less than 6 cm in size. The gland may be approached transabdominally or retroperitoneally via the flank or back.

Open adrenalectomy via an anterior or flank approach is advisable for lesions greater than 6 cm or for those with aggressive characteristics on imaging studies (significant heterogeneity, nodal involvment, local soft tissue or vascular invasion). Even if all of the malignant tissue cannot be removed, palliative therapy is easier if as much tumor as possible is resected.

Palliative chemotherapy can be offered to those patients who have unresectable or incompletely resected malignancies and, during the lag phase, to those undergoing radiation treatment. Remissions can be obtained in about 60% of the cases, but relapse is rapid after drug cessation. Two groups of drugs exist with differing sites of action.

Drugs acting on the adrenal cortex, inhibiting steroid synthesis, include mitotane (formerly called o,p'-DDD), metyrapone, trilostane, and aminoglutethimide.

Centrally acting drugs appear to be fast acting and less toxic. They apparently act by affecting the hypothalamic release of CRF and, therefore, pituitary ACTH production. These drugs include cyproheptadine (a serotonin antagonist) and bromocriptine (a dopamine agonist).

F Primary hyperaldosteronism (Conn's syndrome)

Overview. Conn's syndrome is due to the excess secretion of aldosterone by the adrenal cortex as a result of a unilateral adenoma of the adrenal gland in 85% of the cases and to bilateral adenomas in fewer than 5%. Bilateral hyperplasia causes about 5%–10% of the cases. Rarely, the syndrome is due to an adrenocortical carcinoma.

Types. It is important to distinguish primary from secondary hyperaldosteronism. It is also important to distinguish hyperaldosteronism due to an adenoma from that due to hyperplasia because surgical excision is curative for most cases of adenoma, but the response is not as good in hyperplasia.

In the primary form, plasma renin levels are normal or low.

In the secondary form, there is an increase in plasma renin and, subsequently, in aldo-sterone. This results from a decrease in pressure on the juxtaglomerular cells of the kidney. Common causes include renal artery stenosis, malignant hypertension, and edematous states, such as congestive heart failure, cirrhosis, and the nephrotic syndrome.

Signs and symptoms. The increased secretion of aldosterone leads to hypertension, muscle weakness, fatigue, polyuria and polydipsia, and headaches.

Diagnosis. Most of the laboratory abnormalities follow from the hypersecretion of aldosterone but can be influenced by antihypertensive drugs. Therefore, antihypertensive drugs should be discontinued before laboratory testing.

Plasma electrolytes. Frequently, the potassium level is low, and the sodium level is slightly elevated. The carbon dioxide content may be increased due to alkalosis.

Sodium loading. Hypokalemia and a significant increase in urinary potassium may be induced (or will persist if already present) by giving the patient a high-sodium diet (200 mEq/day).

Plasma and urinary aldosterone levels

One of the most common causes of a missed diagnosis is the measurement of aldo-sterone before potassium repletion. Hypokalemia inhibits aldosterone secretion and may lead to a false - negative result.

After potassium repletion, the serum and 24 -hour urinary aldosterone levels are markedly increased in most patients who have Conn's syndrome.

Plasma renin activity. This helps to distinguish primary from secondary hyperaldosteronism. The activity is very high in the secondary form but low, even undetectable, in the primary disease.

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Postural response of aldosterone. The response of aldosterone production to 4 hours of upright posture after overnight recumbency is helpful in distinguishing hyperaldosteronism due to an adenoma from that due to hyperplasia. In patients with an adenoma, there is no change or a decrease in aldosterone production. With hyperplasia, there is an increase in aldosterone levels.

Localization of adenomas

Selective sampling of the adrenal venous blood to determine aldosterone concentration is the most accurate means of identifying an adenoma. However, this test is very difficult to perform and frequently provides incomplete results. Nonetheless, it is currently recommended for most patients to help rule out the possibility of bilateral nodular hyperplasia (seen in as many as 40% of patients) or to detect small functional adenomas that may not be identified with other techniques.

CT and MRI have been shown to be at least 80% accurate in detecting adrenal adenomas and are much less invasive than adrenal venous sampling. However, these tests may either miss small adenomas or may identify adrenal lesions that are actually nonfunctional. This could lead to improper surgical planning.

Iodocholesterol scintigraphy (see II E 5 c [2]) can also be used to localize aldosterone-producing adenomas.

Treatment

Surgical treatment

For patients who have primary hyperaldosteronism due to an adrenocortical adenoma, the treatment of choice is laparopscopic adrenalectomy. Either total adrenalectomy of the involved gland or partial adrenalectomy to include the nodule may be considered.

It is important to restore potassium levels to normal before surgery.

Medical management

Spironolactone , a direct antagonist to aldosterone at the kidney tubule, gradually leads to a reduction in blood pressure and a return to normal potassium levels.

Spironolactone is used in patients with primary hyperaldosteronism caused by adrenal hyperplasia because the results of surgery have been disappointing in these patients.

Spironolactone is also used in the preoperative restoration of normal serum potassium levels in patients who have adenomas.

G Pheochromocytoma

(Table 16 -5)

Overview. Pheochromocytomas are functionally active tumors that develop from the neural crest -derived

chromaffin tissue.

Pheochromocytomas produce excess amounts of catecholamines, particularly norepinephrine and epinephrine.

Most of these tumors (approximately 90%) are benign, but some (10%) are found to be malignant. There is a higher incidence of malignancy with extra-adrenal tumors.

Histologic examination is not an accurate means of determining the malignancy of a pheochromocytoma.

Malignancy is determined by the presence of metastases or direct invasion by the tumor.

Pheochromocytomas can occur as part of the syndrome of multiple endocrine neoplasia type II (Sipple's syndrome—see Chapter 17, I B 2). The adrenal medullary abnormality is bilateral in up to 80% of these cases.

Location

Approximately 90% of all pheochromocytomas are found in the adrenal medulla. Approximately 10% of these are bilateral.

TABLE 16-5 Pheochromocytoma: The Ten-percent Tumor

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Of the extra-adrenal tumors, most are found in the organs of Zuckerkandl, the extraadrenal paraganglia, the urinary bladder, and the mediastinum.

Signs and symptoms

Hypertension results from the excess production of catecholamines.

The hypertension is sustained in about half the patients and intermittent in the others.

However, patients with the sustained variety can have paroxysms of more severe hypertension superimposed on the baseline hypertension.

Other findings include attacks of headaches, sweating, palpitations, tremor, nervousness, weight loss, fatigue, abdominal or chest pains, polydipsia and polyuria, and convulsions.