Treatment
The treatment of pheochromocytoma is surgical. The surgery should be undertaken only by a team experienced and skilled in the management of pheochromocytoma. Before the surgical procedure, complete alpha blockade should be induced to avoid in-traoperative hypertensive crisis. Preparation should begin 7 days before the planned procedure, using phenoxybenzamine at an initial dosage of 10 mg by mouth twice daily. The dose should be increased daily, and by the seventh day, the patient should be taking at least 1 mg/kg/day in three divided doses. Adequate blockade is associated with reduced blood pressure and reduced orthostatic hypotension as the vascular volume is restored.
Malignant pheochromocytoma should be treated with surgical debulking, ongoing alpha blockade with phenoxybenza-mine, and comanagement with an oncologist. Radiation therapy is useful for bone pain, and some success has been achieved with combination chemotherapy, including cyclophosphamide, vincristine, and dacarbazine.
Congenital Adrenal Hyperplasia
There are six enzymatic steps in the biosynthesis of cortisol from cholesterol, and all can be affected by inactivating mutations [see Figure 5]. Because cortisol is essential for life, cortisol concentrations are maintained in the normal range at the expense of adrenal hypertrophy and increased adrenal secretion of the steroid biosynthetic intermediate in the step immediately before the affected enzyme. Depending on which enzyme is blocked, the increased concentrations of the steroid biosynthetic intermediate can lead to virilization in females and to hypertension. In some cases, primarily because of reduced androgen secretion in utero—a time when there is no feedback regulation of testosterone—male fetuses can be feminized.
The most common underlying disorder in congenital adrenal hyperplasia is 21-hydroxylase deficiency. The virilizing form of this disease is thought to be the most common autosomal recessive disorder.
21-Hydroxylase deficiency is categorized according to two clinical distinctions: (1) the classic form, which can be salt losing or non-salt losing, and (2) the nonclassic form.
The degree to which a person with 21-hydroxylase deficiency loses salt in a salt-poor environment correlates with the degree of expression of the enzyme defect in the zona glomerulosa. In persons with mild expression, salt loss is sufficiently minimal that a standard United States diet will maintain a normal salt balance.
The classic form of the disease is usually diagnosed in the neonatal period and is characterized by failure to thrive as a result of the salt loss and by male pseudohermaphroditism in female infants. The nonclassic form of the disease, which is sometimes referred to as adult onset or attenuated, usually becomes clinically apparent in adolescence. It is manifested by a slightly earlier age at puberty (approximately 1 year) and, in females, oligomenorrhea and androgen-mediated hirsutism. Adults who present with the classic form of 21-hydroxylase deficiency usually have a well-documented diagnosis since infancy, have a gender assignment, and have completed a series of genital reconstructive plastic surgical procedures. The usual clinical questions are whether ongoing treatment is necessary and, if so, whether the current regimen is appropriate.
The typical adult patient with the nonclassic or attenuated form is a young woman with oligomenorrhea, infertility, and hirsutism. The most common confounding diagnosis is the polycystic ovary syndrome [see 16:VPolycystic Ovary Syndrome].
The diagnostic test for 21-hydroxylase deficiency is a cosyn-tropin stimulation test: synthetic ACTH is administered in a 250 ^.g intravenous bolus, and plasma levels of 17-hydroxyproges-terone are measured after 45 and 60 minutes. 17-Hydroxyprog-esterone is the steroid biosynthetic intermediate immediately proximal to the enzyme defect. In normal patients, 17-hydrox-yprogesterone levels will rise to no higher than 340 ng/dl after cosyntropin stimulation; in patients with 21-hydroxylase deficiency, 17-hydroxyprogesterone levels will be no lower than 1,000 ng/dl. CT or MRI scanning in these patients will show that the adrenal glands are larger than normal and, in some cases, nodular.
Treatment
All patients with 21-hydroxylase deficiency should be considered to have some degree of salt loss. Fludrocortisone, 0.2 mg every morning, should be the first therapy. Hydrocortisone, 12 to 15 mg/m2 as a single morning dose, should be initiated several days later. After 2 weeks of combined therapy, a morning 17-hydroxyprogesterone level should be measured. If the target level of 400 to 600 ng/dl is achieved, the fludrocortisone dose can be reduced by half. Two weeks later, the 17-hydroxyproges-terone should be measured again; if it is still below 600 ng/dl, that establishes the fludrocortisone dose as the patient’s maintenance dose. If the 17-hydroxyprogesterone level has risen above 600 ng/dl, the fludrocortisone dose should be restored to the initial 0.2 mg/day, which likely will be the maintenance dose. Reduction of 17-hydroxyprogesterone levels to within the normal range is not recommended. Achieving this level often requires doses of fludrocortisone that produce adrenal suppression and lead to Cushing syndrome.
Lifelong treatment is required in patients with 21-hydroxylase deficiency to prevent the appearance of adrenal rest tumors, which are nodules of ectopic adrenal tissue that become hyper-trophic because of ongoing ACTH stimulation. These tumors are usually found in the broad ligament in women and in the testes in men. In women, hemorrhage or necrosis of adrenal rest tumors occasionally necessitates emergency pelvic surgery; in men, these tumors can result in testicular pain, testicular masses, and infertility. Testicular pain may be so severe and intractable that castration is required.
Hyperaldosteronism
Hyperaldosteronism can be primary or secondary. In primary hyperaldosteronism, there is disordered function of the renin-al-dosterone feedback axis; in secondary hyperaldosteronism, the renin-aldosterone axis is responding normally to chronic in-travascular volume deficiency, which may result from such conditions as heart failure or ascites associated with cirrhosis of the liver.
Aldosterone acts on the epithelial cells of the renal collecting tubule to promote reabsorption of sodium and excretion of potassium and hydrogen. Other tissues similarly affected include sweat glands, salivary glands, and intestinal epithelium. Clinically, the result of excess aldosterone is the so-called miner-alocorticoid excess syndrome, characterized by hypokalemia, metabolic alkalosis, and, sometimes, hypertension.
Primary hyperaldosteronism
Primary hyperaldosteronism is caused by benign adrenal adenomas, which are typically unilateral, are usually less than 2.5 cm in diameter, and secrete aldosterone independently of renin-angiotensin stimulation. Patients with primary hyperal-dosteronism present with hypertension; in fact, primary adrenal hypersecretion of aldosterone is thought to account for about 2% of cases of hypertension. Laboratory testing shows hy-pokalemia and metabolic alkalosis, with a serum sodium level that is usually in the high-normal range [see Figure 6]. Diagnosis of this disorder is confirmed by demonstrating normal or elevated plasma aldosterone levels (> 14 ng/dl) along with suppression of stimulated plasma renin activity (PRA) to less than 2 ng/ml/hr. Stimulated PRA is determined by measuring the plasma renin activity level after 2 hours of upright posture (standing or walking).
The differential diagnosis of primary hyperaldosteronism also includes dexamethasone-suppressible hyperaldosteronism, in which aldosterone is secreted in response to ACTH rather than angiotensin [see Dexamethasone-Suppressible Hyperal-dosteronism, below], and idiopathic bilateral adrenal hyperpla-sia, in which the hypertrophic zona glomerulosa secretes aldos-terone independent of renin-angiotensin stimulation [see Idio-pathic Bilateral Adrenal Hyperplasia, below]. Dexamethasone-suppressible hyperaldosteronism is confirmed by the suppression of aldosterone levels with dexamethasone administration, 2 mg/day in divided doses for 7 days. In most cases, aldos-terone levels decrease by the third day of treatment. If dexam-ethasone fails to suppress plasma aldosterone levels and to ameliorate the associated hypertension, CT or MRI should be employed to search for an adrenal adenoma. If an adenoma is not found by CT or MRI, simultaneous adrenal venous sampling for the measurement of aldosterone and cortisol will be needed to define the source of aldosterone secretion.15 If the venous sampling identifies unilateral aldosterone secretion, the patient should be treated as if primary adrenal hypoaldostero-nism is present, despite the absence of a visible adenoma. The surgeon, at the time of operation, can define unilateral versus bilateral disease.
The treatment of primary adrenal hyperaldosteronism is unilateral adrenalectomy, preferably by a laparoscopic procedure. The cure rate, defined as correction of hyperaldosteronism and hypertension, is about 75%.16 Patients whose blood pressure remains elevated postoperatively will require ongoing antihyper-tensive therapy, which is managed as if essential hypertension were present.
Idiopathic Bilateral Adrenal Hyperplasia
The clinical presentation of idiopathic bilateral adrenal hyper-plasia is indistinguishable from that of primary hyperaldoster-onism caused by an adrenal adenoma. However, patients with idiopathic bilateral adrenal hyperplasia have no dominant adrenal adenoma, and aldosterone secretion from both adrenal glands can be documented by bilateral adrenal venous sampling. Adrenalectomy in these patients does not correct the hypertension. Thus, treatment is directed at the hypertension. Interestingly, antagonizing aldosterone activity with spironolac-tone is usually ineffective. Calcium channel blockers, however, are effective antihypertensive agents in these patients, as are ACE inhibitors. If hypokalemia persists during the treatment of hypertension, it can usually be managed by the addition of a potassium-sparing diuretic.
Figure 6 Differential diagnosis of primary hypoaldosteronism. (PRA—plasma renin activity)
Dexamethasone-Suppressible Hyperaldosteronism
Dexamethasone-suppressible hyperaldosteronism is a rare familial cause of hyperaldosteronism and is transmitted as an autosomal dominant trait. The cause of the disorder is a fusion gene in which the coding region for ACTH-responsive regulation of 11-| hydrolase is coupled with the coding region for al-dosterone synthase. Thus, aldosterone secretion becomes entrained to ACTH secretion and is "blind" to renin-angiotensin levels. Because ACTH secretion is not modulated by aldos-terone, aldosterone secretion becomes independent of salt balance, blood potassium levels, and vascular volume.
Treatment for this disorder starts with the use of a potassium-sparing diuretic such as amiloride or triamterene. This regimen has the advantage of not suppressing the HPA axis. If it is unsuccessful, ACTH secretion can be suppressed with dexametha-sone, usually 0.5 mg in a single daily dose.
Decondary hyperaldosteronism
Secondary hyperaldosteronism may or may not be associated with hypertension. Patients with hypertension usually have underlying renal pathology, including renal artery stenosis, renin-secreting tumors, and chronic renal failure. Both plasma renin activity and aldosterone are elevated in such cases. Treatment should be directed at the underlying cause.
Secondary hyperaldosteronism that is not associated with hypertension occurs in disorders characterized by decreased vascular volume. Renal causes include chronic nephritis, renal tubular acidosis, and calcium- and magnesium-losing nephrop-athies. Chronic diuretic abuse also is a cause. Gastrointestinal causes include chronic vomiting, laxative abuse, and chronic diarrhea of any kind. Probably the most common causes are chronic heart failure and cirrhosis of the liver with ascites. Again, treatment is best directed at the underlying disorder.
Finally, there are two forms of congenital adrenal hyperplasia in which overproduction of mineralocorticoids other than aldosterone leads to the syndrome of mineralocorticoid excess. These two disorders are 11-hydroxylase deficiency and 17-hydroxy-lase deficiency. Both renin and aldosterone levels are low in these disorders. Treatment is the same as that for 21-hydroxy-lase deficiency (see above), but without fludrocortisone.
Bartter syndrome is associated with hypokalemic alkalosis, hyperreninemia, and hyperaldosteronism, with normal blood pressure. This pattern can be seen in a number of disorders causing secondary hyperaldosteronism. Bartter syndrome is caused by a deficit in chloride transport in the thick ascending limb of the loop of Henle. Diagnosis is difficult because the pattern of electrolyte abnormalities mimics that seen in diuretic abuse. A more detailed discussion of Bartter syndrome is provided elsewhere [see 10:11 Disorders of Acid-Base and Potassium Balance].
Hypoaldosteronism
Primary hypoaldosteronism
Primary hypoaldosteronism is defined as aldosterone deficiency of adrenal cause. Hypoaldosteronism manifests as an inability to conserve sodium, leading to a negative salt balance in a salt-poor environment. This leads to hypotension, hyperkalemia, dehydration, and volume depletion associated with a mild metabolic acidosis. The disorder can be corrected by a high-salt diet or by replacement of aldosterone with fludrocortisone.
Primary adrenal insufficiency is the most common cause of primary hypoaldosteronism. Diagnosis and treatment are the same as those for adrenal insufficiency (see above). Two rare au-tosomal recessive disorders, corticosterone methyl oxidase (CMO) deficiency types I and II, can result in markedly reduced adrenal secretion of aldosterone. CMO deficiency type I is recognized by the syndrome of mineralocorticoid deficiency and low aldosterone levels associated with high plasma corticosterone concentration. CMO deficiency type II is similar, except that high levels of 18-hydroxycorticosterone will be associated with low levels of aldosterone. These are primarily diseases of childhood, becoming less severe with age and free access to salt.
Secondary hypoaldosteronism
The syndrome of hyporeninemic hypoaldosteronism is the most common form of secondary hypoaldosteronism. The disorder is often referred to as renal tubular acidosis type 4. It has been described in almost every disorder of renal function. Chronic renal disease is present in 80% of patients with the disorder. The clinical picture is that of hyperkalemia, hyponatrem-ia, and metabolic acidosis in association with a low plasma renin activity and a low plasma aldosterone level. The most direct and rational therapy for this syndrome is replacement of aldosterone with fludrocortisone at a dosage of 0.1 to 0.2 mg/day.
Pseudohypoaldosteronism (mineralocorticoid resistance)
Pseudohypoaldosteronism type I and type II are syndromes of end-organ resistance to the effects of aldosterone. Type I is caused by an inactivating mutation in the mineralocorticoid receptor, and type 2 is ascribed to an ill-defined defect in aldos-terone action distal to its binding to the mineralocorticoid receptor. Pseudohypoaldosteronism type 1 is characterized by salt wasting that is resistant to mineralocorticoid replacement. It is best treated with a high-salt diet, 10 to 40 mEq/kg/day. Pseudo-hypoaldosteronism type II (Gordon syndrome) is a non-salt-wasting disorder that can be associated with hypertension, metabolic acidosis, and hyperkalemia. Plasma renin activity and aldosterone are both low, and administration of mineralocorti-coid fails to correct the hyperkalemia and acidosis. The basic defect is thought to be a chloride shunt disorder in the nephron. Treatment is with a potassium-wasting diuretic; hydrochloro-thiazide and furosemide are most often used.
Glucocorticoid Therapy
Glucocorticoids can be valuable, even lifesaving, in the treatment of many inflammatory and neoplastic diseases. Although cortisol accounts for about half of the mineralocorticoid effect produced by the adrenal gland, the synthetic steroids that are customarily used for glucocorticoid therapy (e.g., prednisone and dexamethasone) have virtually no salt-retaining activity and, therefore, do not cause unacceptable salt retention. On the other hand, their glucocorticoid effect is far more powerful than that of cortisol. Gram for gram, prednisone has four times the glucocorticoid potency of cortisol; dexamethasone has about 25 times the potency.
The target tissues in glucocorticoid-responsive diseases are glucocorticoid resistant. The basis for this resistance remains unknown, but the prevailing hypothesis is that the chaperone proteins produced in stressed cells, particularly the heat shock proteins, in some way attenuate glucocorticoid action. Overcoming glucocorticoid resistance may require dosages of prednisone as high as 100 mg/day and dosages of dexamethasone as high as 20 mg/day. These high doses expose the rest of the tissues in the patient’s body, which have normal responsiveness to glucocorti-coid, to an extremely enhanced glucocorticoid effect. Over time, this leads to Cushing syndrome, whose potentially lethal effects may force the tapering or even discontinuance of glucocorticoid therapy.
An invariable aspect of Cushing syndrome induced by exogenous glucocorticoid is suppression of ACTH secretion. In contrast to the recovery of pituitary secretion of other hormones, such as thyroid-stimulating hormone or luteinizing hormone and follicle-stimulating hormone, recovery of ACTH secretion is very slow; the return to normal may require a year or more. Thus, the physician must ensure that the HPA axis is intact before completely withdrawing long-term glucocorticoids.
Pharmacologic glucocorticoid therapy is typically initiated at a high dose (e.g., prednisone, 60 mg daily in divided doses). As soon as the disease process is controlled, the dose is reduced in 5% increments weekly in an attempt to find the lowest effective dose as quickly as possible. The ultimate goal is to taper to normal replacement doses of the glucocorticoid. When the gluco-corticoid dose approximates the replacement level, the preparation is changed to an equivalent dose of hydrocortisone given at a dosage of 12 mg/m2 once a day in the morning. This dose remains unchanged until it is safe to withdraw glucocorticoid therapy completely or until the disease reactivates, in which case the process is begun anew. Patients receiving hydrocorti-sone at the replacement dose should undergo cosyntropin stimulation testing every 3 months. When the plasma cortisol response to cosyntropin exceeds 20 ^g/dl, hydrocortisone can be discontinued safely. In the event that the dose cannot be lowered to replacement levels because of recurrent disease activity, alternative and adjunctive non-glucocorticoid-based therapies must be aggressively pursued in the hope that they might permit tapering of the glucocorticoid to replacement dose before the ravages of Cushing syndrome demand cessation of gluco-corticoid treatment in the setting of an uncontrolled inflammatory or neoplastic illness.
