1Oregon Health Sciences University
The author has no commercial relationships with manufacturers of products or providers of services discussed in this chapter.
There are two adrenal glands, which are adjacent to the rostral pole of each kidney. The glands weigh 3 to 5 g each and are about 5 cm in largest dimension. They are the shape of a flattened sphere, with one side invaginated. Hence, on tomographic views, the gland has an upside-down Y shape, with a trunk and two limbs [see Figure 1]. The thickness of the gland in a given person should be no greater than that of the ipsilateral crus of the diaphragm.
Figure 1. Normal Adrenal Gland
A computed tomographic image shows a normal adrenal gland.
Histologically, the adrenal gland is composed of a cortex and a medulla. The cortex has three zones [see Figure 2]. From the capsule inward, these zones are the glomerulosa, the fasciculata, and the reticularis. The glomerulosa is a thin, discontinuous zone in which the cells are arranged in a fashion similar to that of glomeruli. In the process of fixation, lipid is lost from these cells disproportionately; as a result, they are histologically clear. The glomerulosa accounts for about 5% of the cortical volume. The cells of the fasciculata are arranged in linear fashion, vertically, similar to that of the fascicles of pages in the spine of a book. The fasciculata accounts for about 70% of the volume of the adrenal cortex. The reticularis is intensely eosinophilic, with cells arranged in a poorly organized netlike fashion. This zone of the cortex is referred to as the x-zone in fetal life, when it accounts for most of the cortical volume. The reticularis disappears in childhood and then reappears at the time of adrenarche, which usually takes place 2 to 3 years before the onset of puberty. In the mature adrenal cortex, the reticularis accounts for 10% to 20% of the volume of the gland. The innermost zone of the adrenal gland is the medulla. Its structure is analogous to that of a sympathetic ganglion, being composed of chromaffin cells innervated by presynaptic sympathetic axons.
Figure 2. Zones of the Adrenal Cortex
Hematoxylin and eosin staining distinguishes the zones of the adrenal cortex.
The adrenal gland makes three principal hormones: hydrocortisone, or cortisol, which is necessary for life; aldosterone, which promotes salt retention and thereby permits maintenance of salt balance in a salt-poor environment; and adrenaline, or epinephrine, which features prominently in the fight-or-flight response (etymologically, the two terms are identical, with the former deriving from the Latin ad renal and the latter from the Greek epi nephros). Additionally, the adrenal gland secretes small amounts of estrogen and androgen, as well as two androgen precursor steroids, androstenedione and dehydroepiandrosterone (DHEA). These hormones and prohormones are products of distinct zones of the gland: aldosterone from the glomerulosa, cortisol from the fasciculata, DHEA from the reticularis, and epinephrine from the medulla.
Cortisol levels are regulated by a feedback loop [see Figure 3]. The synthesis and secretion of cortisol are stimulated by adrenocorticotropic hormone (ACTH) from the pituitary gland. Once in the bloodstream, cortisol levels rapidly regulate the synthesis and secretion of ACTH by the pituitary. ACTH release is also dependent on corticotropin-releasing hormone (CRH) from the hypothalamus. CRH is also regulated by cortisol, but at a much slower tempo.
Figure 3. Feedback Regulation of Cortisol and Aldosterone
The feedback regulation of cortisol and aldosterone. (ACE—angiotensin-converting enzyme; ACTH—adrenocorticotropic hormone; CRH—corticotropin-releasing hormone)
Aldosterone levels are also regulated by feedback loops [see Figure 3]. Renin, a polypeptide hormone secreted by the juxtaglomerular cells of the kidney, is converted to angiotensin II, notably in the lungs, and stimulates adrenal aldosterone synthesis and secretion. Aldosterone acts on the thick ascending limb of the loop of Henle to enhance salt retention and thus expand vascular volume. The juxtaglomerular cells monitor vascular volume in the afferent artery of the glomerulosa and decrease renin secretion in response to expanded volume. DHEA and epinephrine have no known feedback regulation. All the adrenal hormones can now be measured specifically and accurately by radioimmunoassay, greatly facilitating the study of adrenal physiology and pathophysiology.
Diseases of the adrenal gland can be conveniently categorized as conditions associated with increased or decreased activity of the key hormones: hypercortisolism and hypocortisolism, hyperaldosteronism and hypoaldosteronism, virilization and feminization from sex hormone secretion, and catecholamine excess or deficiency.
Hypercortisolism (Cushing syndrome)
Cortisol is normally secreted at a rate of 6.5 mg/m2/day.1 Secretion of cortisol in excess of this rate can, with time, lead to Cushing syndrome. Harvey Cushing described this syndrome in his book The Pituitary Body and Its Disorders, published in 1919.2 The classic clinical presentation of Cushing syndrome includes central obesity, striae, moon facies, supraclavicular fat pads, diabetes mellitus, hypertension, hirsutism and oligomenorrhea in women, and erectile dysfunction in men [see Table 1].3
Table 1 Sensitivity and Specificity of Selected Findings in Cushing Syndrome
The causes of cortisol excess can best be categorized as ACTH dependent or ACTH independent. The two categories can be distinguished by the measurement of ACTH in the blood. ACTH-dependent causes account for about 90% of cases of noniatrogenic Cushing syndrome, and they most often result from ACTH secretion by a pituitary microadenoma that is relatively insensitive to the feedback effects of cortisol (i.e., Cushing disease). The most common cause of ACTH-independent Cushing syndrome is iatrogenic long-term glucocorticoid administration. The most common naturally occurring cause of ACTH-independent Cushing syndrome is cortisol secretion from a benign adrenal adenoma [see Table 2].
Table 2 Differential Diagnosis of Cushing Syndrome
The diagnosis of Cushing syndrome is principally clinical. The more signs and symptoms of the syndrome that are present, the more confident of the diagnosis the physician can be. The firmer the clinical diagnosis, the less important is biochemical confirmation. Typically, patients will have some, but not all, of the clinical manifestations of Cushing syndrome, and the diagnosis will require confirmation by demonstrating an elevated urinary free cortisol excretion on 24-hour urine testing, which is the single best biochemical marker of Cushing syndrome. The upper limit of the normal range of urinary free cortisol in unstressed persons is generally agreed to be about 100 µg/day as measured in commercial laboratories. If the patient has florid signs of Cushing syndrome, the diagnosis can be made even in the absence of convincing biochemical confirmation. On the other hand, if the patient has few clinical signs of Cushing syndrome, the urinary free cortisol must be greater than 300 µg/day to permit the diagnosis on that basis alone.
Taken together, the number of clinical manifestations and the level of urinary free cortisol define three general categories of Cushing disease: atypical, anorexia-associated, and classic [see Figure 4]. Atypical Cushing syndrome is characterized by low levels of urinary free cortisol but many clinical manifestations. Anorexia-associated Cushing syndrome is characterized by high levels of urinary free cortisol and few clinical manifestations. Classic Cushing syndrome is characterized by high levels of urinary free cortisol and many clinical manifestations.
Figure 4. Categories of Cushing Syndrome
The severity of the clinical manifestations and the level of urinary free cortisol can be used to define three categories of Cushing syndrome: classic, atypical, and anorexia associated.
Each of these general categories of Cushing syndrome has an associated differential diagnosis. The most common cause of atypical Cushing syndrome is glucocorticoid use, whether iatrogenic or factitious, and that of anorexia-associated Cushing syndrome is small cell carcinoma of the lung. The most powerful tool in the identification of these less common causes of Cushing syndrome is the clinical history.
In patients with classic Cushing syndrome, a search for the cause should not be undertaken unless the diagnosis is secure. Once that is accomplished, the first step in the differential diagnosis is to determine whether the condition is ACTH dependent or ACTH independent. This is most easily done by measuring the level of circulating plasma ACTH. There is no need to perform dexamethasone suppression testing.4
Although an ACTH level greater than 10 pg/ml indicates ACTH dependence, this threshold will fail to identify 5% of ACTH-dependent cases. Consequently, patients with a random plasma ACTH level of less than 10 pg/ml should undergo a CRH challenge. In this test, ACTH levels are measured 10 to 30 minutes after injection of an intravenous bolus of CRH.5 If the plasma ACTH is less than 10 pg/ml after a CRH challenge and if the urinary free cortisol level is normal or high, the disorder is adrenal in origin; in other words, it is ACTH independent. Either CT or MRI scans will reveal these lesions with a high degree of accuracy. If no tumor is found on adrenal imaging studies, micronodular adrenal dysplasia should be suspected.6 The familial form of micronodular adrenal dysplasia, Carney syndrome, is an autosomal dominant disorder characterized by pigmented lentigines, blue nevi, and multiple tumors.
ACTH-secreting pituitary microadenomas are often too small to be visible on MRI scans [see 3:V Pituitary]. Consequently, patients with ACTH-dependent Cushing syndrome and a normal pituitary MRI should undergo an inferior petrosal sampling procedure to search for a gradient in ACTH levels between blood draining the pituitary gland (inferior petrosal sinus blood) and peripheral antecubital blood. An ACTH gradient greater than 3 between simultaneously sampled central and peripheral blood confirms a pituitary etiology for Cushing syndrome.7 If the gradient is less than 3, the search for an ectopic source of ACTH should be undertaken. Chest CT and MRI scans (with CT scans typically performed first) are central to this investigation, because 95% of these tumors are intrathoracic. The most common offending tumor is a bronchial carcinoid.
Except for atypical Cushing syndrome, in which the treatment is to discontinue exogenous glucocorticoid, all treatments for Cushing syndrome are surgical. ACTH-independent cases should be treated with adrenal tumor resection or, in the case of micronodular adrenal dysplasia, bilateral adrenalectomy. ACTH-dependent cases should be treated with transsphenoidal microadenomectomy or ablation of the ectopic ACTH-secreting tumor. When an ectopic source for ACTH cannot be identified, the patient can be treated temporarily with a cortisol synthesis inhibitor, most commonly ketoconazole, until the lesion is found. If it is not found within 18 to 24 months, bilateral adrenalectomy should be performed.
Effective surgery for an ACTH-secreting tumor renders the patient adrenally insufficient. This is documented by measurement of the plasma cortisol level on the morning after surgery. If the level is greater than 20 µg/dl, the operation has not been successful and no cortisol therapy is indicated. If the plasma cortisol level is below the normal range (i.e., less than 5 µg/dl), the operation has been successful, and steroid replacement therapy will be required until the hypothalamic-pituitary-adrenal (HPA) axis can recover—possibly 1 year or longer. During this period, the patient should be treated with hydrocortisone at a rate of 12 mg/m2 in a single daily dose with breakfast. Adrenal function is tested with a synthetic ACTH (cosyntropin) stimulation test at 3-month intervals. In patients with cortisol values between 5 and 20 µg/dl after cosyntropin stimulation, cortisol replacement therapy can be withdrawn; but 3-month testing should continue, and cortisol replacement therapy should be reinstituted if signs and symptoms of adrenal insufficiency appear. As soon as the cortisol level reaches 20 µg/dl or greater after cosyntropin stimulation, discontinuance of cortisol replacement without continued testing is safe.
If the operation has not been curative, Cushing syndrome will reappear with time. In addition to cortisol replacement, patients who have undergone bilateral adrenal resection will also require aldosterone replacement in the form of fludrocortisone, 0.1 mg each morning.
Without treatment, Cushing syndrome is fatal. Except for adrenal cancer, however, all causes of Cushing syndrome can be cured. Successful treatment restores normal life expectancy.
Adrenocortical cancer is a rare disease, with an annual incidence of 1 in 600,000.8 Thus, about 500 new cases are diagnosed in the United States each year. This disease usually presents clinically as a combination of steroid hormone excess syndromes, the most common being Cushing syndrome with virilization. Differential diagnostic tests will generally show ACTH-independent Cushing syndrome associated with increased serum testosterone levels in hirsute or virilized women. Occasionally, increased serum estradiol levels will be found in feminized men with Cushing syndrome. In rare instances, patients will present with virilization or feminization only, and some will have hypertension caused by tumor secretion of aldosterone precursors. CT or MRI scans usually show a large unilateral adrenal mass. Masses greater than 6 cm have a greater chance of being malignant. These tumors tend to be large when first discovered because the adrenal steroidogenic cells, in the course of dedifferentiation, become less efficient in cortisol synthesis. As a result, the tumor burden has to be large to yield the same clinical effect as a small, highly differentiated, benign adenoma.
The treatment of adrenocortical cancers is surgical. The first operation should focus on complete resection with clear margins. However, the incidence of surgical cure is unknown and is believed to be low, perhaps zero. With recurrence, each subsequent operation should focus on removing all visible disease, including accessible metastases. If left untreated, about half the patients with adrenocortical cancer will die in a few months. With aggressive surgery, their survival can be extended to about 48 months. When surgery is no longer feasible, treatment with steroid hormone synthesis blockers is indicated. Ketoconazole is typically used for this purpose. In addition, ortho, para′-DDD (mitotane) can be considered. At full dosages (> 2 g/day in divided doses), mitotane can produce remission in about 25% of patients. The average remission is 7 months long. Lengthened life span has not been demonstrated, and mitotane has severe side effects—nausea, vomiting, lethargy, and vertigo—so some physicians argue that the cost-to-benefit ratio (quality of life versus days of life gained) does not justify the use of this drug. Other chemotherapeutic regimens are under development, and patients with this rare disease are best served by referral to a center engaged in this research.9
Incidental Adrenal Masses
About 300,000 abdominal CT and MRI procedures are done annually in the United States for indications unrelated to the adrenals. An incidental adrenal mass (incidentaloma) is found in about 4% of these procedures, or 12,000 newly discovered masses each year.10Assuming that this is the incidence in the general population, there would be roughly 12 million such masses in the United States population. Assuming that adrenal cancers are detectable by MRI 6 years before they become clinically evident, the prevalence of adrenal cancer would be about 1 in 3,000 population. Therefore, 1 in 4,000 incidentally discovered adrenal masses will be an adrenal cancer.
Measurement of serum potassium and bicarbonate levels is appropriate in patients with an incidentaloma. Plasma free metanephrine measurement may disclose a pheochromocytoma. Dexamethasone suppression testing has been advocated,10 but its predictive value is only 0.5—no better than tossing a coin.
The central question in the management of the incidental adrenal mass is whether surgical removal is indicated. Certainly, the tumor should be removed if it is metabolically functional, as manifested by Cushing syndrome, the syndrome of mineralocorticoid excess, or virilization or feminization for which there is no other explanation. If there is no evidence of functionality, the tumor should be studied with a CT contrast washout study. Benign adrenal adenomas are lipid rich, whereas malignant ones tend to contain much more cellular and intercellular water. Thus, water-soluble contrast agents tend to wash out of benign lesions much faster than they do from malignant ones. The accuracy of this procedure in experienced hands is very high, with greater than 90% specificity and sensitivity.11,12
A mass that displays slow washout can be assumed to be a metastasis. If the patient has a known malignancy, the adrenal mass can be treated as part of the primary process. If there is no known primary malignancy, the mass could be the first manifestation of metastasis or a rare nascent adrenocortical carcinoma. Percutaneous needle biopsy can readily differentiate between these two possibilities, but it does involve risks, such as pneumothorax and tumor seeding. Alternatively, the mass can be removed laparoscopically and a pathologic analysis done.
In most series, 5% to 6% of incidental adrenal masses are pheochromocytomas.13 This possibility should be excluded before biopsy or operation so as to avoid the hypertensive crises that can be associated with surgery. The safest course is to assume that the lesion is a pheochromocytoma and to prepare all such patients for surgery with adequate alpha blockade [see Pheochromocytoma, below].
Adrenal insufficiency (Addison disease) is categorized as primary or secondary. Primary adrenal insufficiency results from destruction of the adrenal cortex. There is a long list of causes of primary adrenal insufficiency [see Table 3]; worldwide, tuberculosis is the most common cause, and in the industrialized nations, idiopathic or autoimmune adrenal destruction is the most common cause. Secondary adrenal insufficiency results from disruption of pituitary secretion of ACTH, which by far is most commonly caused by prolonged treatment with exogenous glucocorticoids. With time, doses of exogenous glucocorticoids sufficient to suppress ACTH secretion will lead to dysfunction of CRH-secreting neurons and attendant ACTH deficiency; subsequent withdrawal of glucocorticoids, for whatever reason, will then unmask the deficiency. Recovery of function may require a year or more. A far less common cause of disrupted ACTH secretion is destructive lesions in and around the pituitary gland and hypothalamus [see Table 4].
Table 3 Causes of Primary Adrenal Insufficiency
Table 4 Causes of Secondary Adrenal Insufficiency
The symptoms and signs of adrenal insufficiency can be grouped into chronic and acute syndromes. The chronic syndrome is characterized by anorexia, weight loss, fatigue, and orthostatic hypotension. In patients with primary disease, the predominant signs are weight loss and hyperpigmentation of the skin, especially of the sun-exposed areas and extensor surfaces. The acute syndrome is closely analogous to cardiogenic or septic shock, with reduced cardiac output into a dilated and unresponsive vascular system. Symptoms include prostration and all of the signs and symptoms of the shock syndrome. Shock in this setting tends to be unresponsive to volume replacement and vasoconstrictor therapy.
With both chronic and acute syndromes, the diagnosis should be suspected on clinical grounds, but it requires laboratory confirmation. The critical test for the diagnosis of chronic adrenal insufficiency is the cosyntropin stimulation test. Synthetic ACTH (cosyntropin) is administered in a 250 µg intravenous bolus, and plasma cortisol levels are then measured after 45 and 60 minutes. Values greater than 20 µg/dl exclude adrenal insufficiency as a cause of the clinical findings. Values less than 20 µg/dl suggest that adrenal compromise could be a contributing factor. In this situation, treatment with glucocorticoids is mandatory until the clinical situation is clarified with more precision.
In acute adrenal insufficiency, the most useful test is measurement of the plasma cortisol level. Cosyntropin stimulation testing is not necessary; the illness, which is sufficiently severe to merit admission to an intensive care unit, represents an endogenous source of maximal physiologic stress. Plasma cortisol levels in patients with acute stress are greater than 20 µg/dl, with the only exception being in patients who have a low plasma albumin concentration, which lowers the total cortisol concentration.14 Unfortunately, there are no published data on the interpretation of plasma cortisol values in patients with low albumin concentrations, so most clinicians adhere to the 20 µg/dl standard. Currently, if the cortisol value is less than 20 µg/dl, it should be confirmed with a standard cosyntropin stimulation test.
The differential diagnosis of adrenal insufficiency requires the discrimination of primary and secondary causes; the most useful test is measurement of the circulating plasma ACTH level. ACTH levels greater than normal define primary disease; values in the normal range or below define secondary disease.
Patients with primary adrenal disease should have the adrenal glands imaged with CT or MRI. Infectious, malignant, and vascular causes of adrenal insufficiency all result in enlargement of the adrenal glands. In idiopathic or autoimmune adrenal insufficiency, the glands are normal or small in size. Patients with secondary adrenal insufficiency should first be assessed for exogenous glucocorticoid use. If that can be eliminated as a cause, they should undergo CT or MRI scanning of the hypothalamus and pituitary gland to exclude destructive lesions in this area.
The goal in treating adrenal insufficiency is to replace the missing hydrocortisone and aldosterone in quantities calibrated to the clinical situation. Hydrocortisone can be replaced with oral or intravenous hydrocortisone. Aldosterone is replaced with oral fludrocortisone. Exogenous hydrocortisone and fludrocortisone are both equipotent with the endogenously secreted hormone. Unstressed persons secrete hydrocortisone at a rate of 6.5 mg/m2 daily. In the face of stress, such as a surgical procedure or serious trauma, hydrocortisone secretion can rise more than 10-fold. The secretion rate of aldosterone is 100 µg/day in persons consuming large amounts of sodium (i.e., a typical United States diet).
Primary chronic adrenal insufficiency is treated with oral hydrocortisone, 12 to 15 mg/m2/day. This is roughly double the amount of hydrocortisone that is normally secreted; the added amount is needed to compensate for first-pass hepatic metabolism. Hydrocortisone is best given as a single daily dose with breakfast. Fludrocortisone is given at a dose of 0.1 mg/day. When moderate stress is anticipated (e.g., a root canal procedure), the dose of hydrocortisone is temporarily doubled, beginning the day before the stress and continuing until 2 days afterward. It is not necessary to alter the fludrocortisone dose. With anticipated major stress (e.g., appendectomy with general anesthesia), the hydrocortisone dosage is increased to 100 mg every 6 hours from the day before the procedure until 2 days afterward. Hydrocortisone dosage increases are not required for periods of psychological stress, such as major depression, psychosis, or grief.
These replacement regimens roughly reproduce the patterns of cortisol and aldosterone secretion in persons with normal adrenal function. The need for these temporary dosage increases has not been clearly established, on either clinical or biologic grounds, but this has become the standard of practice and is not likely to change. Chronic secondary adrenal insufficiency is treated in the same way as chronic primary disease but with replacement of hydrocortisone only, not aldosterone.
Patients with acute adrenal insufficiency are treated in the same fashion as those with chronic adrenal insufficiency who are experiencing major stress. Treatment is monitored clinically. Signs of Cushing syndrome indicate overtreatment; hyponatremia, orthostasis, and anorexia indicate undertreatment. There is no good clinical evidence to suggest that the dosage regimens ever need to be exceeded. If a patient on recommended replacement doses of hydrocortisone and fludrocortisone fails to do as well as expected, the reason is something other than the adrenal replacement regimen.
All patients with adrenal insufficiency should wear a medical-alert bracelet imprinted with the words “adrenal insufficiency” and carry a similar wallet card at all times.
The adrenal medulla accounts for about 10% of the weight of the adrenal gland. It is composed primarily of chromaffin cells, which are named for the yellow-brown color they take on when stained with chromatic salts. The cells of the medulla are directly innervated by preganglionic sympathetic nerve cells. Hence, these epinephrine-secreting cells are analogous to the postganglionic neurons in the other areas of the sympathetic nervous system. These cells are not neurons, however, and have no dendrites or axons. In addition, the primary secretory product of the adrenal medulla is epinephrine, whereas the remainder of the sympathetic nervous system employs norepinephrine as the neurotransmitter. The reason for this difference is that the blood supply to the adrenal medulla is derived from the capillary plexus draining the adrenal cortex. This capillary blood is extremely rich in cortisol—perhaps the highest concentration of cortisol in the human body is in the adrenal medulla—and cortisol induces catechol-O-methyl transferase, the enzyme that converts norepinephrine to epinephrine. The primary disease of the adrenal medulla is pheochromocytoma; 90% of pheochromocytomas occur in the adrenal medulla. Extra-adrenal tumors of the chromaffin cell are known as paraganglions or chemodectomas, depending on the location. All have similar clinical presentations, and all are treated in the same way (see below).
The main clinical manifestation of pheochromocytomas is hypertension. The hypertension can be sustained or episodic; the two forms occur with equal frequency. Paroxysmal hypertension is associated with tachycardia, diaphoresis, anxiety, and a sense of foreboding. Patients also complain of nausea and abdominal pain. The association of headache, palpitations, and sweating with hypertension has a high (> 90%) sensitivity and specificity for pheochromocytoma. The differential diagnosis for pheochromocytoma is extensive and includes anxiety and panic attacks, thyrotoxicosis, amphetamine and cocaine use, and use of over-the-counter cold medicines that depend upon catecholamines for effect, such as atomizers for nasal congestion [see Table 5]. Pheochromocytomas are usually benign (90%) and usually unilateral (90%). The incidence of pheochromocytoma is markedly increased in several genetic syndromes: multiple endocrine neoplasia types 2a and 2b and the phakomatoses, including neurofibromatosis, cerebelloretinal hemangioblastosis, tuberous sclerosis, and Sturge-Weber syndrome.
Table 5 Differential Diagnosis of Pheochromocytoma
The traditional tests for diagnosing pheochromocytoma are measurements of the urinary fractionated catecholamines and urinary metanephrine excretion in 24-hour urine samples. Total catecholamine excretion is normally less than 100 µg/day, with no more than 25% being epinephrine. Urinary metanephrine excretion is normally less than 1.3 mg/day. The urine for these tests must be collected in an acid medium (laboratories typically provide appropriate containers) and need not be refrigerated. Creatinine should also be measured, as an indicator of completeness of collection. The patient should be taken off all medications when possible. If the hypertension must be treated, diuretics, vasodilators, calcium channel blockers, and angiotensin-converting enzyme (ACE) inhibitors interfere minimally with the assays. When there is concordance between the clinical picture and the biochemical tests, CT or MRI scans should be employed to localize the tumor. MRI is particularly useful because these tumors almost always “brighten” with T2-weighted images. If CT and MRI fail to reveal an adrenal tumor, radiolabeled meta-iodobenzylguanidine (MIBG) can be a useful scanning technique for locating tumors outside of the adrenal gland, such as those in the carotid body, heart, urinary bladder, and the organ of Zuckerkandl.
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 intraoperative 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 phenoxybenzamine, 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.
Figure 5. Congenital Adrenal Hyperplasia
Congenital adrenal hyperplasia may result from mutations that inactivate any of the six enzymatic steps in the biosynthesis of cortisol from cholesterol. The clinical manifestations of the disorder vary with the enzyme deficiency.
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:V Polycystic Ovary Syndrome].
The diagnostic test for 21-hydroxylase deficiency is a cosyntropin stimulation test: synthetic ACTH is administered in a 250 µg intravenous bolus, and plasma levels of 17-hydroxyprogesterone are measured after 45 and 60 minutes. 17-Hydroxyprogesterone is the steroid biosynthetic intermediate immediately proximal to the enzyme defect. In normal patients, 17-hydroxyprogesterone 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.
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-hydroxyprogesterone 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 hypertrophic 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 can be primary or secondary. In primary hyperaldosteronism, there is disordered function of the renin-aldosterone feedback axis; in secondary hyperaldosteronism, the renin-aldosterone axis is responding normally to chronic intravascular 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 mineralocorticoid excess syndrome, characterized by hypokalemia, metabolic alkalosis, and, sometimes, hypertension.
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 hyperaldosteronism present with hypertension; in fact, primary adrenal hypersecretion of aldosterone is thought to account for about 2% of cases of hypertension. Laboratory testing shows hypokalemia and metabolic alkalosis, with a serum sodium level that is usually in the high-normal range [seeFigure 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).
Figure 6. Diagnosis of Primary Aldosteronism
Differential diagnosis of primary hypoaldosteronism. (PRA—plasma renin activity)
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 Hyperaldosteronism, below], and idiopathic bilateral adrenal hyperplasia, in which the hypertrophic zona glomerulosa secretes aldosterone independent of renin-angiotensin stimulation [see Idiopathic 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, aldosterone levels decrease by the third day of treatment. If dexamethasone 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 hypoaldosteronism 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 antihypertensive therapy, which is managed as if essential hypertension were present.
Idiopathic Bilateral Adrenal Hyperplasia
The clinical presentation of idiopathic bilateral adrenal hyperplasia is indistinguishable from that of primary hyperaldosteronism 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 spironolactone 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.
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-β hydrolase is coupled with the coding region for aldosterone synthase. Thus, aldosterone secretion becomes entrained to ACTH secretion and is “blind” to renin-angiotensin levels. Because ACTH secretion is not modulated by aldosterone, 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 dexamethasone, usually 0.5 mg in a single daily dose.
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 nephropathies. 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-hydroxylase deficiency. Both renin and aldosterone levels are low in these disorders. Treatment is the same as that for 21-hydroxylase 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:II Disorders of Acid-Base and Potassium Balance].
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 autosomal 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.
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, hyponatremia, 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 aldosterone 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. Pseudohypoaldosteronism 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 mineralocorticoid 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; hydrochlorothiazide and furosemide are most often used.
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 glucocorticoid, 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 glucocorticoid 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 hydrocortisone at the replacement dose should undergo cosyntropin stimulation testing every 3 months. When the plasma cortisol response to cosyntropin exceeds 20 µg/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 glucocorticoid treatment in the setting of an uncontrolled inflammatory or neoplastic illness.
Figures 3, 4, and 5 Seward Hung.
Editors: Dale, David C.; Federman, Daniel D.