Diseases of the adrenal cortex

DISEASES

OF THE CORTEX

C. R. Kannan,

ADRENAL

M.D.

Associate Professor in Medicine Rush-Presbyterian-St. Luke’s Medical Center Chairman of Endocrinology Cook County Hospital Chicago, Illinois

DM 34(10):601-674, 1988 0 1988, Year Book Medical 0011~5029mvlO-601-6x-$9.%

Pubtbhen,

Inc.

F+omwoRD Multiple recent advances have occurred in our understanding of diseases of the adrenal cortex. In this monograph, Dr. Kannan provides a framework to understand these diseases and the recent advances that have taken place in diagnosis and treatment. Dr. Kannan is adept at the application of basic concepts to clinical situations, as this monograph demonstrates. This is a superb contribution to Disease-a-Month. Roger C. Bone, M.D. Editor-in-Chief mu, October 1sss

DISEASES

OF THE ADRENAL

CORTEX

ABSTRACT.-The adrenal cortex is functionally a three-dimensional gland that secretes glucocorticoids, mineralocorticoids, and sex steroids. Of these three classes of steroids only the gluco- and mineralocorticoid hormones are necessary to sustain life. The availabllity of sensitive and specific radioimmunoassays has permitted accurate measurement of practically every steroid hormone secreted by the adrenal cortex. As in other endocrinopathies, suppression studies are employed when hyperfunction is suspected, while provocative tests are used to detect hypofunction. These dynamic studies enable the clb& cian to evaluate the functional status of the adrenal cortex. The anatomic configuration of the adrenal cortices is delineated by high-resolution computed tomography (and magnetic resonance imaging), obviating the need for invasive procedures such as venography or arteriography. The disorders of the adrenal cortex can be viewed from the dual perspectives of hyperfunction and hypofunction. Clinical expressions of hyperfunctional adrenocortical syndromes include Cushing’s syndrome, primary hyperaldosteronism, and the adrenogenital syndrome. The expressions of hypofunctional syndromes include Addison’s disease and selective hypoaldosteronism. The diagnosis and treatment of these disorders are outlined in this issue. IN CUSHZNG’S

BRIEF

SYNDROME

Cushing’s syndrome refers to a constellation of features that evolve as a result of sustained hypercortisolism. The most common cause of endogenous hypercortisolism is pituitary disease, usually secondary to microadenomas of the anterior pituitary that secrete corticotropin (ACTH). The non-ACTH dependent causes for Cushing’s synfIo9

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drome include intrinsic adrenal disease conditions (such as adenoma, carcinoma, or bilateral nodular hyperplasia of the adrenal cortex) as well as the ectopic secretion of ACTH (or, rarely, corticotropin-releasing hormone [CRHI) by neoplasms in the chest or abdomen. The clinical features of hypercortisolism can be strikingly obvious or misleadingly subtle. Indeed, nonspecific features such as obesity, hypertension, glucose intolerance, and mild hirsutism often initiate the search for hypercortisolism. When these features are associated with myopathy, easy bruisability, atrophic skin with striae, psychopathy, or bone loss, screening for Cushing’s syndrome becomes mandatory. The diagnosis of hypercortisolism can be established by demonstrating an elevated level of urinary free cortisol in a 24-hour collection. The hormonal maneuvers that are used to arrive at an etiologic diagnosis of hypercortisolism revolve around the basic issue of whether or not the hypercortisolemia is ACTH dependent. Thus, the combination of preservation of suppressibility to high-dose dexamethasone, and preservation of responsiveness to metyrapone administration denote ACTH dependency, indicating a pituitary source of hypercortisolemia. In contrast, lack of response to either or both maneuvers would tend to point to an autonomous adrenal disease condition (tumor, bilateral nodular hyperplasia, carcinoma) or to ectopic ACTH secretion by neoplasm. Measurement of basal ACTH levels, while being of adjunctive help, does not always separate pituitary-dependent disease from ectopic ACTH-secreting neoplasms, particularly carcinoids. Despite the availability of sophisticated hormone assays and imaging equipment, the identification of the cause can, at times, be extremely difficult. Nowhere is this illustrated better than in the distinction between pituitary-dependent Cushing’s disease not identified on computed tomography (CT) and an occult neoplasm with ectopic secretion of ACTH. The availability of synthetic CRH for studying the ACTH response to CRH, as well as the emergence of selective catheterization of the inferior petrosal sinus, should-one hopes-aid in making the distinction. The treatment of Cushing’s syndrome depends on the cause. The ideal therapy for Cushing’s disease caused by pituitary microadenoma is transsphenoidal microadenomectomy, while adrenal adenomas are treated by unilateral adrenalectomy. Surgical debulking also plays a major role in the therapeutic strategies for the devastating adrenal carcinoma. Bilateral total adrenalectomy is the choice of therapy for bilateral nodular disease. Finally, the treatment of ectopic ACTH secretion is aimed at the primary neoplasm. Adrenolytic therapy with metyrapone, mitotane, and more recently ketoconazole, can be used to lower cortisol levels regardless of the cause of disease. DA4, October

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ADDISON’S

DISEASE

Addison’s disease results from progressive destruction of both adrenal cortices by intrinsic disease processes. The adrenal cortices are highly resilient to destruction and, hence, clinically overt adrenal failure results only after more than 70% to 80% of tissue is destroyed. However, partial adrenal insufficiency, with lim ited reserve, can lead to acute decompensation when triggered by stress. Partial adrenal insufficiency is probably underdiagnosed, as the symptoms and signs of this entity are m isleadingly vague. The three most common causes for adrenal failure are autoimmune adrenalitis, chronic infections (particularly tuberculosis or fungal disease), and metastatic carcinomatosis of the adrenals. Of these autoimmune adrenalitis is noteworthy owing to its propensity of being part of the pluriglandular autoimmune syndromes that involve other endocrine glands. Iatrogenic causes for adrenal failure should be always considered in the etiology of adrenal failure. The most notable of these are sudden withdrawal from glucocorticoid therapy, use of anticoagulants, and exposure to high-dose ketoconazole or to the anesthetic agent etomidate. The clinical diagnosis of Addison’s disease involves a high index of suspicion, since several symptoms of this disease are nonspecific. Thus, it is not uncommon for patients to have seen specialists in gastroenterology, dermatology, psychiatry, gynecology, and hematology before the entire picture is put together by the astute internist. The three cardinal features of chronic adrenocortical insufficiency are weight loss, fatigue, and weakness. When present, generalized hyperpigmentation, orthostasis, and electrolyte abnormalities thyponatremia and hyperkalemia) are strong clues for the presence of the disease. The laboratory hallmark of Addison’s disease is the inability of the adrenal cortex to respond to sustained administration of exogenous ACTH. Measurement of basal cortisol levels alone does not provide clear separation between healthy individuals and patients with limited adrenal reserve. After documentation of Addison’s disease by hormonal tests, CT scanning of the adrenals can provide valuable insight into the cause. The treatment of Addison’s disease is lifelong replacement with glucocorticoid (and, when indicated, m ineralocorticoid) hormones. PRIMARY

HYPERALDOSTERONZSM

Primary hyperaldosteronism refers to absolute or relative omy of the zona glomerulosa, resulting in m ineralocorticoid This contrasts with secondary hyperaldosteronism, in which alocorticoid excess is secondary to hyperreninemia. Primary 60s

autonexcess. m inerhyper-

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aldosteronism is most commonly caused by a unilateral adenoma. mess common causes include bilateral hyperplasia, glucocorticoidsuppressible hyperaldosteronism, and adrenal carcinoma. Regardless of the cause, the manifestations of hyperaldosteronism are hypertension and hypokalemia. The hypertension in primary hyperaldosteronism is usually, but not invariably, benign. Although hypokalemia is an important clue for hyperaldosteronism, approximately 20% of patients may have normal concentrations of serum potassium. The hormonal diagnosis of primary hyperaldosteronism rests on demonstration of elevated, nonsuppressible aldosterone levels, and suppressed plasma renin activity. The two hormonal tests that help in the distinction between adenoma and hyperplasia are the response of plasma aldosterone to the patient’s standing posture between 8 AM and noon, and plasma levels of 1%hydroxycorticosterone with the patient in the recumbent state. The definitive localizational procedures for determining the source of hyperaldosteronism are CT study of the adrenals, and selective catheterization of both adrenal veins for effluent studies. The treatment for primary aldosteronism depends on the cause. Thus, unilateral adrenalectomy is the ideal treatment for unilateral adenoma. Idiopathic hyperplasia and glucocorticoid-suppressible hyperaldosteronism are treated with long-term administration of spironolactone and dexamethasone, respectively. SELECTIVE

HWOALDOSTERONISM

The term selective hypoaldosteronism denotes impaired or absent mineralocorticoid secretion by the zona glomerulosa in the presence of intact glucocorticoid reserve. While structural, enzymatic, and functional lesions can selectively involve the zona glomerulosa, the most commonly encountered form of selective hypoaldosteronism is called hyporeninemic hypoaldostenmism. The aldosterone deficiency in this disorder is a result of inadequate generation of renin by the juxtaglomerular apparatus. The most common renal disease process that underlies hyporeninemic hypoaldosteronism is diabetic renal disease. However, the syndrome can be seen in association with a spectrum of renal diseases such as interstitial nephropathy, glomerulosclerosis, gout, lead nephropathy, and analgesic nephropathy, particularly with the use of indomethacin. The prototypical patient with hyporeninemic hypoaldosteronism is middle-aged, diabetic, and has mild to modest renal insufficiency. The presence of hyperkalemia out of proportion to the degree of renal insufficiency is the biochemical marker for hyporeninemic hypoaldosteronism. While diabetics with neuropathy and orthostatic hypotension are more prone to develop this syndrome, the condiDM, October

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tion can occur in diabetic patients without neuropathy, or other chronic complications of diabetes. The diagnostic triad for hyporeninemic hypoaldosteronism consists of a subnormal renin level that poorly responds to posture, a unique variety of renal tubular acidosis (type IV RTA) and intact glucocorticoid reserve demonstrated by a normal Cortrosyn stimulation test. The treatment of hyporeninemic hypoaldosteronism involves prolonged treatment with an oral mineralocorticoid such as So-fludrocortisone. Although relatively supraphysiologic doses of mineralocorticoids are required, the response to such therapy is usually impressive, with gradual improvement in the hyperkalemia and the metabolic acidosis. In addition to hyporeninemic hypoaldosteronism, selective deficiency of mineralocorticoids can result from congenital absence of the enzyme corticosterone methyl oxidase, acquired defects in the zona glomerulosa (autoimmune destruction), and heparin use. ADRENOGENZTAL

SYNDROMES

The adrenogenital syndromes are a group of diverse disorders characterized by adrenal androgen excess originating from enzymatic defects in cortisol biosynthesis. The basic abnormality that sets the stage for androgen hypersecretion is partial or complete lack of one or more enzymes involved in the synthesis of cortisol. As a result, ACTH release is stimulated, with consequent increase in the adrenal biosynthesis of several precursors proximal to the block. These precursor products are eventually channeled into increased androgen synthesis by the zona fasciculata and reticularis zones. Although any enzyme within the steroidogenesis cascade can be involved, in clinical practice the two most commonly encountered enzyme blocks involve 21-hydroxylase and lip-hydroxylase. The clinical expressions of adrenogenital syndrome depend on the degree of enzyme deficiency (partial or complete), the type of enzyme involved (2l- or I#-hydroxylase), and whether or not the zona glomerulosa is also involved. Thus, the “simple virilizing form” evolves when 21-hydroqlase is completely absent in the zona fasciculata only. The term “salt losing” variety of 21-hydroxylase deficiency implies complete lack of the enzyme in both the zona fasciculata and glomerulosa, with consequent loss of mineralocorticoid hormones as well. The “hypertensive” variety of adrenogenital syndrome is encountered when the ll-hydroxylase enzyme is completely absent, resulting in excess of both androgen precursors and mineralocorticoid precursors. Thus, the three major manifestations in the neonate with adrenogenital syndrome are virilization of the female fetus, electrolyte disturbances, and adrenal insuRiciency. Partial defects in cortisol biosynthesis manifest in childhood as premature adrenarche in girls and isosexual precocious development in 810

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boys, or in adulthood as hirsutism, oligomenorrhea, and infertility in women, and oligospermia in men. The diagnosis of the various forms of adrenogenital syndromes can be accomplished by accurate measurement of the precise precursor. Plasma levels of 17&-hydroxyprogesterne serve as an excellent marker in the detection of 21- and Il-hydroxylase deficiencies. Recent developments in this dynamic field have permitted diagnosis of 21-hydroxylase deficiency in utero, as well as identification of siblings at high risk by study of the human lymphocyte antigen type. The treatment of all forms of adrenogenital syndrome is glucocorticoid replacement in an attempt to suppress ACTH secretion.

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C. R. Kannan, M.D., is the Chairman of Endocrinology at Cook County Hospital and Associate Professor in Medicine at Rush-Presbyterian-St. Luke’s Medical Center. He obtained his M.D. degree from the University of Madras, Zndia, receiving the Johnstone Gold Medal Award for academic e.xcellence. He did his residency and fellowship training at the Cook County Hospital. As a specialist in endocrinologv, Dr. Kannan has single authored numerous textbooks, such as A Clinician’s Approach to Endocrine Problems, Essential Endocrinology, The Pituitary Gland, and The Adrenal Gland. 612

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DISEASES

GUSHING’S

OF THE

ADRENAL

COFWEX

SYNDROME

The term “Cushing’s syndrome” refers to a constellation of features that reflect the expression of sustained glucocorticoid hypersecretion. For semantic clarity, the generic term “hypercortisolism” denotes all forms of glucocorticoid excess, regardless of cause. The term “Cushing’s disease” (CD) refers to the pituitary-corticotropin (ACTH) dependent form of hypercortisolism, while the term Cushing’s syndrome, in a purist sense, has come to be associated with the form of hypercortisolism arising from primary adrenal disease or from ectopic secretion of ACTH by nonadrenal neoplasms. The iatrogenie variety of hypercortisolism that evolves from chronic glucocorticoid therapy is often referred to as exogenous hypercortisolism, in contrast to true hypersecretion of cortisol by the adrenal cortex, which is referred to as endogenous hypercortisolism. ETIOLOGY Pituitary ACTH-Dependent Hypercortisolism Kushing’s Disease) This form of hypercortisolism represents 65% to 70% of cases of endogenous hypercortisolism, and is most often secondary to microadenomas (tumors < 1 cm) of the anterior lobe of the pituitary. Less commonly, CD can be secondary to macroadenomas that are localized or invasive. Very rarely, Cushing’s disease can develop because of corticotrope hyperplasia, intermediate lobe tumors, or carcinoma of the pituitary. While the anatomic etiology of CD is relatively clear, the physiologic basis for the development of the disease is far from explicit. The controversy revolves around a very basic issue: Is CD a “primary derangement of the pituitary gland,” as originally proposed by Dr. Harvey Cushing in 1932,’ or does it represent ACTH hypersecretion as a consequence of hypothalamic overdrive? The body of evidence that supports a predominantly pituitary etiology includes the high percentage of pituitary microadenomas found during surgery on patients with CD, the increasing number of “cures” attained following successful microadenomectomy, and the behavior of tumorous corDM, October

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ticotropes grown in cultme Several in vitro studies3’4 of isolated tumor cells from patients with CD have demonstrated that tumor cells respond to neuropharmacologic agents such as reserpine and cyproheptadine, while being partially suppressible to dexamethasone. These data impart inherent behavioral properties to tumorous corticotropes in the obvious absence of any hypothalamic mediation. The body of evidence that supports hypothalamic overdrive as a mechanism for CD is also compelling and includes the following lines of evidence: the persistence of abnormal ACTH-cortisol dynamics in patients with CD even after restoration of eucortisolemia5; the suppression of pituitary ACTH by various neuropharmacotherapeutic agents, particularly cyproheptadine, a drug that predominantly exerts its action on the central nervous system and hypothalamus’; the provocative effect of exogenous administration of synthetic ovine corticotropin-releasing hormone (CRH) on pituitary ACTH in patients with CD’; the observation that ectopic CRH-secreting tumors can mimic several dynamic features seen in CD’; and, finally, the development of Nelson’s syndrome following bilateral adrenalectomy for CD. While controversy continues as to the exact nature of the underlying abnormality in CD, support has been provided for the existence of two subtypes of CD, one CRH dependent and another that is CRH independent. While most ACTH-secreting tumors of the pituitary arise from the anterior lobe, occasionally they can originate from the intermediate lobe, an area that is not anatomically well delineated in humans. The five characteristics of such tumors are’: 1. The presence of argyrophilic nerve fibers coursing within and around the tumor, suggesting a neural origin. 2. Resistance to dexamethasone suppression, but response to dopamine agonists such as bromocriptine. 3. The frequent occurrence of hyperprolactinemia. 4. The relatively poor visualization by imaging techniques. 5. Most important, the poor response to transsphenoid microadenomectomy.

Adrenal Tumors Adrenal adenomas, and less commonly adrenal carcinomas, represent autonomous secretion of cortisol by primary adrenal neoplasms. The hallmark of these tumors is their nonsuppressibility by any dose of exogenously administered dexamethasone. In addition to these solitary, unilateral neoplasms, bilateral nodular disease of the adrenals can result in Cushing’s syndrome. The entities of micronodular and macronodular adrenal hyperplasia causing Cush614

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ing’s syndrome are regarded as “hybrid disorders,” characterized by semiautonomy of the adrenal nodules-with predominance of the pituitary influence at one time and of the adrenal at another.‘“-‘2 Abnormalities of the hypothalamic pituitary axis may have initiated the process, with eventual transformation of diffuse hyperplasia into nodular (micro or macro) hyperplasia. The therapeutic importance of recognizing the bilateral nature of these disorders is obvious. In recent years, another form of bilateral nodular adrenal disease termed “primary adrenocortical nodular dysplasia” (PAND) has emerged as a distinct entity.13-15 Functionally, these nodules, present in both adrenal cot&es, are believed to originate de novo from the adrenal glands without any ACTH mediation, and are thus autonomously functioning. Anatomically, these nodules show a characteristic black or brown pigmentation, with atrophy of the normal internodular adrenal tissue. Clinically, PAND is highlighted by several important features: the young age of onset (in children, adolescents, or even infants), the familial tendency, the mild nature of hypercortisolism and the high incidence of osteopenia. The hypercortisolism of PAND is nonsuppressible to dexamethasone administrati’on, and is curable only by bilateral total adrenalectomy, with practically no incidence of Nelson’s syndrome. Several somatic abnormalities have been described in association with PAND, the three most common being spotty pigmentation of skin, cardiac myxomas, and Sertoli cell tumors of the testes. Ectopic ACTH Secretion Although the ability of certain malignant tissues to synthesize precursors of ACTWendorphin appears to be ubiquitous, ectopic ACTH secretion evolves only when the tumor tissue possesses the machinery to cleave the precursors into biologically active ACTH. The ectopic ACTH molecule has a larger molecular weight than native ACTH, and contains the N-terminal region of pro-opiocortin, a fragment that has been clearly shown, in vitro, to possess adrenocorticotropic properties. Comparisons of the immunoreactivity with the bioactivity of the ectopic ACTH molecule reveals that this molecule possesses much lower bioactivity, relative to its immunoreactivity.16 While any tumor can secrete ACTH, the ectopic ACTH syndrome is most commonly associated with tumors of the APIJD (amine precursor uptake decarboxylation) system. Thus, oat cell carcinoma of the lung, carcinoids of the bronchus or pancreas, gastrinomas, malignant thymoma, pheochromocytoma, and medullary carcinoma of the thyroid are all notorious for their proclivity toward ectopic ACTH secretion. In addition, certain tumors can secrete CRH, which in turn stimulates pituitary ACTH. The similarity between ectopic CRH secretion and pituitary ACTH-dependent CD is legendary. DM, October

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CLINICAL

FEATURES

The features of hypercortisolism can be striking enough to be recognized at a glance, or subtle enough to elude the diagnosis. The evolution of the classic cushingoid facies is a gradual process. The characteristic fat distribution results in truncal obesity-with fat deposition in the abdomen, face, and the dorsocervical and supraclavicular regions, striking an odd contrast with the thin extremities that are wasted from the catabolic effects of glucocorticoids. The characteristic cushingoid striae result from skin atrophy coupled with loss of collagen, imparting a peculiar violaceous hue to the broad striae. In several series,17-1g the frequency of findings encountered in patients with hypercortisolism have been analyzed. Although many features of hypercortisolism can be encountered in diverse disease states, when they collectively occur in the same patient, Cushing’s syndrome is more likely to be present. Indeed, the old aphorism that “the presence of thin skin, thin muscle, and thin bones in a fat person should raise the possibility of Cushing’s” is still an excellent one, since cutaneous atrophy W%), myopathy (90%), osteopenia (>50%), and obesity (defined as >15% ideal body weight) (80%) are frequently encountered features in Cushing’s syndrome. The myopathy of Cushing’s syndrome is a direct result of chronic glucocorticoid excess.2o The primal action of glucocorticoids is to provide the liver with substrates for gluconeogenesis. These substrates are derived from skeletal muscle. Hypercortisolemia decreases uptake of amino acids by skeletal muscle, in addition to promoting increased breakdown of skeletal muscle protein. As a result, there is weakness of muscle, with eventual wasting. Subjective or objective muscle weakness is a strong clue to the presence of underlying hVypercortisolism, and is seen in 85% to 90% of patients. Like most endocrine myopathies, the proximal muscles bear the brunt, with minimal and nonspecific chemical, structural, and electromyographic abnormalities. Of course, myopathy is less likely to be present when the Cushing’s syndrome has rapidly evolved, or when excessive androgens, anabolic in nature, are present, as in adrenal carcinoma. Finally, the presence of hypokalemia in some patients with Cushing’s syndrome can compound the muscle weakness. Hypertension, present in more than 60% of patients with Cushing’s syndrome, is usually modest and responds excellently to therapy. It is generally agreed that mineralocorticoid mediation is not a factor in the development of the hypertension, and that the reninangiotensin-aldosterone axis shows no significant alteration in patients with hypercortisolism. Increased retention of sodium, as well as a direct effect of glucocorticoids on vascular smooth muscle, is 616

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considered to play a role in the causation of hypertension. The possible role of decreased activity of the kallikrein-kinin system in Cushing’s syndrome is speculative. Psychiatric disturbances dominate the clinical spectrum of Cushing’s syndrome. Thus, depression, paranoid ideation, emotional lability, delusions, and suicidal tendencies are often present regardless of the etiology. Occasionally, acute psychosis can be the sole The relevance of psychopathy in manifestation of hypercortisolism.21 patients suspected of having Cushing’s syndrome is twofold: first, the spectrum of psychiatric abnormalities encountered in patients with Cushing’s syndrome is entirely reversible upon restoration of eucortisolemia, and second, endogenous depression per se can mimic the steroid dynamics of Cushing’s syndrome, causing confusion in the diagnosis. In addition to the plethoric appearance, cutaneous atrophy, myopathy, hypertension, and psychiatric abnormalities, several other features can be encountered with variable frequency. Thus, easy bruisability, backache, menstrual irregularities, headache, glucose intolerance or even overt diabetes, and nephrolithiasis can be seen in patients with Cushing’s syndrome. Growth retardation is an important expression in childhood Cushing’s. In rare cases fat deposition can occur in unusual areas (“lipomatosis”) such as the mediastinum, liver, paracardiac space, and even the epidural space. Other unusual but important features that may be seen in patients with Cushing’s syndrome are the occurrence of cyclical edema, and an increased tendency for developing thromboembolic phenomena and superficial cutaneous fungal infections. In addition to the clinical features common to all forms of hypercortisolism, specific physical findings may be seen depending on the underlying causes for the hypercortisolism. Pituitary-dependent CD is characterized by its slow evolution. When the disease is caused by invasive macroadenoma the clinical picture can be dominated by sellar compression symptoms such as headache or visual field cuts. Increased pigmentation and galactorrhea am seen in less than one third of patients. While hirsutism can be present, it is generally mild and is seldom associated with virilization. In contrast, impressive hirsutism and even virilization characterize the Cushing’s syndrome caused by adrenal cortical carcinoma. The hallmark of this carcinoma is the massive hypersecretion of adrenal androgens. The hypercortisolism secondary to ectopic ACTH secretion can take several forms. The usual variety is seen in patients with a documented cancer, such as oat cell cancer of the lung, and is highlighted by the triad of wasting, pigmentation, and striking metabolic alterations (hypokalemia, metabolic alkalosis, and hyperglycemia). The plethoric features of Cushing’s syndrome are characteristically absent because of the terminal nature of the underlying malignancy. However, pleDM, October 1988

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thoric Cushing’s syndrome can be caused by ectopic ACTH secretion when the underlying malignancy is relatively nonaggressive. This is the case with bronchial carcinoids, medullary carcinoma of the thyroid, and pheochromocytomas that secrete ACTH. In such instances the clinical, hormonal, and dynamic features can closely mimic those of pituitary-dependent Cushing’s disease. The fact that such tumors can remain occult adds to the diagnostic difficulties in such cases. LABORATORY

FEATURES

The laboratory features of Cushing’s syndrome can be viewed from several vantage points: routine laboratory tests, hormonal tests for screening, hormonal tests that provide the etiologic diagnosis, and procedures for localization. Routine

Laboratory

Tests

While routine laboratory tests hardly provide diagnostic specificity, the first clue for the presence of hypercortisolism may be derived from these tests. Two in particular, electrolyte and glucose, deserve mention. Hypokalemic alkalosis, spontaneous or diuretic induced, not infrequently represents the starting point for the pursuit of hypercortisolism. Hypokalemia is much more common in ectopic ACTH secretion, presumably because of the magnitude of cortisol elevation in the plasma as well as the glomerulotropic effects of the ectopic ACTH molecule, resulting in increased concentrations of desoxycorticosterone (DOC) 18-hydroxy-DOC and rarely even aldosterone. The hyperglycemia of hypercortisolism is the result of two factors: the increased hepatic glucose output from steroid-induced gluconeogenesis and glycogenolysis, and the anti-insulin effect of glucocorticoids, believed to be exerted at the postreceptor level. Rarely, abnormal radiologic studies may initiate the diagnostic work-up for hypercortisolism. An abnormal radiograph of the chest (mediastinal lipomatosis), the finding of osteopenia, the demonstration of nephrolithiasis, or a serendipitously discovered adrenal mass lesion are a few examples where the diagnostic spotlight may have been focused on Cushing’s syndrome by the radiologic studies. Screening

for Hpercortisolism

The following list represents indications where screening for hypercortisolism is appropriate, and even mandatory. 1. In the hypertensive patient with puffiness of face or ankle edema, recent weight gain and easy bruisability, and/or spontaneous hypokalemia. 618

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2. Significant weight gain of recent onset in presence of muscle weakness, menstrual irregularity, or unexplained psychiatric symptoms. 3. Unexplained osteopenia. 4. Growth retardation. While the best screening test for hypercortisolism is the measurement of the 24-hour urinary free cortisol, the overnight dexamethasone suppression test continues to be in vogue because of its simplicity. .&&Hour Urinary Free CorksoL-This test measures the amount of cortisol that is “free” (i.e., unbound to transcortin). Hence, it represents the metabolically active moiety of cortisol. The binding of cortisol to its globulin (transcortin) typically begins to reach saturation when the serum cortisol exceeds approximately 24 kg%. Above this level, there is a disproportionate increase in the excretion of the unbound or “free” cortisol. Because the globulin-bound cortisol is not filtered by the kidneys, measurement of the ‘free” cortisol, which is freely excreted by the kidneys, reflects the amount of cortisol above and beyond the saturation of transcortin. The measurement of the W-hour urinary free cortisol in screening for hypercortisolism has three distinct and outstanding advantages. First, the urinary free cortisol measures the integrated glucocorticoid activity in a 24-hour period. Second, this measurement is not affected by transcortin levels, unlike plasma cortisol, which can be elevated whenever the binding globulin is increased (pregnancy, obesity, and so forth). Third, and more important, in situations of true hypercortisolism, the rise in urinary free cortisol proceeds in an exponential fashion because of the saturation of all sites within transcortin. This contrasts with the rise in metabolite (17-hydroxycorticosteroid; 17-OH-CS) excretion, which proceeds in a linear fashion. This is the reason why measurement of 24-hour urinary free cortisol is clearly superior in its sensitivity for screening patients suspected of hypercortisolism. The sensitivity and specificity of urinary free cortisol measurement in detecting true hypercortisolism approaches 96%.22 Excellent as the test is, false positive elevations may be seen in situations of stress, as well as in endogenous depression, and of course in patients receiving cortisone or hydrocortisone in supraphysiologic amounts. The Overnight De,xamethasone Suppression Test.-This test23’24is based on the principle that when 1 mg of dexamethasone is administered orally to healthy individuals around midnight, before sleep, it abolishes the nycterohemeral ACTH rise. As a result, the cortisol level at 8 AM on the morning after dexamethasone will be suppressed below 5 pg% . The dexamethasone administered is potent enough to DM, October1988

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suppress the hypothalamic pituitary axis but does not interfere with measurement of cortisol. The unique features of the overnight dexamethasone suppression test (DXM test) are the ease with which it can be performed, as well as its simplicity and inexpensiveness. Also, the test carries an extremely low incidence of false negative results (i.e., in patients with true hypercortisolism plasma cortisol is seldom suppressed below 5 ~g after overnight dexamethasone). Unfortunately, the factor that limits the diagnostic utility of the DXM test relates to the unacceptably high incidence of false positive resUlts.25,26For instance a sizable percentage (20% to 35%) of patients with obesity, as well as those with depression, stress, alcohol abuse, and use of certain medications (birth control pills, anticonvulsants) will demonstrate nonsuppression to overnight dexamethasone. The discriminatory value of the test can be enhanced by simultaneous assay of dexamethasone levels in the plasma. This, however, has not found widespread application. The other tests used in the past for screening purposes fall short of diagnostic specificity. For instance, measurement of basal plasma cortisol is affected by too many variables to be used as a sensitive screening test. Some of these variables include stress, increase in transcortin, obesity, alcohol abuse, and therapy with estrogens or diphenylhydantoin. The physiologic range of cortisol in normal plasma is wide, variable, and subject to marked fluctuations owing to the pulsatile nature of cortisol secretion. The variable between the highest and lowest values in a single 24-hour period can be as much as a tenfold difference. This magnitude of fluctuation undermines the interpretation of a single cortisol level drawn at random. Similarly, the fact that cortisol is episodically secreted as bursts in a pulsatile fashion also diminishes placing undue reliance on the presence or absence of circadian rhythm. While it is true that the diurnal variation in plasma cortisol is lost in patients with Cushing’s syndrome, comparisons of randomly drawn 8 AM and 4 PM cortisol levels do not provide diagnostic confirmation for the presence or absence of hypercortisolism. Attempts to analyze timed integrated concentrations of cortisol for diagnosing hypercortisolism are too tedious and cumbersome. Measurement of urinary metabolites of glucocorticoids (such as 17-OH-W are not nearly as sensitive as measuring urinary free cortisol for diagnosis of hypercortisolism. This is not surprising since the Porter-Silber reaction (the color reaction between corticosteroids and phenylhydrazine) measures only 50% to 60% of extractable glucocorticoids in the urine. the Etiology of Hypercortisolism Once the presence of hypercortisolism has been established by the demonstration of an elevated 24-hour urinary free cortisol, the second step is to determine the source of the disorder (i.e., whether fal DM, October 1988 Establishing

it is originating from the pituitary, the adrenal, or an ectopic source). The most important dynamic study for such a purpose is the highdose dexamethasone suppression test (HD DXM test). In addition, measurement of basal ACTH levels, and evaluating the response of plasma ll-deoxycortisol to metyrapone serve as excellent adjuncts. The availability of synthetic ovine CRH has added another diagnostic dimension to the etiologic diagnosis of hypercortisolism. High-Dose DeKamethasone Suppression Test.-In its standard form? the HD DXM test evaluates the response of urinary 17-OH-CS (or recently the urinary free cortisol) to the oral administration of 8 mg of dexamethasone per day in divided doses for 2 days. In the classic setting, patients with pituitary-dependent disease demonstrate a decline in 17-OH-CS by 50% of the baseline, whereas in patients with adrenal tumors or ectopic ACTH syndrome there is no suppression at all. The basis for such classic responses is that the servo feedback mechanism is reset at a higher threshold in patients with pituitary-dependent CD, and hence supraphysiologic doses of dexamethasone suppress ACTH secretion. In contrast, patients with adrenal neoplasms and those with the ectopic ACTH syndrome already have profound suppression of ACTH levels that cannot be suppressed any further by administration of dexamethasone. A recent modification of the standard HD DXM test circumvents the collection of urine. Tyrrell et al.” performed the test by administering 8 mg of dexamethasone as a single dose orally at midnight and comparing the plasma cortisol level on the following morning with that obtained the day before at 8 AM; a 50% drop in the postdexamethasone plasma cortisol indicated suppression and was most commonly seen in patients with pituitary-dependent CD, whereas patients with adrenal tumors and the ectopic ACTH syndrome showed no such decline. The simplified test, in terms of predicting the presence of CD, had a sensitivity of 92%, a specificity of lOO%, and an accuracy of 93%. These values were equal or exceeded those of the standard test. Despite the accepted “classic” responses of the various forms of hypercortisolism to the HD DXM test, exceptions prevail. For instance, patients with pituitary-dependent CD may remain nonsuppressible to the high dose, mimicking the response seen in association with adrenal neoplasms or the ectopic ACTH-secreting syndromes. There are four important reasons for such a phenomenon, which may be encountered in as many as 15% to 20% of patients with pituitary-dependent CD: 1. Profound elevation in the hypothalamic-pituitary threshold for suppressionzg; these patients respond to 16 or 32 mg of dexamethasone (the dose given in the HD DXM test). DM,oct0ber1988

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2. Nonsuppression with dexamethasone but suppressible by intravenous cortisone3’; this is an unusual but important phenomenon in which the receptors at the hypothalamic pituitary level do not recognize dexamethasone, but do “see” cortisone. 3. Intermediate lobe tumors that secrete ACTH may not show suppression with dexamethasone, although they respond to dopamine agonists.’ 4. Periodic hormonogenesis, in which the pituitary “tumor on a timer” secretes ACTH on a cyclic basis, and the administration of the test dose of dexamethasone is purely fortuitous, resulting in a seemingly paradoxic rise in cortisol following the dexamethasone.31’ 32 Conversely, patients with ectopic ACTH syndrome may demonstrate suppressibility to HD DXM.33J”This is particularly so with carcinoids of the bronchus, as well as in extraadrenal tumors secreting CRH alone or in combination with ACTH. Plasma ACTH Assay.- The concentration of circulating ACTH in the plasma is highly responsive to the ambient concentrations of cortisol in the plasma. Therefore, measurement of ACTH in plasma should, and indeed does, permit distinction of various forms of hypercortisolism. In the classic setting, patients with adrenal tumors would demonstrate very low (i.e., suppressed) ACTH concentrations, while patients with pituitary-dependent CD should demonstrate levels of ACTH inappropriate to the circulating cortisol level (i.e., mildly elevated or even “normal” levels). Although patients with the ectopic ACTH syndrome generally demonstrate marked elevation in ACTH levels, in approximately 20% of patients with the syndrome the levels overlap with that of CD. The issues that cloud interpretation of the ACTH assay are the meticulousness in collection and processing of the sample, the pulsatility of ACTH, the immunoheterogeneity of the hormone (especially in patients with the ectopic ACTH syndrome), and the differences in assay systems employed by various reference laboratories. The plasma ACTH assay enjoys an important place as an adjunctive aid in the etiologic diagnosis of hypercortisolism. is a drug that blocks llj3 hyThe Metyrapone Test. -Metyrapone droxylation. The triple effects of metyrapone administration to healthy subjects are a decrease in the serum cortisol, an increase in ACTH, and a rise in plasma ll-deoxycortisol (compound S), the product proximal to the block. When metyrapone is administered to patients with pituitary-dependent CD, the anticipated rise in plasma ll-deoxycortisol levels following the drug is well preserved. Such a response is obviously lost in patients with adrenal tumors and the 822

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ectopic ACTH syndrome, situations characterized by profound corticotrope suppression that is unlikely to respond to metyrapone-induced lowering of cortisol. The test has been rated favorably in the etiologic diagnosis of Cushing’s syndrome.% Corticotropin Releasing Hormone Test.-In a sense, all three diagnostic studies previously mentioned above (the HD DXM test, the plasma ACTH level, and the metyrapone study) focus on corticotrope responsiveness. The availability of synthetic ovine CRH has provided a new tool with which to study the old phenomenon of ACTH responsiveness. The 41 residue ovine hypothalamic peptide selectively stimulates the secretion and release of ACTH/endorphin when administered intravenously to healthy subjects. The ACTH r-csponse patterns following CRH administration in patients with Cushing’s syndrome have been evaluated in several studies.7’36,37In general, patients with pituitary-dependent CD show a robust increase in plasma ACTH following CRH, while patients with adrenal neoplasms and the ectopic ACTH syndrome fail to respond. It is interesting to note that when pituitary tumor cells are taken from patients with CD and maintained in culture, these cells poorly respond to CRH, highlighting the dichotomy between behavior in vivo and in vitro. Notwithstanding this discrepancy, the CRH test is becoming an important diagnostic tool in the evaluation of patients with hypercortisolism. Studies that compare the CRH test with the standard DXM test have quite favorably appraised the CRH test. The test is of maximal help in diiferentiating pituitary-dependent CD from the ectopic ACTH syndrome. While the general consensus is that ectopic ACTH syndrome is characterized by lack of ACTH (or cortisol) response to CRH administration, reports of patients with the ectopic ACTH syndrome that responded to CRH continue to appear in the literature. Given the heterogenous nature of ectopic ACTHKRH secreting tumors, coupled with the lack of a precise definition of a “normal” response to CRH, caution is required when interpreting this test in an individual patient. Localization of the Cause The procedures for localization of the source of hypercortisolism depend on the information derived from the steroid dynamic data. When all the data point to a pituitary source, the procedures are aimed at imaging the pituitary. When the data point to the adrenal as the primary source, the adrenals are evaluated by computed tomography (CT). When the data are indicative of the ectopic ACTH syndrome, CT scans of the chest, mediastinum, and abdomen become necessary. An additional procedure, selective venous sampling of the inferior petrosal sinus has added a novel dimension in the diagnosis of difficult cases. DM, October

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023

CT Scanning.-CT of the adrenals is a high-yield imaging procedure for detecting tumors of the adrenals that hypersecrete cortisol. These tumors are generally larger than 2 cm, and are, owing to their abundant cholesterol content, 10 to 20 Hounsfield units lower in density when compared with the adjacent soft tissue. The diagnostic yield of detecting unilateral cortisol-secreting tumors of the adrenal by CT is so excellent that this procedure is the initial imaging procedure when intrinsic adrenal disease is suspected. Even when unilateral tumors are not present, the adrenal CT study can provide information suggestive of CD (in which both the adrenals are slightly enlarged or normal) or ectopic ACTH syndrome (in which both adrenals are usually enlarged). In contrast, CT scanning of the pituitary is much less sensitive for detecting ACTH-secreting microadenomas. The incidence of identifying pituitary microadenomas in patients with CD ranges from 40% to 70%. When the CT scan of the pituitary shows completely normal anatomy but the CT scan of the adrenals shows “normal sized” or slightly enlarged adrenals bilaterally, an ACTH source (eutopic or ectopic) can be presumed. Unequivocal documentation of a pituitary origin would have to rest on selective sampling of the inferior petrosal sinuses bilaterally, to demonstrate an ACTH gradient. Selective Venous Sampling of the Inferior Petrosal Sinus3&40.-The venous anatomy of the pituitary is such that each half of the gland is drained by a venous plexus into either the ipsilateral inferior petrosal sinus or into the intercavernous sinus crossing the floor of the pituitary fossa. Since the pituitary venous drainage is lateralized, a laterally placed ACTH-secreting microadenoma would be expected to result in increased ACTH levels in the ipsilateral inferior petrosal sinus. Accordingly, measurement of the ACTH gradient (the ratio of central to peripheral ACTH concentrations) by catheterization of the inferior petrosal sinus can accurately delineate the pituitary source of the ACTH. The diagnostic yield of the procedure can be considerably enhanced by administering CRH just prior to sampling. This invasive procedure is indicated in cases where the differentiation between CD and ectopic ACTH syndrome caused by an occult neoplasm cannot be made by noninvasive means. The sampling study, clearly an invasive one, requires expertise and carries the small risk of inducing cavernous sinus thrombosis if inadvertently the catheter enters the cavernous sinus. It is crucial that both the inferior petrosal sinuses are sampled simultaneously, since ACTH secretion by the microadenoma can be pulsatile. The procedure has the added advantage of allowing access to several other veins such as the azygous vein and various segments of the superior and inferior vena caval system for sampling. This would assist in detecting an ACTH 624

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gradient in the venous effluents from ectopic ACTH-secreting tumors. Other localization studies such as adrenal venography, or adrenal venous sampling, and iodocholesterol scintigraphy are not commonly used for localization of adrenal tumors. The main reasons for this is the excellent yield by CT (or magnetic resonance imaging) of the adrenals in detecting the tumor. TREATMENT The treatment of hypercortisolism depends on the cause. Although adrenolytic therapy can lower cortisol levels regardless of etiology, specific treatments are required for permanent cure of hypercortisolism. Pituitary-Dependent

Cushing’s Disease

Transsphenoidal Pituitary Surgery.-The procedure of transsphenoidal pituitary surgery UPS) has gained immense popularity in the past decade. It is now generally accepted that the cure rate with TPS far exceeds every other therapeutic modality available for CD. The overall cure rate of 80% to 88% is applicable when CD is caused by tumors confined to the sella. The success rate drops significantly when the tumor is no longer confined to the sella. The success of TPS can be evaluated within a few days of surgery. If the source of pituitary ACTH was completely removed, the adrenals become rapidly hypofunctional because the normal corticotropes have been rendered dormant owing to the suppressive effects of hypercortisolism. Thus, transient secondary hypoadrenalism is an anticipated reflection of successful resection of an ACTH-secreting pituitary microadenoma. The adverse side effects of TPS are few and include transient diabetes insipidus and, rarely, cerebrospinal fluid leakage, meningitis, or optic nerve damage. Persistence or recurrence of hypercortisolism following TPS is usually seen in association with corticotrope hyperplasia, invasive tumors, intermediate lobe tumors, or an erroneous diagnosis (usually a missed occult ectopic ACTH-secreting tumor). Conventional Radiation.-In this form of therapy, 5,000 rads are delivered to the pituitary gland over a 4- to 5-week period. The major advantage of this form of treatment is its relative freedom from side effects, particularly hypopituitarism. The main drawback is the low cure rates (approximating 20% to 30%) and the long duration (6 to 8 months) taken for attaining a cure.’ The results of conventional radiation are more encouraging in children with CD, approximating a cure rate of 8O%,.44The lack of adverse effects, particularly hypopi-

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tuitarism, is especiaJly important in children, since preservation of somatic and sexual growth are vital concerns in this group. Thus, conventional radiation is favored as the first option in children and adolescents with CD. Heavy particle (or proton beam) radiation is a highly effective method of radiating the pituitary gland; however, the major limitations of this modality are the higher incidence of complications such as hypopituitarism and oculomotor nerve palsies, and the lack of availability in most centers. Bilateral AdrenaZectomy.-This surgical method reverses hypercortisolism immediately and, for the most part, permanently. However, this line of therapy should not be the first line of treatment for several reasons. First, removal of the target organs without removing the obvious seat of primary disease is unsound strategy. Second, the morbidity and mortality of bilateral adrenalectomy for CD is significant, exceeding 5%. Third, permanent adrenal failure with the need for lifelong treatment is a high price to pay at an age when TPS is widely available. Finally, the most important objection to bilateral adrenalectomy is the possibility of Nelson’s syndromer45’46which is characterized by pigmentation, visual field defects, and a rapid, aggressive growth of the previously nonaggressive ACTH-secreting pituitary tumor. Despite these objections, bilateral adrenalectomy does have a place in the management of CD. Thus, when hypercortisolism is life threatening and cannot be managed by drug therapy, or when pituitary surgery has failed, bilateral adrenalectomy is the only choice for a permanent cure. Of course, patients with macronodular hyperplasia, particularly the pigmented nodular variety, respond only to bilateral adrenalectomy. Neuropharmacotherapeutic Agents.-The role of neuropharmacological agents in the management of CD is, at best, adjunctive. The basis for the use of drugs that antagonize serotonin (and to a lesser extent dopamine) is that at least some cases of CD possess a strong hypothalamic component. Despite the initial encouragement, longterm use of cryproheptadine,47 reserpine,& or bromocriptine4’ are used, at best, adjunctively while the results of definitive therapy such as radiation or surgery are awaited. Adrenal

Tumors

Adrenal adenomas respond extremely well to unilateral adrenalectomy. Adrenal surgery is usually followed by a complete recovery from the hormonal and clinical features of Cushing’s syndrome, with gradual functional restoration in the atrophied contralateral adrenal cortex. This process is a slow one, and during this phase hydrocortisone replacement is essential. The treatment of adrenal carcinoma, sztl

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a devastating malignancy, includes surgical debulking with chemotherapy employing mitotane (O,p’-DDD).

combined

Bilateral Macronodular Hyperplasia The treatment for this variety of Cushing’s syndrome is controversial, since its pathogenesis is not well understood. Because varying degrees of adrenal autonomy are present in both adrenals, bilateral adrenalectomy is the choice of treatment. Patients with the common form of macronodular hyperplasia need close follow-up to detect the evolution of Nelson’s syndrome following bilateral adrenalectomy. It is not certain if these patients should undergo pituitary radiation treatments in conjunction with bilateral adrenalectomy. Ectopic AC’I’H Syndrome The treatment here is aimed at the primary tumor, along with drug therapy to lower hypercortisolemia. Several drugs can be employed for this purpose. Metyrapone, in doses of 750 mg four times daily, interferes with conversion of ll-deoxycortisol to cortisol, and thereby lowers the levels of the metabolically active glucocorticoid. Adrenolytic drugs such as O,p’-DDD or aminoglutethimide can also be effectively used to perform a “medical adrenalectomy.” However, the side effects of these drugs in patients already compromised by cancer and other chemotherapy may limit their protracted use. The drug currently favored to lower cortisol in such a setting is the antifungal agent ketoconazole. In doses ranging from 600 to 800 mg daily, the drug can satisfactorily lower cortisol levels. It works by inhibiting the cytochrome P-450 dependent mitochondrial enzymes, and thus impairs several steps in the synthesis of glucocorticoids. The drug also mildly inhibits the peripheral effects of glucocorticoids. In this regard, the new agent RU 486 has been shown to be a powerful antagonist of all the peripheral effects of glucocorticoids.50 In addition to causing marked subjective and objective improvement, the drug is extremely well tolerated, with very few adverse side effects. If proved in large series, competitive inhibition of glucocorticoid action at the receptor level may become an important strategy in the management of patients with all forms of Cushing’s syndrome. ADDISON’S

DISEASE

Addison’s disease refers to partial or complete adrenocortical insufficiency that results from destruction of both adrenal cortices by intrinsic disease within the adrenal. While complete adrenal failure is relatively rare, partial adrenal insufficiency with limited adrenal reserve occurs more frequently. Although Addison’s disease affects DM,October1988

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both sexes with equal frequency, autoimmune adrenal failure tends to occur more commonly in women and in Caucasian patients. ETIOLOGY The three major causes of Addison’s disease are represented by autoimmune adrenalitis, infections, and metastatic disease. Less commonly adrenal failure can be secondary to drugs, hemorrhage, and rare infiltrative disorders. Autoimmune Adrenalitis Autoimmune adrenalitis caused by circulating antibodies directed against adrenocortical tissue is the most common cause of primary adrenal failure. In a series of 108 patients with Addison’s disease reported by Nerup,‘l 66% had autoimmune adrenal disease. This form of adrenal disease can occur sporadically, or can be familial, as part of the polyglandular autoimmune (PGA) syndromes, affecting multiple endocrine glands, most notably the ovaries, adrenals, parathyroids, the thyroid, and the islet cells.52’53The evolution of adrenal failure in autoimmune adrenalitis is slow, the mean duration of the process being approximately 3 years. The autoimmune destruction is confined to the cortex and does not involve the medulla (in contrast to tuberculosis [TB] or metastatic disease). These patients often go through a triphasic evolution, characterized by an initial phase of compensated adrenal reserve (normal cortisol, elevated ACTH concentrations, and near normal adrenal reserve) followed by a phase of limited adrenal reserve, which eventually culminates in complete adrenal insufficiency. Autoadrenal antibodies can be demonstrated by indirect fluorescence in more than 70% of patients with this disease.54The application of a technique utilizing unfixed human adrenal tissue has had a major impact in detecting autoadrenal antibodies in the circulation. The specificity of this method is impressive in that fewer than 0.1% of controls and fewer than 1.5% of patients with other diseases have demonstrable antibodies with this technique. The most common disease groups include patients with insulin-dependent diabetes mellitus as well as those with other autoimmune endocrinopathies. It is now becoming apparent that asymptomatic, euadrenal, but antibody-positive subjects carry a significant risk of eventually developing adrenal failure.55 Thus, the test for adrenal antibodies by complement fixation can be used as a marker for prospectively identifying subjects at a higher risk. The role of human lymphocyte antigen (HL4) type in predisposing to autoimmune adrenalitis is still controversial. A close correlation between the demonstration of adrenal antibodies in the sera of addisonian patients and the presence of DRW3 in the HLA typing has been suggested? 628

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Infections Tuberculous and fungal disease are the two broad categories of chronic infectious processes that may result in adrenal insui5ciency. In the distant past tuberculous adrenalitis dominated the etiologic spectrum of Addison’s disease. For instance, a 1930 review conferred a striking 70% incidence to TB as a cause of adrenal failure.57 The prevalence has, of course, declined in recent years. Yet, tuberculous adrenalitis still continues to represent an important etiology in patients from developing nations, as well as in some parts of the United States, particularly among the impoverished and among American Indians. Adrenal involvement by TB usually occurs in conjunction with evidence of the disease elsewhere; rarely, however, tuberculous adrenalitis may present as an isolated event without evidence of TB elsewhere. A recent review of TB in the Boston, Massachusetts area has emphasized the presence of extraadrenal disease when TB underlies Addison’s disease.58 The usual extraadrenal sites are in the genitourinary system and the lungs. The development of tuberculous Addison’s disease in association with extensive tuberculosis of the fallopian tubes, uterus, and gastrointestinal tract has been well recognized. It is important to recognize that tuberculous adrenalitis can manifest years after the initial occurrence of TB at the primary focus. Clinically, tuberculous admnalitis evolves more rapidly than the autoimmune variety; further, the destructive effects are not limited to the cortex, since medullary involvement is very often discernible at autopsy. This may explain the frequency and severity of orthostatic symptoms experienced by patients with TB of the adrenals, reflecting combined loss of mineralocorticoids and catecholamines. Fungal disease-particularly histoplasmosis, coccidioidomycosis, or blastomycosis- can result in the development of adrenal failure. Of these, histoplasmosis most frequently invades the adrenals. Adrenal involvement by Histoplasma capsdatum is encountered in the progressive disseminated form of that disease. In one study59 of 54 patients with disseminated histoplasmosis, adrenal insufficiency developed in half of the patients regardless of the treatment and was the most common cause of death. Dissemination of histoplasmosis occurs more frequently in men, in those with underlying diseases, and in those with occupational exposure. Disseminated histoplasmosis is characterized by fever, weight loss, malaise, night sweats, and evidence of systemic involvement (hepatic, hematologic, renal) by the fungus, which can be cultured from blood, bone marrow, or other tissues. The extraordinarily high incidence of adrenal insufficiency in progressive disseminated histoplasmosis mandates screening of adrenal function in this setting. Rarely, histoplasmosis can smoulder in the adrenal gland for years and present as bilateral mass lesions mimicking TR or metastatic disease.” DA4,October1988

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Recognition of adrenal involvement by fungal disease has a threefold importance. First, treatment with the antifungal agent ketoconazole can further compromise an already impaired reserve. Precipitation of adrenal crisis in such a setting is well recognized. Second, early treatment of the fungal infection may, albeit rarely, restore adrenal reserve. Third, fungal disease can mimic the CT appearance of a unilateral mass lesion, resembling adrenal tumor. The need for surgery can be obviated by correct preoperative diagnosis. Me&static

Disease

Autopsy studies indicate that the adrenal glands are frequent sites for metastases, as reflected by an incidence of 27% y1j6’Antemortem demonstration of enlarged adrenals is being noted with increasing frequency as an incidental finding in patients with cancer undergoing CT scanning of the abdomen. These data challenge the traditional concept that metastatic destruction of adrenals is a relatively rare cause of adrenal insufficiency. It is becoming clear that adrenal insufficiency in malignant disease is underdiagnosed, perhaps owing to misattributing the symptoms to the underlying neoplasm. Also, the use of steroids in several chemotherapeutic regimens tends to mask the adrenal failure. But perhaps the most important reason for underdiagnosis is not appreciating the fact that a significant percentage of these patients suffer from partial adrenal insufficiency, doing reasonably well at the basal state but decompensating during stress. In general, when the adrenals are involved by metastatic disease, the primary malignancy is evident. Such is the case with cancers of the lung and breast, malignant melanoma, and Hodgkin’s lymphoma. Very rarely, adrenal involvement can antedate the manifestation of the primary malignancy.“3’64 The increasing survival rate of patients with cancer, and the increasing use of CT, have resulted in a heightened awareness of adrenal failure caused by metastases. The current trend is to evaluate adrenal reserve in cancer patients with enlarged adrenals by CT. Such a procedure is likely to uncover a high percentage of patients with limited adrenal reserve who can benefit immensely from steroid coverage during stress6’ Rare Causes of Adrenal

Insuflciency

While autoimmune disease, chronic infectious processes, and metastatic disease dominate the etiologic spectrum of adrenal failure, other etiologies may rarely be involved. These include adrenal hemorrhage, drug-induced adrenal insufficiency, infiltrative disease, and, at the present time, acquired immune deficiency syndrome. AdrenaI

orrhage 630

[email protected] three classic settings for adrenal hemare fulminant septicemia, anticoagulant therapy, and DM, October 1388

trauma to the abdomen or the thorax. The adrenal hemorrhage associated with fulminant septicemia is termed the “Waterhouse-Friderichsen syndrome.” Originally described in association with sepsis from Neisseria meningitis, this syndrome is characterized by the triad of hypotension progressing to shock, hemorrhagic diathesis (often with purpura), and rapidly evolving adrenocortical insufficiency. The relative roles of gram-negative endotoxemia, vascular damage, vasoconstriction, Shwartzman reaction, and disseminated intravascular coagulation in the development of the syndrome are largely unresolved. Regardless, the pathologic hallmark is profound bleeding into both adrenals, which are enormously enlarged and assume a purplish hue. Death usually results from a combination of adrenal failure and irreversible septic shock. Although the Waterhouse-Friderichsen syndrome is most commonly associated with the meningococcus, it can also result from other infections such as those caused by Diplococcus pneunoniae, Hemophilus influenzae type B, or more recently the DF bacillus (dysgonic fermenter). In patients who smvive the Waterhouse-Friderichsen syndrome, the adrenal failure is usually permanent. Adrenal hemorrhage secondary to anticoagulation can be seen with both heparin and Coumadin. The sudden development of abdominal or back pain, anorexia, nausea, vomiting, hypotension, and altered sensorium in a patient receiving anticoagulation therapy should immediately raise the suspicion of adrenal hemorrhage. Such an occurrence is more common in older patients and in those who are overanticoagulated. A high index of suspicion coupled with immediate adrenal reserve testing and CT scanning would readily permit accurate diagnosis. Adrenal hemorrhage can occur secondary to thoracic or abdominal trauma, by crushing one or both adrenals against the vertebral column, resulting in rupture of central vessels. Investigational trauma-particularly adrenal venography-can also result in adrenal hemorrhage. Drug-Znduced Adrenal Zn.suficiency.-The use of adrenolytic drugs such as O,p’-DDD or aminoglutethimide is a deliberate attempt at medical adrenalectomy, and is employed in the treatment of certain hormone-dependent cancers as well as in treatment of adrenocortical carcinoma. Drugs administered for other purposes may inadvertently result in the development of adrenal insufficiency. Four such drugs deserve mention: ketoconazole, etomidate, rifampin, and cyproterone acetate. Ketoconazole, an imidazole derivative, is a broad-spectrum antifungal agent. When used in high doses this drug can inhibit steroidogenesis by the testes and the adrenal cortices. Ketoconazole, when given orally to healthy volunteers, causes significant blunting of cortisol response to ACTH 4 hours after drug DM, October

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administration, and persisting up to 8 hours.66 The drug inhibits the cytochrome P-450 dependent enzymes, the 1ll.Shydroxylase, and the cholesterol side-chain cleaving enzyme. In addition, ketoconazole can bind to the glucocorticoid receptor and exert antagonistic effects at the target level. Although the potential for adrenal suppression by ketoconazole is well recognized, clinical hypoadrenalism with the drug is relatively rare. The use of the drug as a single dose which can only cause short-lived inhibition of steroidogenesis, coupled with built-in adaptive mechanisms that override the enzymatic block, are perhaps reasons for the rarity of clinical hypoadrenalism. Further, limited adrenal reserve may go unnoticed since these patients are asymptomatic. Clearly, individual susceptibility must play a role in the phenomenon of ketoconazole-induced inhibition. Etomidate, a “safe” intravenous anesthetic, can also cause adrenal suppression by inhibiting the cytochrome P-450 dependent enzymes. Patients receiving etomidate have been noted to demonstrate marked impairment in cortisol and aldosterone responses to ACTH administration, sometimes persisting for as long as 4 days after discontinuation of the drug.“’ These responses may assume critical importance in the stressful postoperative period. Rifampin per se does not induce adrenocortical failure. However, the drug accelerates catabolism of cortisol by accentuating hepatic microsomal induction, While such a phenomenon has little impact in healthy individuals, it can precipitate a crisis situation in the person with partial adrenal insufficiency. In most patients in whom rifampin had precipitated adrenal crisis, the event occurred within 2 weeks of instituting therapy. Therefore, in patients with TB placed on rifampin, the importance of anticipating this phenomenon in the first 2 weeks of therapy is emphasized. CLINICAL

FEATURES

Addison’s disease can be the proverbial masquerader. It is a disease with insidious onset and a gradual, almost imperceptible evolution. The symptoms can be so nonspecific as to be passed off as insignificant. The presentations of Addison’s disease can be so diverse, and the recognition so difficult, that the patient may have seen several subspecialists in widely different disciplines before the condition is diagnosed. In describing the clinical presentations of this disease, it is difficult to improve upon the excellent original monograph by Dr. Thomas Addison.68 The diversity of these manifestations are best viewed in terms of the multisystem involvement by the disease. Constitutional symptoms such as malaise, lassitude, loss of energy, and a general feeling of ill health are present in most addison63.2

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ian patients.51’6g,7o In a series of 108 patients reported by Nerup,51 weight loss and fatigue were present in 92%. Pigmentary changes accompany the evolution of chronic adrenal failure, with an 80% to 92% frequency. Increased pigmentation of skin and mucous membrane-with striking involvement of the extensor surfaces such as the dorsum of the hand, elbows, palmar creases, and old scars-can be impressive. While it is generally regarded that hyperpigmentation in Addison’s disease is indicative of chronic@, occasionally pigmentation can be an early and only manifestation of the disease.71The pigmentary changes are the result of increased j3-lipotropin levels in the circulation. In addition to generalized hyperpigmentation, vitiligo may be evident in patients with autoimmune adrenal failure. The incidence of vitiligo in Addison’s disease is variable, ranging from 4%51 to 20%72 of patients. Gastrointestinal symptoms such as lower abdominal cramps, anorexia, and nausea are present in more than 50% of patients with Addison’s disease. These symptoms intensify during addisonian crisis, which is often ushered in with nausea, vomiting, diarrhea, and abdominal pain. The reasons for the gastrointestinal symptoms are unclear, but appear to be somehow related to glucocorticoid deficiency, since dramatic resolution occurs with hydrocortisone therapy. Hypotension is present in 80% to 90% of patients with Addison’s disease. Moderate to occasionally severe orthostasis is seen in nearly all patients. However, fewer than 20% of patients complain of postural dizziness or experience syncopy. In contrast to patients with autonomic neuropathy, patients with Addison’s disease demonstrate presentation of rise in pulse rate upon standing. The orthostatic hypotension is clearly a reflection of mineralocorticoid deficiency and responds dramatically even to subtherapeutic doses of fludrocortisone. Musculoskeletal symptoms such as weakness and fatigue are almost universal in these patients, and probably reflect loss of the anabolic adrenal androgens. Although subjective weakness can be severe, muscle power is reasonably well preserved. Less common rheumatic features include myalgia, flexion contractures, and pain and tenderness in the loin (“Rogoffs sign”1. Psychiatric symptoms in adrenal insufficiency are encountered with variable frequency. Mild to moderate endogenous depression is usual, and can occasionally antedate other manifestations.51 Bizarre psychiatric manifestations, such as severe self-mutilation, have been described in children with Addison’s disease.73 Gonadal symptoms, such as decreased libido in men and oligomenorrhea in women, are frequently seen in patients with chronic DA& october19s8

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adrenal insufficiency. While these symptoms are usually a consequence of chronic illness and debilitation, the possibility of coexistent primary autoimmune gonadal failure should always be considered. Rare manifestations of adrenal failure include the development of the amenorrhea-galactorrhea syndrome74 and precocious puberty.75 The latter is analogous to the development of precocious puberty in girls with primary hypothyroidism, and might be due to a “drift” phenomenon of luteinizing hormone-releasing hormone and/or gonadotropins in response to protracted and profound increases in ACTH concentrations. Associations

of Addison’s

Disease

The numerous clinical situations that may be found in association with Addison’s disease are outlined in Table 1. As can be seen, the most important of these is the spectrum of PGA syndromes seen in association with autoimmune adrenal failure, underscoring the need for periodic screening of the other endocrine glands.

TABLE 1. Associations of Addison’s Disease I% 1’ Polyglandular autoimmune (PGA) Type I PGA syndromes Hypoparathymidism Addison’s disease Hypogonadism Autoimmune thyroid disease Diabetes mellitus Chronic mucocutaneous candidiasis Type II PGA syndrome Addison’s disease Autoimmune thyroid disease Insulin-dependent diabetes mellitus Hypogonadism Vitiligo Neumlogic disease Adrenoleukodystrophy Adrenomyeloneurupathy POEMS syndrome Polyneuropathy Organomegaly Endocrinopathy (hypoadrenalism, hypogonadism) M-proteins Skin changes The achalasia, alachrymia syndrome with Addison’s *Blank spaces indicate percentages

634

82 67 12-17 10

24 73-78 100

69 52 3.5 4.5 -

not known.

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LABORATORY DIAGNOSIS Nonspecific Tests Although nonspecific, the suspicion of Addison’s disease is often derived from certain routine tests. The typical electrolyte abnormality in Addison’s disease is the combination of hyponatremia and hyperkalemia. The reasons for the dual abnormalities are loss of aldosterone effect on the renal handling of these ions, and the loss of glucocorticoid action on the sodium-potassium pump, which maintains a normal gradient between intracellular and extracellular sodium and potassium. Hyponatremia occurs more frequently (88%) than hyperkalemia (64%), which can be masked by vomiting, diarrhea, or diuretics. Hyperkalemia is almost always noted during adrenal crisis and resolves promptly with glucocorticoid administration. Hypoglycemia in Addison’s disease results from inadequate hepatic gluconeogenesis. The presence of hypoglycemia in a patient with “shock” should immediately raise the possibility of addisonian crisis, since in most other situations characterized by shock, the blood glucose is not low, because the counter-regulatory stress hormones are present in adequate amounts. Mild azotemia is often present in Addison’s disease as a result of volume depletion and a decreased glomerular filtration rate (GFR). Patients with adrenal failure have decreased free water clearance and decreased secretion of ammonia and hydrogen ions, resulting in mild metabolic acidosis. Hypercalcemia is a ram feature of Addison’s disease, and is probably the result of enhanced proximal tubular reabsorption of calcium. While the hypercalcemia is generally mild, occasionally hypercalcemic crisis has been reported in Addison’s disease.76 Screening Tests Screening for Addison’s disease is recommended under the following circumstances: 1. Unexplained weight loss. 2. Presence of weakness or asthenia. 3. Presence of nonspecific symptoms in patients with pluriglandular failure or vitiligo. 4. Orthostatic hypotension. 5. Hyperpigmentation. 6. Dehydration and shock, especially when associated with hypoglycemia. 7. Electrolyte abnormalities. The Rapid ACTH Test.- The optimal screening method for adrenal insufficiency is evaluating the response of the adrenal cortex to a DM, October

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bolus of intravenously administered synthetic ACTH. Measurement of basal serum cortisol, urinary free cortisol or urinary metabolites of glucocorticoids (17-OH-W do not provide the desired sensitivity for detection of a potentially fatal disorder. For instance, a plasma cortisol level in the range of 10 to 20 l.@ll should not deter from further screening when Addison’s disease is suspected. The ability of the adrenal cortex to respond under stimulation should be the parameter for detecting impaired function. The “rapid ACTH test” is a safe and simple method for screening adrenal function. In its simplest form, the serum cortisol is measured at the basal state and sequentially (30, 60, and 90 minutes) following intravenous administration of 2.5 kg of synthetic ACTH (cosyntropin). The “normal” response varies according to different investigators.“-” The most stringent of these criteria requires a peak level that doubles and increases by 10 pg/dl over the baseline. Other criteria in usage include an absolute peak level of 25 (Lg at any time during the test, or an increase in plasma cortisol by at least 7 kg over the baseline. The multiplicity of criteria have caused some confusion in interpretation. Regardless of the criteria used, three important statements need to be emphasized with respect to the rapid ACTH test. First, the test is, at best, only a screening procedure, and separates the normal responder from the nonresponder. Second, a blunted or flat cortisol response to rapid administration of ACTH is not specific for primary adrenal failure. Patients with ACTH deficiency (secondary hypoadrenalism) may also show a flat response owing to protracted adrenal dormancy. In such cases, however, the aldosterone response to ACTH is usually preserved?’ Third, and most importantly, the response patterns of patients with limited adrenal reserve, and those under stress (“maximal stimulation”) can be quite variable. For instance, some patients with partial adrenal insufficiency may show a near normal response to the rapid test, while decompensating under continuous stimulation. In contrast, healthy subjects under stress may show no appreciable rise following rapid administration of ACTH because their systems are functioning at full capacity. In patients with acute adrenal crisis, where withholding of therapy is unadvisable, the rapid ACTH test can still be performed, in the following manner. After the basal sample is drawn, 16 to 20 mg of methyl prednisolone and 10 mg of DOC (desoxycorticosterone acetate) are administered for immediate support. Simultaneously, ACTH is administered, and sampling is performed in the usual manner. Other screening tests such as measurement of basal ACTH concentrations and performance of the overnight metyrapone test are not substitutes for the rapid ACTH stimulation test. Con.rmafion of Addison’s Disease.-The confirmation of primary adrenal failure rests on demonstrating impaired or absent adrenal 636

DM, October

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responsiveness to protracted administration of exogenous ACTH, coupled with an elevated basal ACTH level. The standard ACTH stimulation test is used for this purpose. This involves measuring the response of urinary 17-OH-CS (or free cortisol) to 40 mg of ACTH given daily as an &hour infusion for 3 days. This test remains as the “gold standard” for confkming primary adrenal failure. The widespread availability of a sensitive assay for plasma ACTH, coupled with data regarding ACTH response to CRH in various hypoadrenal states, may ultimately obviate the reliance on the elaborate standard ACTH test, and the banal problem of meticulous urine collection. Diagnosis of Addison’s Disease Once the diagnosis of Addison’s disease has been established, the next step is to determine the cause. This is usually done by CT study of the adrenals as well as by marshalling evidence for systemic disease. Demonstration of enlarged adrenals by CT scanning in a patient with Addison’s disease is compatible with diagnoses of TB, fungal infections, or metastatic disease. Decreased size of the adrenals, on the other hand, is indicative of autoimmune disease, idiopathic atrophy, or late sequelae of TB. Nonhomogenous enlargement (multiple lucent areas) of adrenals is consistent with TB, histoplasmosis, or adrenal hemorrhage, while metastatic disease is usually characterized by homogenous enlargement of adrenals with alteration of contours. Adrenal glands involved in hemochromatosis assume a characteristic hyperdense appearance. The presence of calcification, a sign most often associated with TB, can be also seen in fungal infections, metastatic disease, and adrenal hemorrhage. While the CT study is an excellent initial procedure to arrive at the cause of disease, the limitations of the procedure should be realized. For instance, patients with long-standing tuberculous adrenal disease may show small, noncalcified adrenals resembling the “classic” picture of autoimmune adrenal failure. To compound matters, pulmonary (and extraadrenal) TB can be associated with autoimmune adrenal failure?’ This underscores the importance of not relying exclusively on the CT appearance of the adrenal Other studies include obtaining antiadrenal antibody titers (which are now commercially available) as well as marshalling evidence for the presence of such systemic diseases as TB, fungal infections, or malignancy. When autoimmune adrenalitis has been diagnosed, it is mandatory to screen for the presence of other endocrine glandular failure. This usually involves screening for thyroid failure, diabetes, hypoparathyroidism, and gonadal dysfunction. In this regard, it should be underscored that mild elevation of thyroid-stimulating hormone can be encountered from adrenal insuiiiciency per se, normalizing after cortisone therapy.“’ 83 Thus, caution should be exercised in interpreting thyroid function in untreated Addison’s disease.

Etiologic

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637

TREATMENT

Addison’s disease is indeed one of the most gratifying disorders to treat. Replacement glucocorticoid therapy consists of administering cortisone acetate, 25 mg in the morning and 12.5 mg in the evening, or hydrocortisone hemisuccinate, 20 mg in the morning and 10 mg in the evening. Therapy is extremely well tolerated. Dexamethasone should not be used for replacement, because it has little mineralocorticoid activity and a high potential for side effects. Adjustments in dosage are made empirically on the basis of symptoms. In general, measurement of serum cortisol is not a good parameter for dose-titration in patients receiving cortisone or hydrocortisone. However, should the question of bioavailability arise, measurement of cortisol might prove valuable in studying the absorption characteristics. As for measurement of serum ACTH level for titration of the dose of glucocorticoid, this marker has not assumed the status or sophistication of thyroid-stimulating hormone measurement for adjustment of thyroxine dosage in patients with primary hypothyroidism. It has been suggested that measurement of urinary free cortisol might be a useful tool to detect undertreatment or excessive glucocorticoid administration.84 Individual variations in the absorption of the orally administered cortisone acetate or hydrocortisone hemisuccinate are the most frequent reasons for undertreatment despite receiving a conventional replacement dose. The development of diarrhea or vomiting would mandate an increment (usually doubling) in the dose of oral cortisone. If the problem is severe, as in gastroenteritis, parenteral hydrocortisone becomes necessary. Mineralocorticoid replacement with 0.1 mg of fludrocortisone is indicated in the presence of orthostasis or electrolyte abnormalities. Not all patients with Addison’s disease require lifelong mineralocorticoid replacement, since cortisone and hydrocortisone provide reasonable mineralocorticoid coverage. Patients with Addison’s disease should be repeatedly reinforced as to the need for increasing their glucocorticoid dose during stress. Also, such patients should wear on their person some form of disease identification with instructions on how to administer intravenous hydrocortisone in the event the patient is found unconscious. Addisonian crisis, a potentially life-threatening situation, should be managed by intravenous hydrocortisone, 100 mg three times daily, and vigorous hydration with normal saline and glucose, along with treatment of the precipitating factor. The improvement, which often is seen within 24 hours of therapy, is nothing short of spectacular.

PRIMARY HYPRRALDOSTERORnSM Primary hyperaldosteronism refers to absolute or relative autonomy in aldosterone hypersecmtion by the adrenal cortex. The first description of an aldosterone-producing adenoma, by Dr. Jerome Conn in 1955,85established mineralocorticoids as important mediators of hypertension; however, in contrast to original predictions, primary hyperaldosteronism accounts for less than 1% of all hypertensives. ETIOLOGY

Primary hyperaldosteronism can be caused by several distinct entities. The three major etiologies are 1. Solitary aldosterone-producing adenoma (aldosteronoma) .= 2. Bilateral hyperplasia (idiopathic hyperaldosteronism).86 3. Glucocorticoid-suppressible hyperaldosteronism (GSH).*7 Less common causes include aldosterone-producing carcinoma,88 unilateral hyperplasia,8s and, ectopic secretion of aldosterone by nonadrenal neoplasmsW Aldosterone-producing adenoma (APA) represents the most common cause for primary hyperaldosteronism and accounts for 60% to 70% of cases. These adenomas are characterized by their small size, benign nature, and unilaterality. In contrast to hyperplastic tissue, excised adenomatous tissue can, in vitro, synthesize aldosterone. Aldosterone secretion by adenoma is autonomous and is unresponsive to changes in the renin angiotensin system, while retaining varying degrees of sensitivity to ACTH. Excision of the adenoma substantially normalizes the blood pressure in more than 60% of patients, posing a striking contrast with the uniform lack of surgical response in patients with idiopathic hyperplasia. Idiopathic hyperplasia (IH) is characterized by bilateral hyperplasia of the zona glomerulosa. Aldosterone hypersecretion in this entity is not as autonomous as in adenoma. Thus, physiologic responses of aldosterone to the renin angiotensin system are somewhat preserved in this entity. The pathogenesis of IH has been a matter of controversy. Indeed, even its status as a subset of primary hyperaldosteronism was once questioned by investigators in Glasgow, who suggested that idiopathic hyperaldosteronism was “at the upper end of a wider-than-normal distribution of aldosterone in essential hypertension, iiom which it has been separated wx~ngly.“~* Recent data, however, have implied that IH is a distinct entity in which the zona glomerulosa of both adrenals undergo hyperplasia in response to chronic stimulation by non-ACTH secretagogues from DM,octoberl9&8

839

the anterior pituitary. Several substances have vied for the title of the “adrenoglomerulotropic factor” involved in IH. The major contenders include several melanotropic hormones of the proopiomelanocortin molecule, such as y-melanotropin, P-lipotropin, and even OLmelanotropinsLW The most convincing data, however, have implicated the secretion of a glycoprotein, the “aldosterone stimulating factor,” by the anterior pituitary.g5,s6 The role of this factor, as well as its control by biogenic amines such as serotonin and dopamine, are under intense study, conferring a central etiology in the development of IH.g7’s8Regardless of its pathogenesis, IH results in a clinical and biochemical syndrome that is milder than adenoma, with relatively less autonomy. In fact, the aldosterone dynamics of IH can be, in some patients, more reminiscent of and closer to low-renin essential hypertension than to adenoma. In contrast to adenoma, surgery is contraindicated in IH. The third important etiology of primary hyperaldosteronism is the glucocorticoid-suppressible variety: GSH. This condition should be considered in young patients with hyperaldosteronism, as well as in those with a family history of aldosterone excess. The unique aspect of this condition is that dexamethasone administration normalizes the previously elevated aldosterone levels. While the evolution of the clinical and biochemical syndromes in GSH is similar to those in APA or IH, the predominance of ACTH regulation is readily apparent by the complete reversal of the syndrome with small doses of dexamethasone. In this respect, GSH is reminiscent of the various enzymatic blocks in cortisol synthesis, in which abnormal steroid levels can be reversed with glucocorticoid therapy. However, patients with GSH do not have any defects in cortisol synthesis. Although the exact pathogenesis of GSH is far from clear, its recognition has important therapeutic and heredofamilial implications. The condition has been described in three successive generations.” This etiologic perspective on primary hyperaldosteronism focuses on the two most important questions that face the clinician who has documented relative or absolute aldosterone autonomy: Is the mineralocorticoid excess a result of unilateral or bilateral disease and, if bilateral, has GSH been excluded? It is important to recognize that despite the widely different therapeutic approach, several clinical and biochemical features of each entity can be almost identical. PATHOPHYSZOLOGY

In the physiologic state, aldosterone secretion is controlled predominantly by the renin-angiotensin-aldosterone system, and to a lesser extent by potassium, ACTH, and other factors such as dopamine. The factors that regulate the system are outlined in Figure 1. Renin is an enzyme synthesized by the juxtaglomerular cells of the 640

DM,october1988

FACTORS

Rain

THAT

AFFECT

THE RAA SYSI’R M

Renin

inhibitors ANGIOTENSIN

6) COPD,

I

> ACE

(+)

C

Hypoxia ANGI 6 TENSIN (4

Angiotensin Antagonists

activators

I

Sarcoidosis Hyperthyroidism

II \

ANGIOTENSIN

III

4 ALDOSTERONE

RENAL

Sodium retention, Volume expansion, PRA suppression

TUBULE

Kaliuresis Hypokalemia

The renin-angiotensin-aldosteronesystem. Factors that promote (+) and inhibit (-) system chemistry are shown. ACE = angiotensin converting enzyme. CO/W = chronic obstructive pulmonary disease. PRA = plasma renin activity.

kidney. Following release into the circulation, renin acts on an o-2 glycoprotein synthesized by the liver. This substrate is termed renin substrate, or angiotensinogen. As a result, the decapeptide angiotensin I is released from the renin substrate. Angiotensin I is biologically inactive, but is quickly converted into angiotensin II by the enzyme ACE kngiotensin converting enzyme1. This conversion takes place predominantly in the lungs. As a result of this conversion, the biologically active octapeptide angiotensin II is derived. Angiotensin II is degraded by peptidases into numerous smaller peptides, includDM,

October19138

641

ing angiotensin III, which retains its biologic activity. Angiotensin III is further degraded into inactive peptide fragments by angiotensinases present in the circulation. Angiotensin II and angiotensin III have powerful effects on the smooth muscle and the adrenal zona glomerulosa. These peptides are strong pressor agents that effect smooth muscle contraction of the vascular bed, as well as stimulate the synthesis and release of aldosterone by the zona glomerulosa. Physiologically, aldostemne secretion can be turned off by volume expansion and sodium repletion. Similarly, the regulation of renin release is also controlled by the sodium and volume status. The hallmark of all forms of hyperaldosteronism is relative or absolute autonomy of aldosterone secretion by the zona glomerulosa. As a consequence, renin secretion is suppressed and fails to respond to physiologic stimuli that normally provoke renin release. Thus, nonsuppressible aldosterone secretion and nonstimulable renin secretion underlie the pathophysiologic alterations in all forms of hyperaldosteronism. CLINICAL. FEATlJZU33

The dual clinical expressions of primary hyperaldosteronism, regardless of the underlying etiology, are hypertension and hypokalemia. The hypertension seen in association with hyperaldosteronism is usually mild and often indistinguishable from the features of essential hypertension. Headaches are often the only symptom present. While the classic concept is that patients with primary hyperaldosteronism tend to have mild hypertension, often with a benign course, severe hypertension, and even malignant hypertension, have been reported to occur in primary hyperaldosteronism?OO’lo1 In a prospective study of 80 patients with primary hyperaldosteronism reported by Bravo et al.,‘o2 several patients had moderate to severe hypertension. Further, blood pressure could not be satisfactorily controlled with conventional drugs in 30%. On the other extreme of the spectrum, rarely can primary hyperaldosteronism exist in perfectly normotensive individuals presenting with only hypokalemia. Three individual reports have highlighted the syndrome of normotensive hyperaldosteronism?03-*05 The role of severe sodium restriction, early phase of disease, or the presence of coexistent hypotensive mechanisms have all been speculative in explaining this peculiar variant. Symptoms of hypokalemia such as cramps, muscle weakness, nocturia, polyuria, paresthesia, or even overt tetany dominate the symptomatology of primary hyperaldosteronism. The hypokalemia is usually mild, but tends to be more impressive in patients with adenoma than in those with hyperplasia. The hypokalemia can be sponta642

DM, October

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neous, but is often unmasked by the use of diuretics. In approximately 20% to 25% of patients with primary hyperaldosteronism the serum potassium is normal. The salt restriction imposed on hypertensive patients at large tends to minimize, even mask, the hypokalemia. Since most hypertensives are also usually placed on some form of diuretic, hypokalemia induced by diuretics selves as an excellent clue to signal the search for underlying mineralocorticoid excess. Unfortunately, all too often, the hypokalemia is misattibuted to diuretic therapy. Patients with primary hyperaldosteronism have no abnormal physical findings. Characteristically, edema is absent. Mild orthostatic changes may be present. LABORATORY DLAGNOSIS The steps in the diagnosis of primary hyperaldosteronism include screening for the disease, followed by confirmation of the diagnosis and delineating the cause of primary hyperaldosteronism. Screening for Primary Hyperaldosteronism The clinical settings that should prompt screening for this disorder are as follows. 1. The occurrence of spontaneous or diuretic-induced hypokalemia in a hypertensive patient. It should be underscored that sole reliance on serum potassium concentrations is conducive to missing the diagnosis in one fourth of patients with the syndrome. 2. The presence of unexplained polyuria or nocturia in a hypertensive patient. This reflects the vasopressin resistance seen in association with chronic potassium depletion. 3. Hypertension refractory to conventional therapy. The two major screening tests for primary hyperaldosteronism are evaluating the plasma aldosterone response to intravenous saline and evaluating the response of plasma renin activity (PRA) to a variety of provocative stimuli. The hallmark of all forms of primary hyperaldosteronism are nonsuppressibility of plasma aldosterone to salt infusion, and suppressed PRA that is nonresponsive to posture and diuretic. The diagnostic yield is best when both tests are used in conjunction. Measurement of the plasma aldosterone response to 2 liters of normal saline given intravenously over 4 hours is a direct method to ascertain autonomous secretion of aldosterone. Measurement of PRA response to posture and diuretic is an indirect method which evaluates one consequence of aldosterone excess (i.e., renin suppression). Each of these tests provides valuable insight into the mechanism of hypertension. Arguments will continue to prevail regarding which of the two should be performed first. Regardless of DM,

October

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643

which test is chosen as the initial procedure, it is crucial to perform the study in the potassium-repleted state because hypokalemia can lower aldosterone levels even in states of autonomous secretion. Plasma

Renin

Activity

Response

to Posture

and

Diuretic.-The

concept that patients with hyperaldosteronism will demonstrate suppressed PRA and be unresponsive to salt deprivation and ambulation dates back to the landmark article by Conn et al. in 1964.‘06 The value of measurement of stimulated PRA must be viewed in terms of specificity and sensitivity. With regards to specificity, it is well recognized that a subset of essential hypertensives have suppressed, low PRA (“low renin essential hypertension”). In fact as many as 10% to 15% of patients with essential hypertension may demonstrate impairment in renin responses to physiologic stimulation. Thus, a suppressed PRA is not unique for primary hyperaldosteronism. With regards to sensitivity, the discrepancies that abound in the literature relate to differences in the assay, in the performance of the test, and in interpretation. Weinbergerlo7 has reported that 1 day of salt restriction (10 mEq of NaCl) with 40 mg of furosemide three times a day followed by 2 hours of ambulation the next morning served as excellent stimuli for studying PRA, and that a poststimulated PR4 below 2 ng/ml/hr points to the need for further diagnostic studies to confirm or exclude primary hyperaldosteronism. Similar experiences have been reported by others.“’ These data are tempered by another repor?02 which notes that in a prospective series of 80 patients with primary hyperaldosteronism, as many as 35% increased their PM above 2.0 ng/ml/hr after salt depletion and ambulation. Further, these workers noted that 17% of patients with essential hypertension had suppressed PFtA levels identical to patients with primary hyperaldosteronism. Thus, sole reliance on suppression of PRA might be conducive to missing primary hyperaldosteronism. The sensitivity of this test is considerably enhanced when viewed in conjunction with the saline infusion test. The Saline Infusion Test. -This test is based on the principle that volume expansion with normal saline results in a prompt decline of aldosterone levels to approximately below 8.5 ngdl in normal subjects. Physiologically, volume expansion results in suppression of renin and, in turn, angiotensin II and aldosterone secretion (see Fig 1). Patients with primary hyperaldosteronism, on the other hand, fail to do so because aldosterone secretion in these patients is autonomous and unaffected by changes in renin and angiotensin II, which are already quite suppressed. While the aldosterone response to saline infusion has been found to be an excellent screening test by several workers,102’log,‘lo it should be realized that patients with hyperaldosteronism due to idiopathic hyperplasia may show some degree of suppression.

644

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The combination of a suppressed PBA nonresponsive to posture (and diuretic) and an elevated plasma aldosterone level nonsuppressible to saline infusion offers virtual certainty in the diagnosis of primary hyperaldosteronism. These two tests have been the established screening procedures for diagnosis of primary hyperaldosteronism. More recently, the response of plasma aldosterone to a single oral dose of captopril has been used to screen for primary hyperaldosteronism.‘l’ Captopril blocks the conversion of angiotensin I to angiotensin II. Thus, hypertensive patients with an intact renin-angiotensin axis would be expected to lower their plasma aldosterone concentrations 2 hours following a single oral dose of 2.5 mg of captopril. In contrast, patients with primary hyperaldosteronism do not show significant lowering in plasma aldosterone levels following oral captopril. A post-captopril value in excess of 15 ngdl is considered diagnostic of autonomous aldosterone secretion. The test has not yet found widespread application. Confirmation of Primary Hyperaldosteronism The “gold standard” test for confirmation of primary hyperaldosteronism rests on demonstrating nonsuppression of urinary aldosterone levels following 3 days of oral salt loading (110 mEq/day) or following mineralocorticoid administration (intramuscular DOC or oral 9&ludrocortisone). Bravo et al.*” have noted that an aldosterone excretion rate greater than 14 pg for 24 hrs following 3 days of oral salt loading provided the highest sensitivity and specificity in identifying patients with hyperaldosteronism. In principle, the use of oral salt, intramuscular DOC, and oral Florinef, are all maneuvers that demonstrate that these patients have already maximal suppression of the renin-angiotensin axis, and consequently will not show further lowering of this axis following these maneuvers. The main limitation of these studies is the banal problem of urine collection. The main drawback of the test lies in the fact that in the presence of hypokalemia, even patients with hyperaldosteronism may show some degree of lowering in aldosterone excretion following oral salt load. Hence, it is essential to replete potassium prior to performance of these tests. Distinction Between Aldosterone-Producing Adenoma and Idiopathic Hyperplasia The distinction between APA and IH has important therapeutic implications. VVhile the most definitive method of making that distinction rests on measurement of aldosterone gradients in the venous effluent from both adrenals, several hormonal tests have evolved for making that distinction. Table 2 illustrates the numerous studies that attempt to differentiate between adenoma and hyperplasia. The plethora of tests available is attestation to the fact that DM,October1988

645

TABLE 2. Hormonal Tests to Differentiate Adenoma fmm Hyperplasia

Tests dependent on ACTH-mediated maneuvers Aldostemne response to posture between 8 AM and noon Aldostemne response to exogenous ACTH Tests dependent on the renin-angiotensin system Aldostemne response to infusions of angiotensin II or III Aldostemne response to posture and salt depletion Aldostemne response to saralasin Circulating levels of angiotensin II Tests dependent on central mechanisms Aldostemne response to cypmheptadine Aldostemne stimulating factor in urine Other Supine 8 AM levels of plasma 18hydmxy corticostemne level

Adenoma

Hyperplasia

Anomalous decline in aldostemne Often pmsewed

No change or slight rise Negligible

No response

Good response even to small doses Preserved

No appreciable response No response LOW

Increase in aldostemne Normal to low

No response

Significant decline

Absent

Often present

Elevated

Normal

no single test can consistently enable prediction of the presence of adenoma versus hyperplasia. The basis for most of these tests revolves around two principles: adenoma is more sensitive to ACTHmediated maneuvers and shows very little dependence on the reninangiotensin system, while bilateral hyperplasia retains responsiveness to renin-mediated maneuvers and possibly to central stimuli that originate at the pituitary level. Despite the availability of a multitude of tests, in clinical practice only two of these are commonly employed: the aldosterone response to erect posture between 8 AM and noon, and measurement of basal, 8 AM plasma 18-hydroqcorticosterone (l&OH-B) levels with the patient in the supine state. Aldosterone Response to Standing Posture Between 8 AM and Noon.-In 1973, Ganguly et al.‘12’1’3 described an anomalous decline in aldosterone concentrations when patients with APA assumed an erect posture between 8 AM and noon. This contrasted with the response in patients with hyperplasia, who often showed an increase in plasma aldosterone concentrations with posture. The reason for the drop in aldosterone levels in APA is a reflection of declining ACTH levels in the plasma between 8 AM and noon. The conse646

DM, October 1988

quences of fluxes in ACTH levels override even the effects of posture, which is a physiologic stimulus for aldosterone release. Hence the term “anomalous” is used in describing the inordinate sensitivity of APA to changes in circulating concentrations of ACTH. This characteristic response is noticeable in 65% of patients with adenoma. However, 10% to 15% of patients with hyperplasia may also show a similar response. The false positive and false negative results with this test can be reduced, and the sensitivity enhanced, if the study is performed with the patient in the volume expanded state.‘14 Plasma l&Hydro~corticosterone Levels.-The measurement of circulating levels of M-OH-B in the recumbent state is emerging as an important marker for adenoma.l15’‘I6 This steroid is the penultimate precursor in aldosterone biosynthesis and is preferentially hypersecreted by adenomatous tissue. Biglieri and Schambelanl” measured plasma 18-OH-B levels in 23 patients with primary hyperaldosteronism after overnight recumbency and found that a value greater than 100 ng/dl was an effective predictor for the presence of an adenoma. Similar findings have been reported by Kern et aL116 This is a simple test, but requires the use of a specific assay for 18OH-B. This assay is not a commonly available one, and interpretation of the basal levels can be affected by numerous factors such as assay specificity, time of the day, dietary sodium, and drugs that affect aldosterone biosynthesis. When one is making the hormonal differentiation between APA and hyperplasia, the entire picture must be reviewed. In general, patients with APA demonstrate more profound hypokalemia, along with more pronounced abnormalities in plasma aldosterone and renin (i.e., more marked elevations in plasma aldosterone and more profound suppression of PRA) than those with hyperplasia. The PRA is more resistant to stimulation, and the plasma aldosterone is more resistant to suppression with volume expansion in comparison with hyperplasia. APAs tend to show an anomalous decline in plasma aldosterone concentrations with posture, and are more frequently associated with an elevated (>lOO ng/dl) basal plasma M-OH-B level with the patient in the supine state. In general, patients with bilateral hyperplasia tend to have milder abnormalities in potassium, aldosterone, and PRA in comparison to adenoma. The plasma and urinary aldosterone in such patients, while not completely suppressible to normal with volume expansion, demonstrates preservation of partial suppression. The PRA of patients with hyperplasia can be stimulated, albeit to a minor degree, with protracted salt depletion and prolonged standing. The plasma aldosterone often demonstrates a rise with erect posture, and the basal plasma 18-OH-B concentrations in the supine state are usually below 100 ng/dl. The administration of cyproheptadine is asLJM, October

1388

647

sociated with a decline in plasma aldosterone concentrations and the glycoprotein “aldosterone stimulating factor” can be demonstrated in the urine of some, but not all, patients with hyperplasia. Localizational Procedures The three procedures that are usually employed for locating the site of tumor secreting aldosterone are CT scanning of the adrenals, iodocholesterol scintigraphy, and bilateral catheterization of adrenal veins for aldosterone concentrations. Of these CT study has the advantages of easy availability, lower cost, relatively low radiation exposure, and noninvasiveness. Therefore, it is the first imaging procedure in patients documented to have hormonal evidence of primary aldosteronism. Since aldosteronomas are often the smallest of adrenal tumors, it is necessary to employ CT equipment with high-contrast resolving power, approaching 1 mm. CT scanning accurately localizes the adenoma with a sensitivity of 86% and an accuracy of 83% .l17-11’The most common reason for CT-negative adenomas is the small size of these tumors. The sensitivity of this imaging procedure considerably drops in detection of tumors smaller than I cm.lzo Iodocholesterol imaging using 1311-19-iodocholesterol or 1311-6B-iodomethyl norcholesterol (NP-59) for delineating aldosterone-secreting tumor has been reported to separate tumors from hyperplasia effectively.‘21’“’ However, the success rate with this procedure, pioneered in 1971 by workers from the University of Michigan, is not shared by others. For instance, in one study, iodocholesterol scintigraphy correctly localized the tumor in only 47% of patients.“’ Not infrequently, bilateral uptake of isotope (“hyperplasia pattern”) can be encountered in patients with adenoma. In addition to the limited availability of the procedure, the practical problem with iodocholesterol scintigraphy is the need for repeated imaging to allow for the disappearance of localized extraneous activity of the isotope, which can be concentrated in several organs besides the adrenals. Since interpretation of a positive scan heavily relies upon asymmetry between the two glands, minor inequalities, when present, need to be confirmed by repeat study. The role of iodocholesterol scintigraphy has indeed receded into the background after the emergence of high-resolution CT and, more recently, magnetic resonance imaging of the adrenals. Bilateral Venous Efluent Study.-Aldosterone measurements in the adrenal venous effluent obtained by venous catheterization of both adrenals is considered the most effective method for localizing ApAs~102,108,123-125 In experienced hands this procedure has a localizing yield that approaches 100% .lo2’ lo8 The procedure, an invasive one, consists of cannulation of both adrenal veins and obtaining 948

DM, October

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samples from both veins as well as the inferior vena cava, which reflects peripheral hormone levels. Comparison of aldosterone levels in the different samples, and calculation of the aldosterone gradient in each will readily reveal the unilateral source of the hormone in the case of an adenoma. The factors that limit the usefulness of the procedure are its invasiveness, the difficulty in cannulation of the right adrenal vein, the small risk of trauma to the veins, the episodic secretion of aldosterone by tumor, and the potential problem of dilution of the venous effluent by blood from nonadrenal sources. These limitations can be overcome by the use of advanced, polyethylene “cobra-shaped” tapered catheters to minimize trauma; by administering ACTH intravenously before obtaining samples, to magnify the gradient on the side of the tumor, which is exquisitely sensitive to ACTH; and by measuring both cortisol and epinephrine in the samples to ascertain the adrenal source of the blood. With these developments, coupled with technical expertise, venous sampling has remarkable-even universal-localizing value. The procedure is costly and does involve hospitalization. Di@rential Diagnosis The differential diagnosis of aldosterone excess revolves around various causes of endogenous or exogenous mineralocorticoid excess, and the various conditions that result in secondary hyperaldosteronism (Table 3). The distinction between primary and secondary hyperaldosteronism can be readily made by measuring PIN The differential diagnosis of mineralocorticoid excess with low PRA involves primary hyperaldosteronism, certain types of adrenogenital syndromes, isolated hypersecretion of DOC, ectopic ACTH syndromes, and the abuse of licorice, as well as mineralocorticoid-containing nasal sprays or skin ointments. TREATMENT The treatment of primary hyperaldosteronism depends on the cause. When a unilateral adenoma is localized, the therapy of choice is removal of the tumor, often with unilateral adrenalectomy. Preparation for surgery includes a 4- to 6-week course of spironolactone for normalization of the blood pressure as well as restoration of normokalemia. The success rate of curing or improving the hypertension following surgery for adenoma ranges between 68% and 80%. In contrast to patients with adenoma, surgery is not indicated in patients with bilateral hyperplasia. The treatment of choice here is chronic treatment with the mineralocorticoid antagonist spironolactone. This drug exerts its action by competitive binding to receptors that are located at the aldosterone-dependent sodium-potassium exchange sites in the distal convoluted tubule. As a result, there is DM, October

1988

649

TABLE 3. Differential

Diagnosis of Hyperaldostemnism

Condition

Features*

Endogenous hypermineralocorticism Primary hyperaldostemnism Adrenogenital syndromes I#-hydmvlase deficiency 17a-hydmxylase

deficiency

DOC hypersecretion alone by neoplasms 1. adenoma 2. carcinoma Ectopic ACTH secretion Use or abuse of substances with mineralocorticoid activity Licorice Nasal sprays or ointments containing Sa-flumprednisolone Secondary hyperaldostemnism Edematous states (ascites, nephmtic syndrome, etc.1 Nonedematous, normotensive conditions (renal tubular acidosis, Bartter’s) Hypertensive states Renovascular hypertension Renin-secreting tumors Essential hypertension

Elevated nonsuppressible aldostemne; suppressed PRA t t t &

compound-S, 17a-OH-progesterone Pregnenolone, 17a-OH-progesterone

t DOG t DOC, t DHEA-S r ACTH, t cortisol, nonadrenal tumor

History of tobacco chewing 4 PRA, -1 aldostemne Mimics primary hyperaldostemnism

t PRA t PRA, tubular abnormalities

t PRA, abnormalities in angiography and split function studies t PRA, presence of tumor t PRA, vascular changes

l PRA = plasma renin activity. DOC = desoxycorticosterone acetate. DHEA-S = dehydmepian-

dmstemne sulfate.

increased excretion of sodium and water, with a simultaneous retention of potassium. The effectiveness of spironolactone in lowering, even normalizing, blood pressure, as well as in restoring normokalemia is impressive. The dose required in patients with hyperplasia is variable, ranging between 100 and 200 mg per day in divided dose. The limiting factor in the long-term use of spironolactone relates to its antiandrogenic side effects. These include decreased libido, impotence, and gynecomastia in men, and menstrual irregularities and painful breast enlargement in women. The drug has a wide spectrum of antiandrogenic activity that includes inhibition of the P-450 dependent enzyme, 17-hydroxylase, involved in testosterone synthesis; drug-induced alterations in the sex steroid binding protein, as 660

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well as the free estradiol concentrations; and even peripheral antagonism to the action of testosterone at the receptor site. Finally, small doses of dexamethasone (0.5 to 1 mgl are extremely effective in normalizing the hyperaldosteronism of glucocorticoidsuppressible hyperaldosteronism. Normalization of the blood pressure and the serum potassium level, as well as reversal of abnormal renin and aldosterone dynamics, is observed with chronic administration of dexamethasone to patients with GSH. If and when side effects of chronic glucocorticoid therapy occur, the blood pressure can be controlled with other antihypertensive agents, while the hypokalemia can be readily managed with spironolactone or amiloride. SELECTIVE

RYPOALDOSTERONISM

Selective or isolated hypoaldosteronism refers to the development of aldosterone deficiency in presence of intact glucocorticoid reserve. While the causes for selective impairment in the secretion and release of aldosterone are several (Table 41,the most common variety is referred to as hyporeninemic hypoaldosteronism (HHA). Once thought to be a rarity, the HI-IA syndrome is being recognized with increasing frequency. For instance, up until 1975, only 30 cases had been documented in the literature; but by 1986, nearly 100 had been reported. In one study of 100 patients with hyperkalemia, 10% had biochemical and hormonal data consistent with HHA.lz6 Since there are several components to this entity, this disorder is conceptually viewed as a syndrome. These components are (1) hyperkalemia, (2) a unique variety of metabolic acidosis called type IV RTA, (3) varying degrees of renal insufficiency, (4) hyporeninemia, (5) hypoaldosteronism, and (6) intact glucocorticoid reserve. TABLE 4. Etiology of Selective Hypoaldostemnism Hyporeninemic hypoaldostemnism interstitial renal disease Decreased pmstacyclin Iz Sympathetic dysfunction Impaired conversion of pmrenin to renin Hypen-eninemic hypoaldostemnism Addison’s disease Enzymatic defects in aldostemne synthesis Acquired defects in zona glomerulosa Critical illness Pseudohypoaldostemnism Tubular resistance Miscellaneous Heparin DM, October lsss

651

ETZOLOGY Three underlying factors, when taken together, are present in nearly all patients with HHA; these are chronic renal disease, diabetes mellitus, and advancing age. The single factor common to all three is defective generation of renin. Chronic renal failure of varying degrees is usually present in HHA. The spectrum of renal diseases that can cause HHA, while dominated by diabetes mellitus, includes diverse conditions such as gout, pyelonephritis, analgesic nephropathy, cystic disease, metabolic stone disease, and even hypertensive nephrosclerosis. 0f particular interest is the development of the syndrome in diabetics. The mechanisms for such a phenomenon are multifactorial: damage to the juxtaglomerular apparatus by diabetic nephropathy12’; the development of autonomic neuropathy with consequent impairment in renin release128;the effect of insulin deficiency on aldosterone synthesis by the zona glomerulosa12g; defective conversion of prorenin to renin; and, finally, interstitial damage by diabetes, resulting in defective excretion of potassium loads by the tubules.13’ PATHOGENESZS The pathogenesis of HHA can be viewed from three perspectives: the hyporeninemia, the hypoaldosteronism, and the metabolic acidosis . Hyporeninemia The presence of hyporeninemia, subresponsive to physiologic stimulation with posture or ambulation, is the hallmark of HHA. Several theories have been proposed to explain the hyporeninemia of the syndrome. 1. Renin suppression by volume expansion. According to this postulate the hyporeninemia is presumed to be a secondary phenomenon in response to subtle volume expansion. This is supported by observations by several workers that indicate an increase in the total exchangeable sodium and extracellular fluid volume in patients with HHA.'31,132 Further, it has been also shown that salt depletion by dietary means as well as by furosemide can result in substantial rises in the PRA of patients with HHAT31,133J lW Finally, hypertension is present in nearly 50% of patients with HHA, a phenomenon that is clearly related to and perhaps mediated by volume expansion. The above lines of evidence not only point to volume expansion, at least in part, as a causal mechanism, but also indicate a valuable role for diuretics in the management of these patients. 2. Renin suppression by impaired sympathetic signals. This is a 662

DM, October

1988

particularly relevant mechanism for the development of HHA in diabetics and elderly patients. As a group, diabetics demonstrate considerable heterogeneity in PRA and aldosterone responses to posture. While the postural responses of PRA and aldosterone are most profoundly impaired in diabetics with orthostatic hypotension, autonomic neuropathy, and nephropathy, subnormal PRA responses can be encountered even in diabetics without detectable autonomic dysfunction or vasculopathy.1zs,‘35-137These observations suggest that hyporeninemia and hypoaldosteronism can be found in some diabetics even in absence of clinically evident nephropathy or neuropathy. It is not clear if this phenomenon represents a harbinger for the subsequent development of the syndrome of HHA. While sympathetic dysfunction is clearly an important factor in the development of HI-IA in diabetics, this cannot be the sole factor. For instance, the hyperkalemia, in some diabetics, correlates closely with hyperglycemia, suggesting a relationship between poor glycemic control and hypoaldostemnism. 3. Role of prostaglandins in the development of HHA. Renal prostaglandins play a crucial role in the secretion and release of renin and are believed to directly stimulate renin release from the juxtaglomerular apparatus. Among the various renal prostaglandins, prostacyclin (prostaglandin I,) is particularly effective in stimulating renin secretion and release in a dose-dependent manner, quite independent of other mechanisms?38 The development of HHA in association with the use of indomethacin lends strong su port for the role of renal prostaglandins in the evolution of HI-&l3 f: The recent demonstration of markedly reduced levels of prostacyclin metabolites in the urine of patients with HI-IA clearly imparts a role for prostacyclin deficiency in the pathogenesis of the syndrome.140 However, it is unclear if this is due to an anatomic or functional defect. Other mechanisms such as decreased conversion of prorenin to renin, and damage to the juxtaglomerular apparatus are, at best, incidental features encountered in patients with HI-IA, and do not completely explain the mechanism of hyporeninemia. H’oaldosteronism While it is generally agreed that the hypoaldosteronism seen in the syndrome of selective hypoaldosteronism is a functional phenomenon secondary to hyporeninemia, other factors, albeit minor, contribute to the phenomenon. Some patients with the syndrome have been shown to have impaired responses of aldosterone to direct stimulation by angiotensin II infusion, indicating an added primary defect in the zona glomerulosa. Enzymatic defects in aldosterone biosynthesis, selectively involving the enzymes 3R-hydroxy dehydrogenase and A4,5-isomerase within the zona glomerulosa, has been proposed to coexist in some patients with the syndrome of DMoctober1988

933

HHA?41 When present, these enzymatic defects superimpose a structural component to the preexisting functional component (suboptimal renin generation) inherent to HHA. Acidosis Patients with HHA usually demonstrate mild to moderate hyperchloremic metabolic acidosis. This is not surprising since aldosterone normally promotes secretion of both hydrogen and potassium ions. However, in contrast to patients with Addison’s disease, where impressive metabolic acidosis is seldom seen, and urinary acidification is reasonably preserved, patients with HHA show significant metabolic acidosis. The high frequency of metabolic acidosis seen in patients with HHA is undoubtedly related to the underlying renal disease that is present in a high proportion of patients with HHA. The acidosis in HHA is unique, and is characterized by a constellation of features142: 1. The urine is acidic and bicarbonate-free during spontaneously occurring acidosis. 2. Reduction in the bicarbonate threshold results in subnormal reabsorption of filtered bicarbonate at normal plasma bicarbonate concentrations. The magnitude of this reduction, however, is not sufficiently great to implicate an impairment in hydrogen ion excretion in the proximal tubule. 3. The urinary excretion of ammonia is greatly reduced, even in the presence of a urine that is highly acidic. 4. Absence of proximal tubular dysfunction such as glucosuria, aminoaciduria, or phosphaturia and 5. Reduced renal clearance of potassium. These features are quite distinct from those of RTA types 1 and 2.'43,144The combined defect in renal tubular secretion of hydrogen ion and potassium has led Sebastian et al.l& to designate this disorder “type 4 RTA.” (Type 3 RTA is a term used to describe a variant of type 1.) The four major mechanisms responsible for the metabolic acidosis of HHA are: 1. Shift of hydrogen ions out of the cells in exchange for potassium ions. The reciprocal changes in the cellular content of H+ and K+ may in part account for the metabolic acidosis seen in HHA. This occurs as hyperkalemia evolves, resulting in shift of H+ out of the cells in exchange for K+ . 2. Reduction in the bicarbonate threshold. Two independent studies have documented a small reduction in the bicarbonate 664

DM, October

1988

threshold of patients with HHA.‘MJ’47 Acid-base studies in patients with HHA have shown intact hydrogen-ion generating capacity of the distal nephron, coupled with signiscantly decreased net acid excretion. The reduction in net acid excretion is owing to a decrease in both NH, and titratable acid excretion. Although bicarbonaturia is seen in most patients with HHA, the magnitude of this phenomenon is not sufficient to account for the degree of metabolic acidosis seen in this syndrome. 3. Decreased ammoniagenesis. A new facet was added to the multifactorial nature of the metabolic acidosis of HI-IA, when Szylman et al.lM demonstrated distinct and significant blunting in urinary excretion of ammonium in a patient with HHA. When the hyperkalemia was corrected by use of exchange resin, the urinary excretion of ammonium markedly increased by several fold, with disappearance of metabolic acidosis. Importantly, the improvement in ammonium excretion and in the metabolic acidosis correlated with reduction of serum potassium levels with no changes in other variables such as renal function, hypervolemia, or the PRA status. The concept that hyperkalemia per se can impair urinary acidification by interfering with diffusion of ammonia from the tubular cell into the urine is not new, but the concept that such a mechanism plays a dominant role in the metabolic acidosis of HHA is a novel one. The relative roles of hyperkalemia and mineralocorticoid deficiency are complementary to each other in the causation of the acidification defect and the metabolic acidosis of HHA. 4. Decreased hydrogen ion secretion. Since aldosterone stimulates secretion of both H+ and K+ by the kidney, loss of aldosterone results in decreased Hf secretion. However, aldosterone deficiency alone cannot be the sole cause of metabolic acidosis, since administration of mineralocorticoids in “physiologic” amounts has little effect on ameliorating the metabolic acidosis of patients with HHA. The presence of chronic renal disease must be a limiting factor that renders the tubules resistant to the effects of physiologic amounts of mineralocorticoids. The metabolic acidosis of HHA is complex and multifactorial in origin, with the underlying renal disease setting the stage for several perturbations in acid-base and electrolyte balance. CLINICAL

FEATURES

The clinical features of HHA are highly nonspecific. The typical patient with HI-LAis usually middle aged or elderly, generally asymptomatic, and almost always has underlying renal disease, particularly related to diabetes. Hypertension of varying degrees is present in 40% to 50% of patients, with or without orthostatic changes. The symptoms experienced by patients with HHA are related to hyperDM,Octobfs1988

665

kalemia. Muscle weakness, cardiac arrhythmias, and resultant neurologic dysfunction may accompany the hyperkalemia. Typically, symptoms of glucocorticoid deficiency are conspicuously absent. Dizziness may be encountered in some patients owing to the combination of sodium loss and mineralocorticoid deficiency. However, this is less common in comparison to Addison’s disease. Symptoms related to renal insufficiency are usually absent, since the degree of renal failure is mild. LABORATORY

DIAGNOSIS

The laboratory features of hyporeninemic

hypoaldosteronism

are:

1. Hyperkalemia in presence of mild renal insufficiency. 2. Hyperchloremic metabolic acidosis. 3. Subnormal renin and aldosterone responsiveness to posture and Rn-osemide administration. 4. Normal glucocorticoid reserve. The focal point that initiates the suspicion of underlying HHA is hyperkalemia. The occurrence of hyperkalemia in association with mild renal failure must always invoke the suspicion of HHA, because potassium retention in chronic renal failure occurs only when the GFR declines below 20 ml/mm The triad of hyperkalemia, mild renal failure, and hyperchloremic acidosis is characteristic of HI-IA. The urinary excretion of potassium, and to some extent sodium, is lowered. The urine pH is low, but most in patients with HI-IA, urine pH is lowered during acid loading. Once HI-IA is suspected, the further hormonal studies include evaluation of the renin aldosterone responses to posture and furosemide. While the vast majority of patients with HI-IA show blunted PRA and aldosterone responses to posture and diuretic, such a response is not universal. In an excellent review of the subject, DeFronzo130 points out that the baseline or the stimulated PRA was found to be normal in 13 of the 74 patients with the syndrome. In terms of aldostemne responsiveness to direct stimulation by ACTH or angiotensin II administration, there is considerable heterogeneity of responses. While theoretically the zona glomerulosa of patients with HHA should respond normally to direct stimulation, the aldosterone response to angiotensin II in patients with HHA can be blunted, indicating functional or structural impairment in the cells of the zona glomerulosa. Of course, the cortisol reserve to ACTH is invariably normal in patients with HHA, indicating intact function of the zona fasciculata. The differential diagnosis of HI-IA is essentially the differential diagnosis of hyperkalemia. The stepwise approach includes the first 666

DM october1988

step of exclusion of “pseudohyperkalemia”; this is followed by exclusion of iatrogenic causes of hyperkalemia. The third step involves evaluation of the pH to exclude acute acidemia (as in diabetic ketoacidosis) as a cause for hyperkalemia. The next step is exclusion of renal disease. When the GFR is greater than 20 ml/m& other causes besides renal failure should be considered. In this regard, several systemic diseases can manifest with impaired renal tubular function. These include sickle cell disease, systemic lupus erythematosus, amyloidosis, and the post-transplantation kidneys. After exclusion of systemic disease, the differential diagnosis of hyperkalemia should focus on adrenal disorders. The most important one to exclude is Addison’s disease, followed by enzymatic defects in mineralocorticoid synthesis. Of course, both these conditions are characterized by an elevated PRA, in contrast to HHA, which generally is associated with a low PRA. TFiEATMENT

The main indication for treatment of patients with HHA is the hyperkalemia. The main therapeutic modality is the use of synthetic mineralocorticoids such as Sar-fludrocortisone. In contrast to patients with Addison’s disease, the correction of the hyperkalemia in patients with HHA requires supraphysiologic doses of mineralocorticoid. The main reason for such “resistance” is the underlying renal disease. Mineralocorticoid therapy is associated with a remarkable amelioration of the metabolic acidosis as well as the hyperkalemia within 4 weeks of therapy. In addition, diuretics therapy and anion exchange resins can be used as adjunctive therapy. TRJ3 ADRENOGENITAL

SYNDROMES

The adrenogenital syndromes (AG syndromes) are diverse disorders that originate from enzymatic defects in the synthesis of cortisol. Recognition of these syndromes at birth is crucial, not only for sexual assignment but also in preventing potentially life-threatening electrolyte disturbances in the neonatal period. PATHOPHYSIOLOGY

The basic abnormality that sets the stage for adrenogenital syndromes is complete or partial enzymatic blocks in cortisol synthesis. In Figure 2 the conventional model of steroidogenesis is outlined. The enzymatic blocks that cause adrenogenital syndrome may occur at several sites within the “steroidogenic cascade.” The pathophysi-

DM, October 1988

657

ADRENAL

Sll3ROlDOGBNJ3SB

CHOLESTEROL 1 PREGNENOLONEA 1 1

1,

OH

PREGNENOLONE

17 OH

PJIOGESTERONE

a

I

I

DHEA --+

2

1

2

4 5 ANDROSTENEDIOL 1

2

4 PROGESTERONE+

1 5 DOC 1

I 5 DEOXYCORTISOL

6

1

CORTICOSTERONE 1

---+

ANDROSTENEDIONE

1 ESTRONEB

-3TESTOSTERONE

1 ESTRADIOL

6

CORTISOL

7

18 OH CORTICOSTERONE 1

8

ALDOSTERONE

1. Cholesterol 2.

sidechain

3 6 hydroxysteroid

3.

11 (I hydroxylase

4.

17, 201yase

5.

21 hydroxylase

6.

11 hydroxylam

1. Corticostemne 6.

18 hydroxy

cleaving

enzyme

dehydrogenase

methyloxidase dehydrogenase

FIG 2. Adrenal steroidogenesis.

ology of AG syndromes is simple to understand if the disorder is viewed as a series of chain reactions consisting of the following links: 1. The point of origin is the partial or complete inability to synthesize cortisol, owing to lack of a particular enzyme. 2. The lack of adequate synthesis of cortisol triggers release of ACTH, owing to negative feedback effect. 3. The ACTH release, a compensatory secondary phenomenon, stimulates both adrenal cortices, which undergo hyperplasia (“congenital adrenal hyperplasia”) . 4. Flagellating under the duress of chronic ACTH stimulation, the adrenal cortices respond by secreting excessive amounts of steroids lim

DM, October 1988

proximal to the block (“upstream products”). Thus, steroidogenesis proceeds actively in the open pathways. 5. The markedly increased precursor products are diverted into other channels, particularly the androgen pathways. 6. The resultant accumulation of these adrenal androgens manifest with clinical expressions, the most remarkable of which is virilization of the external genitalia of the female fetus, resulting in female pseudohermaphroditism at birth. Considerable heterogeneity exists in the severity of enzymatic defects that underlie adrenogenital syndromes. Thus, on one end of the spectrum are patients with the complete block, presenting with sexual ambiguity at birth, while at the other end are the patients with partial defects who present in adult life with hirsutism and/or oligomenorrhea. In addition to the severity of the enzyme block, the type of enzyme involved also has considerable impact on the clinical expression. The most common enzyme block involves Zl-hydroxylase .14’Current notions favor the existence of two types of 21-hydroxylases, one within the zona fasciculata and another within the zona glomerulosa. Obviously, the clinical expression varies depending on whether the block involves only the enzyme within the fasciculata (“the simple virilizing variety”) or both (“the salt-losing variety”). The next common enzyme deficiency is I#-hydroxylase deficiency,14’ a syndrome that can be viewed as nature’s metyrapone test. Certain enzyme deficiencies, such as complete deficiency of desmolase (cholesterol side-chain cleaving enzyme), are incompatible with life. Rare deficiencies, such as complete 3@-hydroxy steroid deficiency, can result in both female as well as male pseudohermaphroditism.150 Even more fascinating is the observation that certain enzymatic blocks, particularly 17a-hydroxylase deficiency,15’ possess the dubious distinction of occurring in both the adrenals as well as the gonads. Finally, enzyme deficiencies may involve only the mineralocorticoid pathway without involving cortisol synthesis. Such is the case with deficiency of corticosterone methyl oxidase, which mediates the conversion of corticosterone to aldosterone. Since 21-hydroxylase deficiency (21 HD) and I@-hydroxylase deficiency account for more than 80% of adrenogenital syndromes, these two disorders will share the focus of discussion. 21-Hydmpylase

Deficiency

Since its original description in 1865 by the Neopolitan anatomist DeCrecchio, the 21 HD syndrome has evolved from a rare and mysterious disorder to a commonly encountered and extremely well understood condition. The three major developments that have facilitated such understanding are the availability of sensitive and diagnostic immunoassays for detection, the emergence of gene mapDM,october19st?

8369

ping studies to identity heterozygotes, and the ability to diagnose the disorder in utero by amniotic fluid analyses. 7’ypes of the [email protected] terms “classical” and “nonclassical” 21 HD are used to denote complete and partial expressions of 21 HD, respectively. As mentioned earlier, when the deficiency involves only the glucocorticoid pathway it is termed the “simple virilizing” variety, as opposed to involvement of the mineralocorticoid pathway as well, when it is termed “the salt-losing variety.” Incidence.-The availability of a microfllter paper method that measures 17a-OH-progesterone in a heel-prick capillary blood specimen has permitted population surveys in newborns.‘52 The incidence of the classical 21 HD is highest in the Yupik-speaking Eskimo race of Western Alaska, approaching 1 per 280 to 1 per 684.153’154 The incidence is estimated to be 1 in 15,000 in the United States15’and 1 in 13,000 in Canada.15”The exact incidence of nonclassical (late onset) 21 HD is not known, since this condition cannot be screened by the use of the microfilter method. However, other methods have been utilized to define the approximate frequency of the nonclassical variant. It has been estimated in one study15’ that as many as 32% of patients referred for evaluation of premature adrenarche had nonclassical 21 HD. In another study,‘58 14% of patients referred for evaluation of hirsutism were found to have adult-onset 21 HD. These studies, however, do not provide data on the incidence of the condition in the asymptomatic general population. This aspect has been evaluated by studying the “gene frequency” for 21 HD in various ethnic groups using genetic linkage markers for nonclassical 21 HD?5s A high prevalence of heterozygous 21 HD is seen in Ashkenazi Jews, Hispanics, Italians, and Yugoslavians. The gene frequency, the HLA linkage, and the mode of inheritance of both the classical and the nonclassical 21 HD are discussed under the genetics of the disease. Hormonal Milieu.-The classic “simple virilizing” form of 21 HD, in which the enzyme deficiency is severe, is characterized by decreased synthesis of cortisol and ll-deoxycortisol, with elevations in 17o-OH-progesterone, DHEA, and androstenedione. These androgens, by their eventual conversion to testosterone and dihydrotestosterone, exert their virilizing effects on the developing genitalia of the female fetus. The classical “salt-losing” form of 21 HD, in which the deficiency involves both the glucocorticoid and mineralocorticoid pathways, is characterized by all of these features plus decreased amounts of aldosterone corticosterone and desoxycorticosterone. The severe mineralocorticoid deficiency leads to loss of sodium in urine with retention of potassium, resembling Addison’s disease. The nonclassical (late onset, attenuated, partial) 21 HD?60’161in 660

DM,October1988

which the enzyme deficiency is mild and partial, is characterized by near normal cortisol production, varying degrees of elevation in the levels of 17o-OH-progesterone, and DHEA. The hallmark of this form of AG syndrome is the exaggerated response of the precursor 17~ OH-progesterone to the intravenous administration of ACTH. CZir~icaZFeatures.-The clinical expressions of 21 HD can manifest at birth, during puberty, or in adulthood. Neonatal manifestations occur only in the case of classical 21 HD, in which the enzyme deficiency is complete. These are most impressive in female infants. In extreme cases the genitalia undergo complete masculinization, resulting in phallic growth, a penile urethra, and even fusion of the labial folds-resembling those of a male infant.“@ There is considerable heterogeneity in virilization of the urogenital sinus, labial fusion, and clitoral growth. The gonads in these patients are ovaries, and the Mullerian duct derivatives are unaffected. The presentation of these structures is the reason for the capacity of these patients to subsequently become fertile. Men with the classical 21 HD may not show any abnormalities at birth. Occasionally the genitalia may appear oversized. These infants would tend to show progressive precocious virilization as they grow older. In both sexes with the “salt-losing variety” the effects of combined glucocorticoid and mineralocorticoid deficiency can result in acute adrenal insufficiency. The prepubertal manifestations of 21 HD include premature adrenarche and progressive virilization in girls, and isosexual precocious puberty in boys. In the latter, the striking phallic proportions and adrenarche are contrasted by the small, prepubertal dimensions of the testes. The postpubertal manifestations of partial 21 HD include hirsutism, oligomenorrhea, and infertibility in women162-166and oligospermia in men.167 Diagnostic

Studies.-

The criteria required for the diagnosis of 21

HD are: 1. Demonstration of accumulated products proximal to the block (17a-OH-progesterone, and to a lesser extent 17cY-OH-pregnenolone). 2. Demonstration of increased androgens (DHEA, androstenedione) derived from the precursor steroids. The androgen excess is suppressible to the DXM test. 3. Demonstration of decreased synthesis of steroids distal to the block; this is evident only in the classic 21 HD and is seen as decreased cortisol and ll-deoxycortisol levels, in the simple virilizing form. In addition, decreased mineralocorticoid levels would be seen in the salt-losing form. 4. Demonstration of an exaggerated response of precursor steDM, October

1988

6431

roids (l’la-OH-progesterone) to ACTH. This is mostly applicable to the nonclassical forms of 21 HD and represents a single-step diagnostic procedure to unmask the disorder. Diflerential Diagnosis.- The various conditions that enter the differential diagnosis of 21 HD, as well as the diagnostic features that separate them for 21 HD, are outlined in Table 5. Genetics.The 21 HD is transmitted as an autosomal recessive disorder, and both sexes are at equal risk for inheritance?48,168 Genetic mapping studies have established that the human genome includes two 21-hydroxylase genes that alternate with two genes for the fourth component of complement (C4a and C4b1?6s”70These genes are located on the short arm of chromosome 6, between the loci of HLA-B and HLA-DR. Pioneering work by DuPont et al.‘” has established a close genetic linkage between HLA type and 21 HD. Family studies of patients with 21 HD have revealed that all affected children in a given family are HLA identical, and different from their unaffected sibship. In order to transmit the disorder to the offspring it is essential that both parents be obligate heterozygote carriers, each transmitting one HLA haplotype carrying the gene to the affected child. Thus, characterization of the HLA genotype has become a marker for detection of 21 HD in the unaffected carrier. The HLA TABLE Differential

5. Diagnosis of Adrenogenital

Differentiating

Condition At birth Nonadrenal femalepseudohermaphmditism Prepubertal Adrenal tumors Ovarian tumors Leydig cell tumors Ectopic secretion of human chorionic gonadotropin Adulthood Masculinizing

ovarian tumor

Polycystic ovary syndrome Adrenal tumors, usually carcinoma

662

Syndrome Feature(s)

Presence of virilizing tumor in mother, history of drug intake kmdrogenic steroids) during pregnancy Nonsuppression to DXM test, CT study of adrenal abnormal Abnormal CT of ovaries, testosterone elevated Palpable testicular mass, testosterone markedly elevated Usually in women, underlying malignancy obvious

Increased testosterone, abnormal CT and ultrasound 17u-OH-progesterone response to ACTH normal Elevated adrenal androgens nonsuppressible to DXM, CT of adrenal invariably normal DM, October 1988

antigen Bw 47 has been associated with classical 21 HD at a remarkable frequency rate-approaching 35% in some ~mveys.‘~ The inheritance pattern of nonclassical 21 HD is also linked to HLA. It is the current notion that the classical and nonclassical types of the disease are allelic variants of the same disorder.1n8179The existence of both types in the same family supports such a notion. A high correlation between nonclassical 21 HD and the prevalence of HLA-B 14 and Aw 33 has been obsetved.‘66 As with the classical form, an impressive HLA similarity is seen in siblings with nonclassical 21 HD. Thus, HLA marker studies have linked both types of 21 HD to major histocompatibility loci. The information derived from HLA linkage studies assumes importance in genetic counseling. HL4 markers also permit recognition of siblings who might be at high risk for developing the disorder. Most importantly, the development of gene typing techniques have permitted the detection of 21 HD in the fetus. Prenatal diagnosis of 21 HD in the fetus becomes important under the following circumstances. 1. When the mother with classical or nonclassical 21 HD has previously borne a child with classical or nonclassical 21 HD and is pregnant again by the same spouse who fathered the first child; 2. When the spouse of the patient with classic or nonclassic 21 HD is known to have asymptomatic 21 HD, as determined by hormonal data; and 3. When genetic mapping studies in the spouse demonstrate HLA types that are known to be linked with the 21-hydroxylase gene. In these settings, prenatal diagnosis of 21 HD in the fetus can be established by amniocentesis.‘75-1R Hormonal measurements in the amniotic fluid, and HLA typing of cultured amniotic cells, can establish the diagnosis. The prenatal diagnosis of 21 HD in the female fetus provides an option of suppressing the fetal adrenals by giving the mother dexamethasone.*‘* 11 &Hydro~lase

Deficiency

I@-hydroxylase deficiency is the second most common form of congenital adrenal hyperplasia. As a consequence of a block in the penultimate step of cortisol biosynthesis, a cascade of events are set in motion. These include ACTH release, adrenal stimulation, and accumulation of precursors such as ll-deoxycortisol, 17a-OH-progesterone, and DOC. The increased 17a-OH-progesterone serves as substrate for increased synthesis androgens. ll@hydroxylase deficiency resembles 21-hydroxylase deficiency in that both are characterized by accumulation of 17a-OH-progesterone and in their expressions of androgen excess and cortisol defiDM, October

1988

993

ciency. The three main differences are in that ll@hydroxylase is also characterized by elevated ll-deoxycortisol (Compound S) level, elevated DOC level (resulting in mineralocorticoid excess), and in the relative rarity of adult onset types. The clinical triad of this disorder consists of androgen excess; COP tisol deficiency, particularly during stress; and mineralocorticoid (DOC) excess, resulting in hypertension and hypokalemic alkalosis. The biochemical triad of the disorder is characterized by elevated 17or-OH-progesterone (and 11-deoxycortisol) levels, elevated DHEA suppressible to dexamethasone, and a blunted cortisol response to ACTH. Dejiciencies Prognosis of 2% and II-Hydro&se The prognosis of congenital adrenal hyperplasia is generally good if therapy is instituted early. The four important concerns in such patients are the ability of genotypic females with these syndromes to lead a hormonally normal “female” life, the ability to mount a cortisol response to stress, and the effect of androgen excess on stature and on gender identification. Genotypic females with the classical variety of AG syndromes have anatomically normal Mtillerian duct derivatives. Therefore, theoretically, with proper therapy, the occurrence of puberty, menarche, and fertility should be normal in these children. In a large study of 80 patients with 21-hydroxylase deficiency, Mulaikal et al.“’ evaluated fertility rate and found that patients with the simple virilizing form had a fertility rate of only 601, a rate much lower than in the general population. Patients with the salt-losing form had much lower fertility rates. The three factors that influenced the potential for fertility were the type of defect (simple virilizing versus salt losing), the status of the introitus, and compliance with therapy. Salt losers also do poorly in terms of attaining normal adult stature. The effect of androgen excess on the psychosexuality, gender identiilcation, and sexual preference of patients with AG syndromes has been a matter of dispute.*79-181 TREATMENT Treatment of AG syndrome rests on proper endocrinologic, surgical, and psychiatric principles. The goals in treatment of 21- and llhydroxylase deficiency include: 1. Interruption of the chain of events that led to androgen excess. This is done with glucocorticoid administration. 2. In women with these virilizing syndromes, every attempt should be made to allow these patients to develop as normal 664

DIM, October 1988

women. Thus, with proper therapy, pubertal feminization, ovulation, and fertility are hopeful, but unguaranteed, goals. 3. Avoidance of electrolyte abnormalities is particularly important in the salt-losing form of 21 HD and in II-hydroxylase deficiency. 4. Every attempt should be made to provide these patients with external genitalia that match their genotypic sex. The role of the urologist and the plastic surgeon in reconstructing a reasonably normal introitus has a significant impact on the subsequent psychosexual adjustments of the patient. 5. Attempts to avoid short stature, which can result from both undertreatment and overtreatment, constitutes an important, albeit difficult, facet of therapy. 6. Finally, intense psychological support mechanisms need to be drawn upon to help these patients face life as normal women. Despite the problems of prenatal masculinization, most females with virilizing AG syndromes demonstrate excellent adaptability to the female role. The cornerstone of medical therapy is treatment with hydrocortisone. The initial dose and the subsequent maintenance dose have to be individually tailored, based on the responses to treatment. The initiating dose for children under 2 years of age is 25 mg/day, 50 mg/ day for children between 2 and 6 years of age, and 100 mg/day for children over age 6. These doses are considerably higher than replacement glucocorticoid therapy, since the aim here is to achieve complete ACTH suppression. Once the androgen levels (and the precursor levels) are normalized, patients may be switched to maintenance doses of cortisone or hydrocortisone. While dexamethasone has the greatest potency of suppressing ACTH, the side effects of overtreatment are also more pronounced. The selection of the maintenance steroid (dexamethasone versus cortisone, hydrocortisone) as well as the dose am individual decisions, based on patient response. This can be excellently monitored by the assay for 17~OHprogesterone levels, which has obviated the need to collect 24hour urines for pregnanetriol. REFERBNCES 1. Cushing H: The basophilic adenomas of the pituitary body and their clinical manifestations. Bull Johns Hopkins 1932; 50:137. 2. Ludecke DK, Schabet M, Saeger W: In vitro secretion of adenoma and anterior lobe cells in two typical cases of Gushing’s disease. Neurosurgery 1983; 12:549. 3. Suda T, Tozawa F, Mauri T, et al: Effects of cyproheptadine, reserpine, and synthetic corticotrupin-releasing factor on pituitary glands from patients with Cushing’s disease. J Clin &domino/ Metab 1983; 56:1094. 4. Lamberts SWJ, Klijn JGM, Quijada M, et al: The mechanism of the suppresDiU, October

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5. 6.

7.

8.

9.

10.

11. 12.

13.

14.

15. 16.

17. 18. 19. 20. 21. 22.

886

sive action of bromocriptine on adrenocorticotropin secretion in patients with Cushing’s disease and Nelson’s syndrome. J Clin Endocrinol Metab 1980; 51:307. Orth DN, Liddle GW: Results of treatment in 108 patients with Cushing’s syndrome. N Engl J Med 1971; 285243. Krieger DT, Luria M: Plasma ACTH and cortisol responses to TRF, vasopressin or hypoglycemia in Cushing’s disease and Nelson’s syndrome. J Clin Endocrinol Metab 1977; 44361. Chrousos GP, Schulte HM, Oldfield EH, et al: The corticotropin-releasing factor stimulation test-an aid in the evaluation of patients with Cushing’s syndrome. N Engl J Med 1984; 310:622. Carey RM, Varma SK, Drake CR Jr, et al: Ectopic secretion of corticotropin releasing factor as a cause of Cushing’s syndrome. N Engl J Med 1984; 311:13. Lamberts SWJ, De Lange SA, Stefanko SZ: Adrenocorticotropin-secreting pituitary adenomas originate from the anterior or the intermediate lobe in Cushing’s disease: Differences in the regulation of hormone secretion. J Clin Endocrinol Metab 1982; 54286. Levin ME: The development of bilateral adenomatous adrenal hyperplasia in a case of Cushing’s syndrome of eighteen years’ duration. Am J Med 1966; 40:318. Aron DC, Findling JW, Fitzgerald PA, et al: Pituitary ACTH dependency of nodular adrenal hyperplasia in Cushing’s syndrome: Report of two cases and review of the literature. Am J Med 1981; 71:302. Schteingart DE, Tsao HS: Coexistence of pituitary adrenocorticotropin dependent Cushing’s syndrome with a solitary adrenal adenoma. J Clin Endomino1 Metab 1980; 50:961. Ruder HJ, Loriaux DL, Lipsett MB: Severe osteopenia in young adults associated with Cushing’s syndrome due to micronodular adrenal disease. J Clin Eno!ocrinol Metab 1974; 39:1138. McArthur RG, Bahn RC, Hayles AB: Primary adrenocortical nodular dysplasia as a cause of Cushing’s syndrome in infants and children. Mayo Clin Proc 1982; 5758. Larsen JL, Cathey WJ, Odell WD: Primary adrenocortical nodular dysplasia, a distinct subtype of Cushing’s syndrome. Case report and review of the literature. Am J Med 1986; 80976. Ratter SJ, Gillies G, Hope J, et al: Pro-opiocortin related peptides in human pituitary and ectopic ACTH secreting tumours. Clin Endocrinol COfl 1983; 18211. Bertagna C, Orth DN: Clinical and laboratory findings and results of therapy in 58 patients with adrenocortical tumors admitted to a single medical center (1951 to 1978). Am J Med 1981; 71:855. Urbanic RC, George JM: Gushing’s disease-18 years experience. Medicine 1981; 60:14. Ross J, Linch DC: Cushing’s syndrome-killing disease: Discriminatory value of signs and symptoms aiding early diagnosis. Lancet 1982; 2:646. Khaleeli AA, Edwards RHT, Gohil K, et al: Corticosteroid myopathy: A clinical and pathological study. Clin Endocrinol 1983; 18:155. Saad MF, Adams F, Mackay B, et al: Occult Cushing’s disease presenting with acute psychosis. Am J Med 1984; 76:759. Trecan GV, Laudat MH, Thomopoulos JP, et al: Urinary free corticoids: Evaluation of their usefulness in diagnosis of Gushing’s syndrome. Acta Endocrinol (Copenh) 1983; 103:llO. DM,

October

1988

23. Nugent CA, Nichols T, Tyler FH: Diagnosis of Cushing’s syndrome-single dose dexamethasone suppression test. Arch Intern Med 1665; 116:172. 24. McHardy-Young S, Harris PWR, Lessof MH, et al: Single-dose dexamethasone suppression test for Cushing’s syndrome. Br Med .I 1967; 2:740. 25. Meikle AW, Lagerquist LG, Tyler FH: Apparently normal pituitary-adrenal suppressibility in Cushing’s syndrome: Dexamethasone metabolism and plasma levels. J Lab Clin Med 1975; 86:472. 26. Cam JF, Meikle AW, Check JH, et al: Normal suppression to dexamethasone in Cushing’s disease: An expression of decreased metabolic clearance for dexamethasone. J Clin Endocrinoi Metab 1978; 47667. 27. Liddle GW: Tests of pituitary-adrenaJ suppressibility in the diagnosis of Cushing’s syndrome. J Clin Endocrinol Metab 1960; 203539. 28. ‘Qrrell JR, Findling JW, Aron DC, et al: An overnight high-dose dexamethasone suppression test for rapid differential diagnosis of Cushing’s syndrome. Ann Intern Med 1986; 104:180. 29. Linn JE, Bowdoin B, Farmer A, et al: Observations and comments on failure of dexamethasone suppression. N Engl J Med 1967; 277:403. 30. Carey RM: Suppression of ACTH by cortisol in dexamethasone-non suppressible Gushing’s disease. N Erg1 J Med 1980; 302275. 31. Lieberman B, Wajchenberg BL, Tambascia MA, et al: Periodic remission in Cushing’s disease with paradoxical dexamethasone response: An expression of periodic hormonogenesis. J Clin Endocrinol Metab 1976; 43:

913. 32. Brown RD, Van Loon GR, Orth DN, et al: Cushing’s disease with periodic hormonogenesis. J Clin Endocrinol Metab 1973; 36:445. 33. Mason AMS, RatcliRe JG, Buckle RM, et al: ACTH secretion by bronchial carcinoid tumors. Clin Endocrinol 1972; 13. 34. Northrop G, Baldwin D, Faber LP, et al: Dexamethasone suppression of urinary 1Phydroxycorticoids in a patient with an ACTH-producing bronchial adenoma. Presbyterian-St. Luke’s Med Bull 1970; 9:43. 35. Sindler BH, Griffing GT, Melby JC: The superiority of the metyrapone test versus the high-dose dexamethasone test in the differential diagnosis of Cushing’s syndrome. Am J Med 1983; 74.657. 36. Orth DN, DeBold CR, DeChemey GS: Pituitary microadenomas causing Cushing’s disease respond to corticotropin-releasing factor. J Clin EndocrinolMetab 1982;55:1017. 37. Catania A, Cantalamessa L, Orsatti A, et al: Plasma ACTH-response to the corticotmpin releasing factor in patients with Gushing’s disease. Comparison with the lysine-vasopressin test. Metabolism 1984; 331478. 38. Findling JW, Aron DC, Qrrell JB, et al: Selective venous sampling for ACTH in Cushing’s syndrome. Differentiation between Gushing’s disease and ectopic ACTH syndrome. Ann Intern Med 1981; 94z647. 39. Oldfield EH, Chrousos GP, Schulte HM, et al: Preoperative localization of ACTH secreting microadenomas by bilateral and simultaneous inferior petrosal sinus sampling. N En@ J Med 1985; 312:lOO. 46. Manni A, Latshaw RF, Page R, et al: Simultaneous bilateral venous sampling for adrenocorticotropin in pituitary-dependent Cushing’s disease: Evidence for lateralization of pituitary venous drainage. J Clin Endocrinol Metab 1983; 57:1070. 41. Boggan JE, ‘Qrrell JB, Wilson CB: Transsphenoidal microsurgical management of Cushing’s disease. J Neurosurg 1983; 59:195. 42. Hardy J: Gushing’s disease: 50 years later. Can J Neurol Sci 1982; 9:375. 43. Burch Wh4: Gushing’s disease. Arch Intern Med 1985; 145:llOB. mu, October

1988

687

44. Jennings AS, Liddle GW, Orth DN: Results of treating childhood Cushing’s disease with pituitary irradiation. N Engl J Med 1977; 297957. 45. Nelson DH, Meakin JW, Thorn GW: ACTH-producing pituitary tumors following adrenalectomy for Cushing’s syndrome. Ann Intern Med 1960; 52560. 46. Moore TJ, Dluhy RG, Williams GH, et al: Nelson’s syndrome: Frequency, prognosis, and effect of prior irradiation. Ann Intern Med 1976; 85:731. 47. Krieger DT, Amorosa L, Linick F: Cyproheptadine-induced remission of Cushing’s disease. N Engl J Med 1975; 293693. 48. Miura K, Aida M, Mihara A, et al: Treatment of Cushing’s disease with reserpine and pituitary radiation. J Clin Endocrinol Metab 1975; 41511. 49. Lamberts SWJ, Birkenhager JC: Bromocrlptine in Nelson’s syndrome and Cushingb disease. Lancet 1976; 2:811. 50. Nieman LK, Chrousos GP, Kellner C, et al: Successful treatment of Cushing’s syndrome with the glucocorticoid antagonist RU 486. J Clin Endocrino1 Metab 1985; 61536. 51. Nerup J: Addison’s disease-clinical studies. A report of 108 cases. Acta

Endocrinol Kbh) 1974; 76~127. 52. Neufeld M, Maclaren N, Blizzard R: Autoimmune polyglandular syndromes. Pediatr Ann 1980; 93154. 53. Neufeld M, Maclaren NK, Blizzard RM: Two types of autoimmune Addison’s disease associated with different polyglandular autoimmune (PGA) syndromes. Medicine (Baltimore) 1981; 60:355. 54. Nerup J: Addison’s disease-serological studies. Acta Endocrinol (Copenh) 1974; 76342. 55. Scherbaum WA, Berg PA: Development of adrenocortical failure in nonAddisonian patients with antibodies to adrenal cortex. Clin Endocrinol (Oi$l982; 16345. 56. Nerup J, Christy M, Kroman H, et al: Autoimmunity and diabetes mellitus, in Irvine WJ (ed): Immunology ofDiabetes, Edinburgh, Teviot, 1980, p 55. 57. Guttman PH: Addison’s disease. A statistical analysis of 566 cases and a study of the pathology. Arch Path01 1930; 10:742. 58. Alvarez S, McCabe WR: Extra-pulmonary tuberculosis revisited: A review of experience at Boston City and other hospitals. Medicine (Baltimore) 1984; 6325. 59. Sarosi GA, Voth DW, Dahl BA, et al: Disseminated histoplasmosis: Results of long-term follow-up. A Center for Disease Control cooperative mycoses study. Ann Intern Med 1971; 75z.511. 60. Gibb WRG, Ramsay AD, McNeil NI, et al: Bilateral adrenal masses. Br Med J 1985; 291203. 61. Abrams HL, Spiro R, Golstein N: Metastases in carcinoma. Cancer 1950; 3:74. 62. Glomsett DA: The incidence of metastasis of malignant tumors of the adrenal. Am J Cancer 1938; 3257. 63. Shea TC, Spark R, Kane B, et al: Non-Hodgkin’s lymphoma limited to the adrenal gland with adrenal insufficiency. Am J Med 1985; 78:711. 64. Osei K, Falko J, Pacht E, et al: Primary adrenal insufficiency manifesting as malignant lymphoma. Arch Intern Med 1983; 143:1791. 65. Seidenwurm DJ, Elmer EB, Kaplan KM, et al: Me&stases to the adrenal glands and the development of Addison’s disease. Cancer 1984; 54.552. 66. Pont A, Williams PL, Loose DS, et al: Ketoconazole blocks adrenal steroid synthesis. Ann Intern Med 1982; 97:370. 67. Wagner RL, White PF, Kan PB, et al: Inhibition of adrenal steroidogenesis by the anesthetic etomidate. N Engl J Med 1984; 310:1415.

998

LAM,October 1988

68. Addison T: On the Constitutional and Local E@cts ofDisease ofthe Suprarenal Capsules. London, S High@, 1855. 69. Dunlop D: Eighty-six cases of Addison’s disease. Br Med J 1963; 2887. 70. Ask-upma& E, Hull R: Addison’s disease in a university medical department during 20 years. Acta Med Stand 1972; X92:445. 71. Strakosch CR, Gordon RD: Early diagnosis of Addison’s disease; pigmentation as sole symptom. Aust NZ J Med 1978; 8:189. 72. Irvine WJ, Barnes EW: Adrenocortical insufficiency. Clin Endocrinol Metab 1972; 1:549. 73. Rajathurai A, Chazan BI, Jeans JE: Self mutilation as a feature of Addison’s disease. Br Med J 1983; 287:1027. 74. Refetoff S, Block MB, Ehrlich EN, et al: Chiari-Frommel syndrome in a patient with primary adrenocortical insufficiency. Cure by glucocorticoid replacement. N Erg1 J Med 1972; 287:1326. 75. Marilus R, Dickerman Z, Kaufman H, et al: Addison’s disease associated with precocious sexual development in a boy. Acta Paediatr Stand 1981; 70:587. 76. Downie WW, Gunn A, Paterson CR, et al: Hypercaicaemic crisis as presentation of Addison’s disease. Br Med J 1977; 1:145. 77. Wood JB, Frankland AW, James VHT, et aI: A rapid test of adrenocortical function. Lancet 1965; 1243. 78. Musa BLJ, Dowiing J: Rapid intravenous administration of corticotropin as a test of adrenocorticaI insufficiency. JAMA 1967; 201633. 79. Speckart PF, Nicoloff JT, Bethune JE: Screening for adrenocortical insufficiency with cosyntrupin (synthetic ACTH). Arch Intern Med 1971; 128:761. 80. Dluhy RG, Himathongkam T, Greenfield M: Rapid ACTH test with plasma aldosterone levels: Improved diagnostic discrimination. Ann Intern Med 1974; 80693. 81. Vita JA, SiIverberg SJ, Goland RS, et al: Clinical clues to the cause of Addison’s disease. Am J Med 1985; 78:461. 82. Stryker TD, MoIitch ME: Reversible hyperthyrotropinemia, hyperthyroxinemia, and hyperprolactinemia due to adrenal insufficiency. Am J Med 1985; 79271. 83. Wilbur JF, Utiger RD: The effect of glucocorticoids on thyrwtropin secretion. J Clin Invest 1969; 482096. 84. Burch WM: Urine free-cortisol determination: A useful tool in the management of chronic hypoadrenal states. JAMA 1982; 2472002. 85. Conn Jw: Primary aldosteronism, a new clinical syndmme. J Lab Clin Med 1955; 45:6. 86. Nicholls MG, Espiner EA, Hughes H, et al: Primary aldosteronism: A study in contrasts. Am J Med 1975; 59334. 87. GanguIy A: New insIghts and questions about glucocorticoid suppressible hyperaldosteronism. Am J Med 1982; 72851. 88. Arteaga E, Bigiieri EG, Kater CE, et al: Aldosterone-producing adrenocortical carcinoma. Preoperative recognition and course in three cases. Ann Intern Med 1984; 101316. 89. GanguIy A, Zager PG, Luetscher JA: Primary aidosterunism due to unilateral adrenal hyperplasia. J Clin Endocrinol Metab 1980; 51:1190. 90. Todesco S, Terribile V, Borsatti A, et aI: Primary aldosteronism due to a malignant ovarian tumor. J Clin Endocrinol Metab 1975; 4X809. 91. Padfleld PL, Davies D, Lever AF, et aI: The myth of idiopathic hyperaldosteronism. Lancet 1981; 283. 92. Griffing GT, Berelowitz B, Hudson M, et al: Plasma immunoreactive gamma DM, October 1988

663

93. 94.

95.

96. 97. 98. 99.

100. 101. 102. 103. 104. 105.

melanotropin in patients with idiopathic hyperaidosteronism, aldosteroneproducing adenomas, and essential hypertension. .I Clin Invest 1985; 76:163. Matsuoka H, Mulrow PJ, France-Saenz R: Stimulation of aldosterone production by P-melanotropin. Nature 1981; 291:155. Page RB, Boyd JE, MuIrow PJ: The effect of alpha-melanocyte stimulating hormone on aldosterone production in the rat. Endow Aes Commun 1974; 153. Sen S, Bumpus FM, Oberiield S, et al: Development and preliminary application of a new assay for aldosterone stimulating factor. Hypertension 1983; S(supp1 1127. Carey RM, Sen S, Dolan LM, et al: Idiopathic hyperaldosteronism. A possible role for aldosterone-stimulating factor. N Engl J Med 1984; 311:94. Gross MD, Grekin RJ, Gniadek TC, et al: Suppression of aldosterone by cyproheptadine in idiopathic aldosteronism. N En@ J Med 1981; 305:181. Carey RM, Thorner MO, Ortt EM: Effects of metoclopramide and bromocriptine on the renin-angiotensin-aldosterone system in man. J Clin Invest 1979; 63:727. GanguIy A, Grim CE, Bergstein J, et ai: Genetic and pathophysiologic studies of a new kindred with glucocorticoid-suppressible hyperaldosteronism manifest in three generations. J Clin Endocrinol Metab 1981; 53:1040. Clarke D, Wilkinson R, Johnston IDA, et aI: Severe hypertension in primary aldosteronism and good response to surgery. Lancet 1979; 1482. Baxter RH, Wang I: Malignant hypertension in a patient with Conn’s syndrome. Scott Med J 1974; 19:161. Bravo EL, Tarazi RC, Dustan HP, et al: The changing clinical spectrum of primary aldosteronism. Am J Med 1983; 74:641. Snow MH, Nicol P, Wilkinson R, et aI: Normotensive primary aldosteronism. Br Med J 1976; 1:1125. Zipser RD, Speckart PF: “Normotensive” primary aidosteronism. Ann Intern Med 1978; 88855. Shiroto H, Ando H, Ebitani I, et al: Normotensive primary aldosteronism.

Am J Med 1980; 69:603. 106. Conn JW, Cohen EL, Rovner DR: Suppressed plasma renin activity in primary aldosteronism, distinguishing primary from secondary aldosteronism in hypertensive disease. JAMA 1964; 190213. 107. Weinberger MH: Primary aldosteronism, in Genest J, Kuchel 0, Hamet P teds): Hypertension: Physiopathology and Treatment, ed 2. New York, McGraw-Hill Book Co, 1983, pp 922-947. 108. Weinberger MH, Grim CE, Hollifield JW, et al: Primary aldosteronism: Diagnosis, localization and treatment. Ann Intern Med 1979; 90:386. 109. Streeten DH, Tomycz N, Anderson GH: Reliability of screening methods for the diagnosis of primary aldosteronism. Am J Med 1979; 67:403. 110. Kern DC, Weinberger MH, Mayes DM, et al: Saline suppression of plasma aldosterone in hypertension. Arch Intern Med 1971; 128980. 111. Lyons DF, Kern DC, Brown RD, et aI: Single dose captopril as a diagnostic test for primaiy aldosteronism. J Clin Endocrinol Metab 1983; 57892. 112. Ganguly A, Melada GA, Luetscher JA, et al: Control of plasma aldosterone in primary aldosteronism: Distinction between adenoma and hyperplasia. J Clin Endocrino~ Metab 1973; 37765. 113. GanguIy A, Dowdy AJ, Luetscher JA, et al: Anomalous postural response of plasma aldosterone concentration in patients with aldosterone-producing adrenal adenoma. J Clin Endocrinol Metab 1973; 36401. 676

DM, October 1988

114. Vaughan NJA, Slater JD, Lightman SL, et al: The diagnosis of primary hyperaldosteronism. Lancer 1981; 1:lZO. 115. Biglieri EG, Schambelan M: The signtficance of elevated levels of plasma 18hydroxycorticosterone in patients with primary aldostenmism. .I CZinEndocrinol Metab 1979; 4987. 116. Kern DC, Tang K, Hanson CS, et al: The prediction of anatomical morphology of primary aldostemnism using serum 18-hydmxycorticostemne levels.

J Clin Endocrinol Metab 1985; 60~67. 117. White EA, Schambelan M, Rost CR, et al: Use of computed tomography in diagnosing the cause of primary aldostemnism. N Engl J Med 1980; 303:1503. 118. Dunnich NR, Scharer EG, Doppman JL, et al: Computed tomography in adrenal tumors. AJR 1979; 132:43. 119. Presser PR, Sutherland CM, Scullin DR: Localization of adrenal aldostemne adenoma by computerized tomography. N En@ J Med 1979; 366:1278. 126. Linde R, Coulam C, Battino R, et al: Localization of aldostemne-producing adenoma by computed tomography. J C/in Endocrinol Metab 1979; 49642. 121. Conn JW, Cohen EL, Hewig KR: The dexamethasone-modified adrenal scintiscan in hyporeninemic aldostemnism (tumor versus hyperplasia). A comparison with adrenal venography and adrenal venous aldostemne. J

Lab Clin Med 1976; 88~841. 122. Hogan MJ, McRae J, Schambelan M, et al: Location of aldostemne-pmducing adenomas with I-19-iodocholesteml. N Engl J Med 1976; 294:410. 123. Dunnick NR, Doppman JL, Mills SR, et al: Preoperative diagnosis and localization of aldostemnomas by measurement of corticostemids in adrenal venous blood. Radiology 1979; 1331. 124. Scoggins BA, Oddis CJ, Hare WSC, et al: Preoperative lateralization of aldostemne producing tumors in primary aldostemnism. Ann Intern Med 1972;

762391. 125. Horton

R, Finck E: Diagnosis and localization

in primary

aldostemnism.

Ann Intern Med 1972; 761885. 126. Tan SY, Burton M: Hyporeninemic hypoaldostemnism. An overlooked cause of hyperkalemia. Arch Intern Med 1981; 14130. 127. Schindler AM, Sommers SC: Diabetic sclerosis of the renal jwtaglomerular apparatus. Lab Invest 1966; 15877. 128. Christlieb AR, Munichoodoppa C, Braaten JT: Decreased response of plasma renin activity to orthostasis in diabetic patients with orthostatic hypotension. Diabetes 1974; 23835. 129. DeLeiva A, Christlieb AR, Melby J, et al: Big renin and biosynthetic defect of aldostemne in diabetes mellitus. N Engl J Med 1976; 29.5639. 130. DeFmnzo RA: Hyperkalemia and hyporeninemic hypoaldostemnism. Kidney Int 1980; 17:llB. 131. Oh MS, Carroll HJ, Clemmons JE, et al: A mechanism for hyporeninemic hypoaldostemnism in chronic renal disease. Metabolism 1974; 233157. 132. De Chatel R, Weidmann P, Fkunmer J, et al: Sodium, renin, aldostemne, catecholamines and blood pressure in diabetes mellitus. Kidney Int 1977; 12:412. 133. Perez GO, I&pier LE, Oster JR, et al: Effect of alterations of sodium intake in patients with hyporeninemic hypoaldostemnism. Nephron 1977; 18259. 134. Szylman P, Better OS, Chaimowitz C, et al: Role of hypedcalemia in the metabolic acidosis of isolated hypoaldostemnism. N Engl J Med 1976;

294:361. DM, October

1988

671

135. ChristIieb AR, Kaldany A, D’Elia JA: Plasma mnin activity and hypertension in diabetes meIIitus. Diabetes 1976; 25969. 136. Perez GO, Lespier L, Jacobi J, et al: Hyporeninemia and hypoaldosteronism in diabetes meBitus. Arch Intern Med 1977; 137852. 137. ChristIieb AR, KaIdany A, D’Elia JA, et ak Aldosterone responsiveness in patients with diabetes mellitus. Diabetes 1978; 27332. 138. Patrono C, PugIiese F, Ciabattoni G, et al: Evidence for a direct stimulatory effect of prostacyciin on renin release in man. .I Clin Invest 1982; 69231. 139. Tan SY, Shapim R, France R, et al: Indomethacin-induced prostagkndin inhibition with hyperkaIemia. A reversible cause of hyporeninemic hypoaldosteronism. Ann Intern Med 1979; 90:783. 140. NadIer JL, Lee FO, Hsueh W, et ai: Evidence of prostacyclin deficiency in the syndrome of hyporeninemic hypoaldosteronism. N Engl J Med 1986; 314:1015. 141. Lebel A, Grose JH: Selective hypoaldosteronism: Study of biosynthetic pathways under adrenocorticotmphin and angiotensin II infusion. Clin Sci Mel Med [Suppl] 1976; 51:335. 142. Sebastian A, Schambelan M, Lindenfeld S, et al: Amelioration of metabolic acidosis with fludmcortisone therapy in hyporeninemic hypoaidosteronism. N En@ J Med 1977; 297576. 143. Sebastian A, McSherry E, Morris RC Jr: On the mechanism of renai potassium wasting in renal tubular acidosis associated with the Fanconi syndrome (type 2 RTA). J Ckn Invest 1971; 50231. 144. Sebastian A, McSherry E, Morris RC Jr: Renal potassium wasting in renal tubular acidosis (RTA): Its occurrence in types 1 and 2 RTA despite sustained correction of systemic acidosis. J Clin Invest 1971; 50667. 145. Sebastian A, McSherry E, Morris RC Jr: Metabolic acidosis with special reference to the renal acidosis, in Brenner BM, Rector FC Jr teds): The Kidney. Philadelphia, WB Saunders Co, 1976, pp 615-660. 146. Sebastian A, McSherry E, Schambelan M, et al: Renal tubular acidosis in patients with hypoaldosteronism caused by renin deficiency. Clin Res 1973; 21:706. 147. Perez GO, Oster JR, Vaamonde CA: Renal acidosis and renal potassium handling in selective hypoaldosteronism. Am J Med 1974; 57:809. 148. Wilkins L: Adrenal disorders: II. Congenital virikzing adrenal hyperplasia.

Arch Dis Child 1962; 37231. 149. Zachmann M, Vollmin JA, New MI, et al: Congenital adrenal hyperplasia due to deficiency of llB-hydroxylation of l’la-hydmylated steroids. J Clin

Endocrinol Metab 1971; 33501. 150. Bongiovanni AM: The adrenogenital syndrome with deficiency of 3B-hydmxystemid dehydrogenase. J C/in Invest 1962; 412086. 151. New MI: Male pseudohermaphmditism due to 17a-hydmxylase deficiency. J C/in Invest 1970; 49:1930. 152. Pang S, Hot&kiss J, Drash AL, et al: Micmiiiter paper method for 17a-progestemne radioimmunoassay: Its application for rapid screening for congenital adrenal hyperplasia. J Clin Endocrinol Metab 1977; 45:1003. 153. Pang S, Spence DA, New MI: Newborn screening for congenital adrenal hyperplasia with special reference to screening in Alaska. Ann NY Acad Sci 1985; 458:90. 154. Pang S, Murphey W, Levine LS, et aI: A pilot newborn screening for congenital adrenal hyperplasia in Alaska. J Clin Endocrinol Metab 1982; 55:413. 155. Rosenbloom AL, Smith DW: Varying expression for salt losing in related patients with congenital adrenal hyperplasia. Pediatrics 1966; 38215. 672

DM, October

1988

156. Qazi QH, Thompson Mw: Incidence of s&-wasting form of congenital adrenal virilizing hyperplasia. Arch Dis Child 1972; 47302. 157. Temeck JW, Pang S, New MI: Premature adrenarche resulting iium symptomatic nonclassical congenital adrenal hypefplasia, abstract. Pediatr Res 1984; 18:17SA/495. 158. Pang S, Lemer AJ, Stoner E, et aI: Late-onset adrenal steroid 3BHSD deficiency. A cause of hirsutism in pubettal and postpubertal women. J Clin Endixrirwl Metab 1955; 60:428. 159. Speiser PW, Dupont B, Rubinstein P, et al: High frequency of nonclassical stemid 21-hydro@ase deficiency. Am J Hum Genet 1985; 37650. 160. Chrousos GP, Loriaux DL, Mann DL, et al: Late onset 21-hydmxylase deficiency mimicking idiopathic himutism or poIycystic ovarian disease: An allelic variant of congenital viriWng adrenal hyperplasia with a milder enzymatic defect. Ann Intern Med 1962; 96:143. 161. Chetkowski RJ, DeFazio J, Shamonki I, et al: The Incidence of late-onset congenitai adrenal hyperpkxsia due to %I-hydroxylase deficiency among hirsute women. J Clin Endocrinol Metab 1984; 58595. 162. Kohn B, Levine LS, Polk& MS, et aI: Late-onset steroid 21-hydroxylase deficiency: A variant of cIassicd congenital adrenal hyperplasia. J Chin Endocrinol Metab 1982; 551817. 163. Migeon CJ, Rosenwaks Z, Lee PA, et al: The attenuated form of congenital adrenal hyperplasia as an aRelic form of tl-hydmxylase deficiency. .I Chin Enobcrinol Metab 1980; 5U347. 164. Pollack MS, Levine LS, O’NeiIi GJ, et al: HLA ii&age and B14, DRl, Bfs haplotype association with the genes for late onset and cryptic 21-hydroxylase deficiency. Am J Hum Genet 1981; 33546. 165. Lobo RA, Goebelsmann U: AduIt manifestation of congenital adrenal hyperplasia due to incompIete Il-hydm@ase deficiallcy mimicking polycystic ovarian disease. Am J Obstet Gyneco~l960; 138~720. 166. Kuttenn F, CouiBin P, Girard F, et al: Late-onset adrenal hyperplasia in hirsutism.NEngl JMedl985;313224. 167. Wischusen J, Baker HWG, Hudson B: Reversible male infertility due to congenital adrenal hyperplasia. Clin Endocrinol fO@I 1981; 14571. 166. ChiIds B, Grumbach MM, van lA@ JJ: Vbilizing adrenal hyperplasia: A genetic and hormonal study. J Clin Invest 1956; 35213. 169. Canoll MC, Campbell RD, Porter RR: Mapping of steroid 21-hydroxylase genes adjacent to complement component C4 genes in HL4, the major histocompatibiIity compkx in man. Proc Nat1 Acad Sci USA 1985; 82521. 170. White PC, Gmssbetger D, Dnutbr BJ, et al: Two genes encoding steroid 21hydroxyktse are located near the genes encoding the fourth component of complement in man. Proc Nat1 Acad Sci USA 1985; 82:1089. 171. DuPont B, Oberfieid SE, Smithwick EM, et al: Close genetic linkage between HLA and congenital adrenal hyperplasia (21-hydroxylase deficiency). Lancet 1977; 2:1369. 172. Pucholt V, Fitzsimmons JS, Gelsthorpe K, et al: Location of the gene for 21hydmxykise deticiency. J Med Genet 1960; 17:447. 173. Lamn 2, PoRack MS, Zamir R, et ai: Late onset 21-hydmxylase deficiency and HLA in the Ashkenazi population: A new allele at the Il-hydroxyIase locus. Hum Immunol1966; 155. 174. Blankstein J, Faiman C, Reyes FI, et al: Adult-onset familial adrenal 21-hydroxylase deficiency. Am J Med 19% 63:441. 175. Pollack MS, Levine LS, Pang S, et al: Prenatal diagnosis of congenital adrenal hyperplasia (al-hydroxylase deficiency) by HL4 typing. Lancer 1979; 1:1107. DM, October

1333

673

176. Pang S, Levine IS, Cederqvist LL, et al: Amniotic fluid concentrations of Delta 5 and Delta 4 steroids in fetuses with congenital adrenal hyperplasia due to 21-hydroxylase deficiency and anencephalic fetuses. J Clin EndocrinoI Metab 1980; 51223. 177. Forest MG, Betuel H, Gouillin P, et al: Prenatal diagnosis of congenital adrenal hyperplasia NIAH) due to 21-hydroxylase deficiency by steroid analysis in the amniotic fluid of mid-pregnancy: Comparison with HLA typing in 17 pregnancies at risk for CAH. Prenat Diagn 1981; 1:197. 178. Evans MI, Chruusos GP, Mann DW, et al: Pharmacologic suppression of the fetal adrenal gland in utero. Attempted prevention of abnormal external genital masculinization in suspected congenital adrenal hyperplasia. JAMA 1985; 253:1015. 179. Mulaikal RM, Migeon CJ, Rock JA: Fertility rates in female patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. N Engl J Med 1987; 316:178. 180. Money J, Schwartz M: Dating, romantic and nonrumantic friendships, and sexuality in 17 early-treated adrenogenital females, aged 16-25, in Lee LP, Plotnick AA, Kowarski CJ, et al teds): Congenital Adrenal Hyperplasia. Bahimore, University Park Press, 1977, pp 413419. 181. Money J, Schwartz M, Lewis VG: Adult erotosexual status and fetal hormonal masculinization and demasculinization: 46, XX congenital virilizing adrenal hyperplasia and 46, XY androgen-insensitivity syndrome compared. Psychoneuroendocrinology 1984; 9:405.

674

DM, October1988