Aldosteronism

ldosteronzsm J O H N A. L U E T S C H E R

TABLE O F C O N T E N T S CIIANOING CONCEPTS AND TER.MINOLOGY

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ALDOSTERONE SECRETION~ ~ETABOLIS.~f AND EXCRETION REGULATION OF ALDOSTERONE SECRETION

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EFFECTS OF ALDOSTERONE . . . . . . . . . . . . . .

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TIIERAFEUTIG USES OF ALDOSTERONE

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ALDOSTERONE

DEFICIENCY

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ALDOSTERONISI~I (~r

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PRI.~IARY ALDOSTERONIS~[

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OTIIER F O R M S OF HYPERTENSION A N D POTASSIU~I DEFICIENCY ASSOCIATED WITII I-IIGII ALDOSTERONE SECRETION" . . . .

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CLINICAL CONDITIONS %VITH FINDINGS SIMILAR TO PPJMARY ALDOSTERONIShf~ BUT ~VITII N O R M A L OR eo~v ALDOSTERONE SECRETION . . . . . . . . . . . . . . . . . . . .

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ALDOSTERONE A N D EDE~IA

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OTIIER C O N D m O N S ASSOCIATED gVITII INCREASED ALDOSTERONE SECRETION . . . . . . . . . . . . . . . . . .

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is Professorof Medicine at Stanford UniversitySchool of Medicine and is the recipient of a Career Research Award of the National Institutes of tlealth, U.S. Public IIeahh Service. Between 1948 and 1954-,the Stan[ord Metabolic Research group isolated the sodium-retalnlngfactor of human urine and demonstratedits identity with aldosteroneobtained from adrenal cortex. Current studies continue the explorationof the role of this hormone in human ph)'siologyand in dlsea~e.

P A T I E N T S W I T H A D D I S O N ' S D I S E A S E , as well as m e n or a n i m a l s whose adrenals h a v e been r e m o v e d , suffer from disturbances of bodily function, w h i c h c a n be classified into two general types. T h e first is a chronic w a s t a g e of s o d i u m into urine a n d stools, w i t h weight loss, d e h y d r a t i o n , r e d u c e d serum sodium a n d increased serum potassium concentration, fall in blood pressure, p o o r renal function, feeble h e a r t action, collapse a n d death. Tiffs disabling a n d u l t i m a t e l y f a t a l sequence of events could be p a r t l y r e m e d i e d by a d m i n i s t r a t i o n of s o d i u m chloride a n d by restricting potassium intake. A d r e n a l cortical extract contained powerful s o d i u m - r e t a i n i n g activity, b u t the expense a n d small supply of this p r e p a r a t i o n limited its use. T h e synthesis of desoxycorticosterone by Reichstein g a v e physicians the first effective a g e n t for m a i n t e n a n c e of electrolyte b a l a n c e in a d r e n a l insufficiency. T h e i n t r o d u c t i o n of long-acting p r e p a r a t i o n s by T h o r n , NOTE: Some original work described here was supported by a research grant (Am-3062) from the National Institutes of Health, U.S.P.H.S., which also awarded career research support to the author.

Loeb and their associates prolonged the lives of a generation of patients with hypoadrenalism. Ferrebee showed that acute overdosage of this mineralocorticoid could produce abnormal retention of sodium salts and water, or even "congestive heart failure." Chronic overdosage led to hypertension and potassium wasting, as weU as polyuria and polydipsia, which were not corrected by vasopressin (Pitressin). Relman and Schwartz proved that the potassium-wasting effects of desoxycorticosterone were dependent on sodium retention, and they showed how normal men escaped from the renal sodium-retaining effect after limited overhydration and sodium accumulation had occurred. Thus, the symptoms and signs and basic physiology of mineralocorficoid excess were recognized and described. The native hormone was still unknown, however, and physicians could only speculate on the relation of these evidences of synthetic hormone overdosage to the natural phenomena of disease. Meanwhile, other aspects of adrenal insufficiency were clearly demarcated by the failure of desoxycorficosterone to remedy the malnutrition, hypoglycemia, depleted liver glycogen, abnormal cerebral function, impaired renal water excretion and susceptibility to collapse under any stress, to name a few problems among many. These abnormalities of organic metabolism were due to a deficiency of cortisol (also called hydrocortisone), the principal "glucocorticold." The synthesis of cortisone and a host of related derivatives solved the remaining problems of the patient with adrenal insufficiency and opened up a new field of human therapeutics. It also made Cushing's syndrome commonplace and clearly established this syndrome of glucocorticoid overdosage as being quite distinct from that seen in desoxycorticosterone toxicity. The need for further information on endogenous mineralocorticoids in human physiology and disease was obvious. In 1948, Q. B. Deming, B. B. Johnson and I, with an able group of associates, began a systematic effort to isolate and quantitate material with sodium-retaining activity in human urine. It was successively shown that such activity was present in large amounts in the urine of patients who were collecting edema; that the activity could be greatly enhanced by acidification of urine to pH 1 before extraction; that smaller quantities were also present in the urine of normal man and that these could be increased by sodium deple-

tion and depressed by sodium loading; that variations in potassium intake had effects opposite to those of sodium salts; that the output of the sodium-retalning factor in chronic disease and in many physiologic conditions was independent of the level of adrenocorticotropin (ACTH) or of cortisol secretion; and that the biologic activity resided in a previously unknown substance with the chemical characteristics of a typical adrenal corticosteroid, present in urine in very small amounts but of great sodinm-retaining potency. This was later shown to be aldosterone. At about the same time, Simpson, Tait and their associates began a series of investigations of the mineralocorticoid factor in adrenal cortical extract, which culminated in 1954 in its isolation and identification as 18-oxocorticosterone ("aldosterone") by the combined English-Swiss teams of Simpson, Tait, Reichstein, Wettstein and Neher. Wettstein and associates synthesized raeemic aldosterone quite soon thereafter; more recently, the natural isomer, d-aldosterone, has become available. During 1954, 4 patients were admitted to hospitals in England or the United States with a syndrome of muscle weakness, episodic paralysis and tetany, together with vasopressin-resistant polyuria and other abnormalities of renal function which were due to severe hypokalemic alkalosis associated with renal potassium wasting. Hypertension was present in every case. Aldosterone (then called sodium-retaining factor or electrocortin) was found in large amounts in the urine of each patient. Foye and Feichtmeir's patient was the first to be recognized as having a condition due to excessive mineralocorticoid and to have the syndrome relieved after excision of an adrenal carcinoma; unfortunately, the syndrome recurred with the growth of distant metastases secreting aldosterone and a variety of other adrenal steroids. Corm was the first to publish a full and correct analysis of a patient with adrenal adenoma secreting large amounts of aldosterone, the condition of which he named "primary aldosteronism." Numerous other case reports followed in quick succession. Conn's imaginative analysis of "aldosteronism," as he called the syndromes associated with increased aldosterone output, brought together the many strands which have been described in this introduction and represented the best over-all synthesis of knowledge at that time. 7

CHANGING CONCEPTS AND TERMINOLOGY

Ten years have passed since the previously described events occurred. Our knowledge has grown rapidly through the contributions of numerous investigators. Because our perspectives have changed with this increasing knowledge and experience, it is now timely to re-examine the concepts and nomenclature of "aldosteronism." The reader should be aware of the confusion which has arisen, as the same term is used with different meanings; for example, hypertensive, hypokalemic patients with adrenal hyperplasia whose conditions were called "primary aldosteronism" 5 years ago are now called "secondary aldosteronism" by the same authors today. It is necessary to discriminate between causes and syndromes which were associated in earlier writings but which have no necessary connection today. This review will attempt to define some physiologic and pathologic factors involved in the regulation of aldosterone secretion, metabolism and effects; and certain clinical syndromes will be described and their relation to aldosterone secretion will be discussed. The term "primary aldosteronism" will be restricted to those cases owing to an aldosterone-secreting adrenal tumor and does not include cases with similar or identical clinical and laboratory findings but without a demonstrated functioning tumor. This terminolog3, represents a change from that proposed by Conn in an earlier writing in which primary aldosteronism was defined as a clinical syndrome with typical laboratory findings; but it conforms better with current knowledge and usage. The concept of "secondary aldosteronism" has also lost its simple clinical connotation. It comprises a variety of disorders in which the secretion of aldosterone is inappropriately increased by the underlying disturbance. The clinical picture depends on both the effects of aldosterone (sodium retention, potassium wasting or hypertension, in varying degrees, as conditioned by the state of the circulation and of renal function) and the manifestations of the underlying physiologic disturbance or disease. Although a classification of "secondary aldosteronism" may be offered to summarize these conditions, it has no special use or merit in dealing with an individual patient. The physician, faced with a patient's problems, is fundamen-

tally interested in diagnosis and management. He must begin his differential diagnosis without repeated, reliable measurements of aldosterone. It is probably just as well that such measurements are expensive, time consuming and subject to considerable variation, since this measurement by itself will not tell him the diagnosis or treatment. Aldosterone output can be increased in many conditions, but the diagnosis of primary aldosteronism, for example, depends on a more specific set of observations. Taking all these factors into account, this presentation will be organized as follows: 1. The physiologic factors which control aldosterone secretion, metabolism and actions. 2. The differential diagnosis and management of the hypertensive, hypokalemic patient. 3. Other disorders in which aldosterone secretion is inappropriately increased, with a brief survey of the role of aldosteronism and other factors in relation to pathogenesis and management.

ALDOSTERONE SECRETION, METABOLISM AND EXCRETION

Aldosterone is secreted by the zona glomerulosa of the adrenal gland. This zone, which lies just under the capsule, contains different enzyme systems from those which occur in the zona fasclculata, where cortisol is the chief secretory product. In the zona fasciculata, 17-hydroxylase activity is the first step in the conversion of pregnenolone or progesterone to cortisol. This activity is absent in the zona glomerulosa, where the steroid precursors (progesterone and l l-desoxycorticosterone, as well as cortlcosterone) are converted to 18-oxocorticosterone or aldosterone. The biosynthesis of aldosterone is not dependent on the presence of A C T H nor is it stimulated by the low levels of added ACTH which increase cortisol output. Angiotensin, in very small doses, stimulates the release of aldosterone and perhaps of cortlsol also. Biosynthesis of aldosterone is also sensitive to the concentration of sodium and potassium in blood plasma. The dynamics of adrenal cortical secretion are being defined with the aid of radioisotopic tracers, with which the secretion and

metabolism of aldosterone can be measured in man. When tritiated aldosterone is injected, it is diluted in a large apparent volume of distribution and is metabolized quite rapidly (compared with cortisol), with a half-time in plasma of 35 to 50 minutes. Aldosterone is almost completely removed from blood passing through the liver in normal man, but its metabolic clearance may be reduced in diseases or physiologic states associated with reduced hepatic blood flow or impaired liver function. The average secretion rate of aldosterone in normal man is approximately 100|tg. (0.1 rag.) per day, with a range of 40~tg. to 1801~g. in normal subjects on a normal sodium intake. A very tiny amount of free aldosterone is excreted in urine. The remainder of secreted hormone appears in urine as conjugates or metabolites. The acid-labile conjugate, which releases aldosterone on standing at pH 1, is the source of the aldosterone measured in most clinical methods. It has recently been suggested that this conjugate may be an 18-glucuronoside of aldosterone. Approximately 10~b of administered tracer appears in this form in the urine. It is therefore inferred that 1 0 ~ of secreted hormone, or about 10~tg. per day, is normally excreted in this form. During hydrolysis, extraction and purification of this substance, substantial losses may take place and other materials may interfere with its assay. It is important for the physician who depends on the estimation of aldosterone to know the normal range in the laboratory which is performing the analysis, since quite substantial differences exist between results of different methods. It would, of course, be desirable if all such analyses could be corrected for losses by the use of an isotopic tracer added to the urine and checked in the final stages of analysis; however, this adds considerably to the cost of the determination and is not at present available in most laboratories. The other chief metabolite of aldosterone is the tetrahydro derivative, reduced at the 3, 4 and 5 positions, and excreted as a glucuronoside. Methods have also been worked out for the quantitation of this derivative, which comprises approximately 20 to 40~b of secreted aldosterone. Since the biologically effective level of aldosterone is probably best reflected by the plasma concentration of aldosterone, efforts have been made to work out a satisfactory assay method, but none is at present clinically available. Recently, several research laboral0

tories, using improved methods for analysis of plasma~ have obtained normal values of 5 to 12 m~tg./100 ml. of plasma. These results are similar to estimates based on the rates of secretion and metabolic clearance determined with isotope-labeled aldosterone. REGULATION OF ALDO$TERONE SECRETION

Early studies in man indicated that aldosterone secretion is less dependent on pituitary A C T H than is the case with cortisol secretion. Patients with chronic hypopituitarism or with prolonged suppression of A C T H by exogenous corticosteroids continue to secrete normal or reduced amounts of aldosterone, while cortisol secretion almost ceases. Aldosterone secretion usually increases when A C T H is injected, but the increase is not as persistent as the rise of cortisol. The strongest and most persistent stimulus to aldo~terone secretion in man is sodium depletion. The nature of this effect is a complex one. The first effect is probably mediated by the fall in extracellular fluid and plasma volume and the reduced blood flow to critical organs (e.g., kidneys) which aceompanies sodium deprivation and losses after diuretics, sweating or other causes. Later, the fall in serum sodium concentration and the rise in serum potassium concentration probably stimulate aldosterone secretion by a direct effect on the adrenal glands. An increased intake of potassium salts tends to raise aldosterone output in man, but depletion of potassium tends to reduee the output. Acute loss of a large volume of blood is a potent stimulus to aldosterone secretion. Experiments with hypophysectomized dogs have shown that while this effect is somewhat reduced, it still occurs in the absence of the pituitary. Various extracts of the brain can decrease or increase aldosterone secretion, but so far no center or secretion of the brain, independent of the hypothalamuspituitary-ACTH system, has conclusively been shown to increase aldosterone output. Recent work has focused on the role of the kidneys in regulating aldosterone. Nephrectomized, hypophysectomized dogs do not respond to hemorrhage with the expected rise in aldosterone secretion. The "'aldosterone-stimulating hormone" released by the 11

kidneys [ollowing hemorrhage appears to be renin. This enzyme releases angiotensin I from a precursor globulin in plasma, and this in turn is converted into angiotensin II. Infusions of renin or of angiotensin II are followed by a rise in aldosterone secretion. This mechanism can account for the rise in aldosterone secretion which follows acute blood loss in dogs. Studies currently under way suggest that plasma renin is increased in normal men on lowsodium diets. If this can be confirmed and related to increased plasma anglotensin in sodium-depleted subjects, this system must be considered one of physiologic importance in normal control of aldosterone secretion. Another interesting corollary of these studies has been the hyperplasia and increased granularity of the juxtaglomerular cells of the kidneys in circumstances in which a persistent, strong stimulus to aldosterone secretion exists. These observations, together with the demonstration of renin in the juxtaglomerular cells, add weight to the argument that renin is involved in the control of aldosterone secretion. EFFECTS OF ALDOSTERONE

In physiologic concentrations, aldosterone acts primarily on the transport of electrolytes in the cells of the renal tubules, sweat glands, salivary and other glands of the gastrointestinal tract and probably in other sites. The mechanism of action in the rat kidney and in the toad bladder appears to involve increased oxidative activity of enzymes, which increases the transport of sodium after a latent period of exposure to the hormone. Stop-flow studies show that there is increased sodium reabsorption and potassium secretion in the distal tubules of the dog kidney. Magnesium excretion is increased. Aldosterone appears to have some direct effects on the circulation, including an inotropic action on the myocardium. In man, the first obvious effect of injection of aldosterone is a fall in sodium excreted in urine, sweat, saliva and feces. The initial effect on the kidney is a reduction of sodium and chloride excretion, together with an increase in free water clearance, which would seem to localize the effect in the ascending limb of the loop of Henle. With continuing administration of the hormone, the quantities of potassium, hydrogen and ammonium ions in urine 12

also increase, presumably exchanged for sodium in the distal tubules; the extent of this exchange is limited by the amount of sodium which has escaped reabsorption in a more proximal site. The effects of prolonged administration of aldosterone in man vary with circumstances. A high sodium intake exaggerates the effects, but a low sodium intake minimizes them. A normal man on an ordinary diet, given 1 to 2 rag. of aldosterone each day, retains a few hundred milliequivalents of sodium, together with an equivalent quantity of water, and gains 2 or 3 kg. in body weight. Following this initial period of expansion of extracellular fluid and plasma volume, the normal subject "escapes" from the sodium-retaining effect. Urine sodium rises until sodium balance is regained, albeit with an expanded sodium and water content of the body. Potassium excretion continues to exceed intake during the initial period of aldosterone excess. Gradually, the serum potassium falls as the deficit of body potassium increases, and at some point an unstable balance is reached, with output roughly equal to intake but with serum potassium low and renal clearance of potassium high. In some abnormal conditions, particularly those associated with edema, the normal escape from the sodiumretaining effect of aldosterone does not take place. When such a patient is given aldosterone, sodium excretion falls to very low levels and potassium wasting does not occur, suggesting that sodium chloride is being reabsorbed in the proximal tubule fairly completely and that little sodium is available in the distal tubule for exchange with potassium. Further administration of aldosterone is accompanied by continuing sodium retention and edema. It is evident that simple expansion of extracellular fluid does not produce "escape"; and although increased glomerular filtration rate is frequently seen in normal subjects receiving aldosterone in large amounts, "escape" can occur at normal or low filtration rates. The nature of this important mechanism deserves further study. Despite "escape" from the renal sodium retention in normal man at high levels of aldosterone, extrarenal sodium retention continues unabated. Thus, the sodium content (and sodium/potassium ratio) of sweat, saliva and feces remains below normal in hyperaldosteronism, even when renal excretion of sodium and external sodium balance appear normal. 13

THERAPEUTIC USES OF ALDOSTERONE

This potent mineralocorticoid is available in aqueous solution for parenteral administration for investigative and experimental use. While definite indications and doses are still to be worked out, two probable areas of usefulness are in the treatment of adrenal insufficiency and of endotoxin shock. Aldosterone should not be considered as a substitute for cortisol, which is the essential agent in the management of acute adrenal insufficiency. When cortisol is given parenterally in doses above 100 rag. per day initially, the addition of aldosterone or other sodium-retaining hormones is usually unnecessary. When the cortisol dose is reduced, however, some patients require added "mineralocorticoid" to maintain sodium and potassium balance. Aldosterone, or its synthetic analogue, desoxycortlcosterone, may be given parenteraUy; or fludrocortisone may be given by mouth, as circumstances dictate. Contrary to some early reports, aldosterone does not appear to be effective when given by mouth, since it is almost completely metabolized in passing through the liver. Experimental evidence suggests that aldosterone may be useful in the management of refractory shock to supplement vasopressor agents and cortisol. Animal experiments indicate that it may be particularly useful in the management of endotoxin shock assoclated with gram-negative infections. ALDOSTERONE DEFICIENCY ("HYPOALDOSTERONISM") Aldosterone secretion is absent following adrenalectomy and is deficient in Addison's disease. Most patients with hypopituitarism secrete a normal or slightly reduced quantity of aldosterone, which is adequate to maintain a normal plasma level at the reduced rate of metabolic clearance typical of hypothyroidism; as the response to stress and to sodium depletion is frequently inadequate, the patlent should receive supportive treatment at such time. Cases of "hypoaldosteronism" have been described and attributed to a selective defect of aldosterone secretion. The patients may complain of weakness, fatigue, muscle cramps or syncope. Examination shows reduced blood pressure, dehydration and, in some cases, slow and irregular cardiac rhythm with variable or 14

complete heart-block. Serum sodium is lower than normal, and blood urea nitrogen is elevated. High serum potassium may be detected by the abnormally high, peaked T waves of the electrocardiogram and by auriculoventricular block. Administration of aldosterone or its synthetic analogues, desoxycorticosterone or fludrocortisone, corrects these abnormalities. Some patients with congenital adrenal hyperplasia develop signs of adrenal insufficiency in the first days of life. Failure to eat or thrive, with weight loss, dehydration, hypotension and flaccid muscles should suggest this possibility. Typically, serum sodium is low; potassium and blood urea nitrogen are elevated. In the male, sexual precocity may not be obvious; female infants usually show signs of masculinization or ambiguous external genitalia. In these "salt losers," aldosterone secretion is deficient despite the combined stimuli of sodium depletion and increased ACTH. Treatment should include a mineralocorticoid, as well as cortisone. Patients with congenital adrenal hyperplasia also excrete large amounts of abnormal steroid metabolites; and it has been suggested that some of these act as aldosterone antagonists. The finding of hyponatremia without dehydration, but with normal urine sodium, normal serum potassium and reduced aldosterone excretion, should suggest excessive secretion of antidiuretic hormone, especially in cases with carcinoma of the lung or with porphyria. ALDOSTERONISM ("HYPERALDOSTERONISM") Among Webster's definitions of the suffix -ism, the one most appropriate to our discussion is "abnormal state or condition resulting from excess of a (specified) thing (alcoholism)." The addition of the prefL,: hyper- (above normal) or hypo- (less than normal) is analogous to current usage in the terms hyper- or hypothyroidism, implying an abnormal state or condition resulting from too much or too little of the hormone. The term aldosteronism (or hyperaldosteronism) has also been applied to states in which aldosterone secretion or excretion is high, but in which there is no proof that the high output plays a harmful or indeed any significant part in the causation or manifestations of the disorder. The reader will have to decide whether 15

this practice is justified. I n the present review, a tentative effort is made to separate (1) normal stimuli to increased secretion, (2) conditions in which increased secretion causes harmful or demonstrable effects, (3) conditions in which the effects of increased secretion are not obvious and (4) related disorders in which aldosterone secretion is normal or low. T A B L E I.--So~IE CONDITIONS IN W H I C H ALDOSTERONE SECRETION Is INCREASED IN ~'~ORIM[AL ~ E N

A. Increased Secretion Serves a Use[ul Function

Low sodium intake Sodium depletion (including use of diuretics) Severe dehydration Major hemorrhage

OR W O M E N

B. Function o] Increased Secretion Not Established

Standing erect Nervous tension and anxiety Pregnancy (second and third trimesters) Following major surgery, air encephalograms or trauma

Phlebotomy in sodium-depleted subjects Adaptation to a hot, humid environment High potassium intake Table 1 lists some conditions in which normal men secrete increased quantities of aldosterone. I t is important to eliminate these stimuli before attempting to assess the role of the hormone in other conditions or diseases. T h e list is divided into two sections. In the group in the left-hand column, adrenalectomized men or animals maintained on physiologic amounts of cortisone appear at a disadvantage when compared with normal controls who are able to increase their secretion of aldosterone on demand. I n conditions listed in the right-hand column, aldosterone secretion is stimulated by various mechanisms, but an increased requirement for aldosterone may not exist; for example, normal postural responses or normal pregnancy (but not delivery) can be maintained in adrenalectomized patients on ordinary "replacement" doses of cortisone, but in the nervous or stressed patient the acute rise in aldosterone secretion may result from A C T H release and not from a specific stimulus. 16

TABLE 2.--SYMPTOMS, SIGNS AND LABORATORY EVIDENCE OF INAPPROPRIATELY HIGII ALDOSTERONE SECRETION (~ALDOSTERONISM") IN PATIENTS ON A NORMAL SODIUM INTAKE

A. With Normal Escape [rom the Sodium-Retaining Effect (i.e., although the extraeellular and plasma volumes are expanded, dependent edema is not obvious) I. Arterial hypertension 2. Reduced serum potassium concentration 3. High renal clearance of potassium 4. Signs of potassium depletion: a. Hypochloremic alkalosls and tetany b. Muscle weakness, episodic paralysis, loss of deep tendon reflexes c. Abnormal electrocardiogram d. Abnormal renal function: polyuria, reversed diurnal rhythm with nocturia, vasopressin-resistant hyposthenuria, increased ammonia excretion, neutral urine pH, intermittent or slight proteinuria, decreased urea clearance, frequent infection and pyelonephritis e. Polydipsia f. Impaired glucose tolerance g. Cumulative retention of 200 to 1,000 mEq. potassium on intake of 200 mEq. per day 5. Low sodium content and/or increased potassium in sweat, saliva, stool 6. Improvement of 2, 3 and 4 (above) on a low-sodium diet 7. Return of 2, 3, 4 and 5 (above) toward or to normal after spironolactone treatment B. Persistent Sodium Retention without Normal Escape 1. Edema 2. Low urine sodium excretion and positive sodium balance 3. Low sodium a n d / o r increased potassium in sweat, saliva, stool 4. Limited sodium excretion and increased potassium wasting on administration of thiazide diuretic 5. Improvement of 2, 3 and 4 (above) after administration of spironolactone 6. Signs of underlying disease are usually, but not invariably, present C. Delayed Escape alter Some Edema Accumulated 1. A variant of pattern B (above) : edema present, but with sodium balance re-establlshed; no potassium wasting 2. A variant of pattern A (above) : potassium wasting predominates, sodium excretion normal, but some edema present 3. Mixed forms, with sodium retention, edema and potassium wasting 17

In contrast with these reactions of n o r m a l men to stimuli which increase aldosterone secretion in an appropriate or compensatory fashion, we see other patients whose symptoms and signs suggest an inappropriate and possibly harmful excess of aldosterone (Table 2). This last condition might well be termed hyperaldosteronism. In some of these cases, for example, in primary aldosteronism, removal of adrenal tissue or administration of spironolactone produces striking metabolic improvement, indicating that the high level of secretion of this hormone is having a very definite effect. T h e r e are other circumstances in which the effects of equally large amounts of secreted aldosterone are less evident. For example, bilateral adrenalectomy has not proved to be satisfactory therapy for malignant hypertension; other factors appear to play a more important part than the high level of aldosterone secretion. There are still other cases whose symptoms and signs resemble those of hyperaldosteronism but whose aldosterone secretion is normal. In Table 3, the clinical disorders associated with renal potassium wastage are arranged according to blood pressure and aldosterone secretory rates. TABLE

3 . - - D I F F E R E N T I A L DIAGNOSIS OF PRIMARY ALDOSTERONISM

ALDOSTERONESECRETIONINc:m.O,Sr~

NOKMAL ALDOSTERONESECRETIONRATE

A. Arterial Hypertension and Renal Potassium Wasting

1. Primary aldosteronism due to adrenal adenoma or carci-

1. Pseudoaldosteronism, familial

Iloma

2. Malignant hypertension 3. Renal ischemia due to obstruction of a large renal artery 4. Benign, essential hypertension (rare) 5. Thiazlde diuretic in a hypertensive patient 6. Juvenile aldosteronlsm with bilateral adrenal hyperplasia 7. Pyelonephritis and other renal disorders 18

2. Exogenous mlneralocortlcold (excessive doses) 3. Some cases of malignant hypertension, renal ischemia or thiazide-treated benign hypertension 4. Excessive cortisol secretion (especially oat-cell tumors secreting ACTH-Iike material)

B. Renal Potassium Wasting with Normal Blood Pressure

1. Renal disorders (Fanconi's syndrome~ renal tubular acidosis and "sodium-loslng nephritides" leading to aldosteronism) 2. Hyperplasia of juxtaglomerular complex

I. Familial or sporadic forms of idiopathic renal potassium wasting 2. Renal disorders with other recognizable features (e.g., tubular acidosis) without aldosteronism 3. Hyperdesoxycorticosteronism with hypokalemic alkalosis and edema

A source of serious confusion in the literature has been the changing definition of the term primary aldosteronism. At first, this name was applied to a large number of conditions associated with hypertension and potassium depletion. It has now become evident that in a number of these eases, the role of the adrenal is secondary. Increased aldosterone secretion may be responsible for the potassium depletion which occurs in some of these conditions, but arterial hypertension is maintained by other factors, perhaps by increased renin and angiotensin, which could also stimulate aldosterone release. At present, cases with normal or hyperplastic adrenal glands and with evidence of renal ischemia, due to arterial disease, are classified as secondary aldosteronism. Part of the difficulty has been the failure to distinguish between etiologic factors and manifestations of hyperaldosteronism. Early attempts to associate primary aldosteronism with a unique clinical picture have become somewhat artificial, as an increasing number of cases, indistinguishable from primary aldosteronism, have been found before or after surgical exploration to be secondary to renal vascular disease. Thus, the concept that a clinical state can be used to identify hyperaldosteronism of a primary nature is no longer tenable, even though, on a statistical basis, a certain group of symptoms and signs are frequently associated with primary aldosteronism. There is no fundamental reason why the effects of an increased level of the hormone should be related to the cause of the hyperseeretion, unless the response to the hormone is modified by the underlying disease. On this sometimes helpful and sometimes obscure modification, and on the hope that other evi19

dence of the underlying disease will be evident, rests the differential diagnosis of primary aldosteronism. In practice, the combination of historic, physical, radiologlc and laboratory evidence leads to a good statistical probability of correct diagnosis, provided the proper questions are asked. PRIMARY AI.DOSTERONISM

At the present time, the diagnosis of primary aldosteronism is made only in cases with an aldosterone-secreting tumor of the adrenal cortex, leading to hypertension and renal potassium wasting. Conn's initial case was far advanced and included findings which are not seen in earlier stages. The presence of an aldosterone-secreting adenoma can be diagnosed in patients at a much earlier stage, sometimes without any symptoms. The investigation usually begins with the finding of arterial hypertension. Since the trend is toward earlier diagnosis, it may be helpful to describe the natural sequence of events rather than working backward from an end stage which includes phenomena not seen in the early stages. Observations on normal or adrenalectomized men receiving large amounts of mineralocorticoid for weeks or months simulate the earliest stages of primary aldosteronism. The initial retention of sodium and water leads to expanded extracellular volume and plasma volume Which persist for the duration of the disease. Normal escape from the sodium-retaining action on the kidneys leads to resumption of external sodium balance before edema appears. Loads of extra sodium are excreted more rapidly by the "volume-expanded" hypertensive patient than by ~,. normal person. Persistent slow wasting of potassium into the urine now begins. This is not easily measured on the analysis of a single day's specimen, which contains on the average day only slightly more potassium than that which is ingested in the daily diet. Potassium wasting in stools may also be present. As the serum potassium concentration becomes gradually reduced, the whole day's intake of postassium continues to be excreted in urine (high "clearance" of potassium). This contrasts with the behavior of normal persons, who are able to conserve potassium by reducing the excre20

tion of potassium when potassium stores in the body are depleted. Over the next several months, arterial pressure rises as serum potassium falls. If the patient is seen at an early stage in the evolution of his disease, the diagnosis may easily be missed. The blood pressure is not greatly elevated, and the serum potassium concentration may be only at the lower limits of normal. No symptoms are present at this time; but acute, symptomatic potassium depletion may be easily precipitated by hypotensive therapy with oral diuretics. Since measurement of arterial pressure is part of the routine physical examination, and estimation of serum or total body potassium is not routinely performed, it is not surprising that the patient usually comes under scrutiny because of the finding of elevated arterial pressure. It may be pertinent to note also that patients with Addison's disease treated with desoxycorticosterone showed a wide individual variation in response. Patients with a personal or family history of hypertension were frequently quite sensitive to mineralocorticoids and showed a strong rise in arterial pressure before other signs of overdosage were apparent. (Other patients developed electrolyte problems before any rise in blood pressure was evident.) This individual variation in reactivity may account for the occasional absence of appreciable evidence of potassium deficiency after significant hypertension is established in some patients who ultimately turn out to have indubitable primary aldosteronism. This difficulty does not absolve the physician from careful screening of all hypertensive patients for primary aldosteronism; rather, it should alert him to the possible need for repeated and more penetrating analysis of hypertension beyond the routine serum potassium and electrocardiogram. The hypertension of primary aldosteronism is frequently benign and chronic; In women, it may go on for years without complications; but eventually, and perhaps sooner in men, it takes a toll of heart failure and cerebrovascular accidents. The average blood pressure is not as high as that of renal or malignant hypertension, but individual cases overlap. Retinopathy is usually limited to thickened arteries and an occasional hemorrhage. Severe vasospasm and papilledema are uncommon; like an accelerated symptomatic course with very high diastolic pressure, they suggest renal ischemia and vascular disease. Cardiomegaly and signs of left 21

ventricular hypertrophy are common. An alert reader of electrocardiograms frequently can suggest that hypokalemia is present by noting some of the following signs: sagging S--T segments, inverted T waves, large U waves (especially in the precordial leads) and prolonged P - R interval. Edema appears with other signs of congestive heart failure; at this stage, also, thiazide diuretics may precipitate hypokalemic crisis. A prominent symptom, developing early in many patients, is headache. This is frequently a persistent, bursting, central or frontal headache, somewhat different from the morning, occipital, muscle-tension headache of other forms of hypertension. Relief of this headache may be one of the first signs of improvement following removal of the adrenal tumor. Another early complaint is nocturia. This symptom results from reversal of the normal diurnal rhythm of water and sodium excretion, which may become quite evident if the patient is asked to collect urine in two 12-hour periods beginning with the hour of arising. The normal person excretes at least one half of his water and sodium and most of his potassium during the day; many patients with primary aldosteronism excrete most of the day's water and solutes at night. This test is not specific but indicates the need for detailed study. Other effects of potassium deficiency on the kidneys are listed in Table 2. Some of the findings may also be related to coexistent nephrosclerosis, pyelonephritis or other complications, but their presence suggests further investigation. As the potassium deficit increases, the neuromuscular system is involved. The first evidence is usually generalized weakness and fatigue. Alkalosis leads to paresthesias, cramps and tetany which do not respond to calcium administration. Episodes of intermittent paralysis may occur spontaneously or may follow vomiting, diarrhea or administration of diuretics. Deep tendon reflexes are reducedor absent. Severe, generalized paralysis may be life threatening and demands treatment with intravenous potassium chloride (40 mEq. per liter in 5% dextrose solution), given with electrocardiographic monitoring until muscle strength is restored, and followed by oral potassium supplement (100 mEq. per day). Unusual manifestations of aldosteronism may be edema or diabetes. Although most patients with primary aldosteronism 22

escape from the sodium-retaining action of the hormone and maintain an expanded extracellular volume without appreciable edema, a few patients retain sufficient extracellular fluid to give visible pitting edema. Severe potassium depletion is commonly associated with an impairment of glucose tolerance. In a few patients, frank diabetes may be apparent: Both of these manifestations are improved following removal of the adrenal adenoma. In view of the emphasis placed on measurement of serum electrolyte concentrations, a closer look at the changes seen in primary aldosteronism and in some related conditions may be helpful. The serum potassium concentration is not always distinctly below normal in early stages of primary aldosteronism, and a single test may be misleading. If the first result is in the lower range of normal, the test should be repeated. If the patient has been on a reduced sodium intake, hypokalemia and other signs of potassium deficiency may be minimal. If the patient shows increased urine potassium and a fall in serum potassium when sodium intake is increased, this may be taken as confirmatory evidence of aldosteronism. The hypokalemia of aldosteronism is often accompanied by alkalosis: if acidosis is found, it suggests further study of renal function. An increased serum sodium concentration is a confirmatory sign which is found in some, but not all, cases of aldosteronism. A low serum sodium concentration should alert the physician to the possibility of primary renal or vascular disease. Additional tests may be helpful. Total exchangeable sodium is frequently increased, and plasma volume may also be above normal, as well as extraeellular fluid volume. A low concentration of sodium in thermal sweat and in saliva is also indicative of aldosteronism. Since there is some overlap with normal results, these tests should not be relied on unless they are clearly outside of the range of normal. In the early stages of primary aldosteronism, abnormalities of kidney structure and function are largely due to potassium wasting. A dilute, neutral urine which changes less than normal on dehydration or ingestion of an acidifying agent suggests a search 9for other typical changes which have been listed. Later stages are frequently complicated by the presence of vascular disease of the kidneys (nephrosclerosis) and by pyelonephritis, which is com23

monly noted in patients with long-standing potassium deficiency. These processes may result in renal insufficiency, which does not respond to appropriate management of hypertension, potassium depletion and infection; under these circumstances, it may be very difficult either to make a diagnosis of primary aldosteronlsm or to find any useful approach to treatment. Pyelograms will probably be made in the course of the investigation to visualize the kidneys and adrenal areas. The routine intravenous test should be modified in hypertensive patients by (1) increasing the dose of the contrast medium, (2) taking a ~eries of films within the first 2 minutes and (3) taking a late film 1 hour after dye injection. The early films may give valuable hints of renal ischemia by demonstrating differences in renal size or i n the development of renal opaeification by dye, while the last film may show delayed excretion of a high concentration of dye by the ischemic kidney. Such changes would, of course, direct the search toward aldosteronlsm secondary to renal artery disease. The odds do not favor demonstration of a small adrenal adenoma by radiography, but these films should be carefully inspected for any evidence of adrenal tumor. The spironolactone test is helpful in demonstrating that potassium wasting is due to excessive secretion of aldosterone. Spironolactone (older preparation 200 mg. every 4 to 6 hours, or Aldactone-A 50 mg. every 4 to 6 hours) is given to the patient daily for 3 to 5 days. Sodium diuresls begins on the first or second day, followed by a fall in urine potassium which persists for several days. Serum potassium concentration continues to increase for a few days after spironolactone is discontinued. The findings just described indicate that aldosterone is involved in the genesis of metabolic alkalosis and hyperkalemia through its effect on the kidneys. It does not show whether hyperaldosteronism is caused by an adrenal tumor or by some stimulus which increases secretion of aldosterone by normal adrenal glands. The demonstration of a high level of aldosterone secretion or excretion is an important part of the diagnosis of primary aldosteronism but is not pathognomonie (see Table 3). All drugs which may affect the analysis should be withheld. The patient should be on a controlled "normal" intake of sodium (120 to 150 mEq. per day) and potassium (70 to 100 mEq. per day). Several 24

collections, each of 1 complete day's total urine, are made and frozen after measuring the volume and taking small aliquots for creatinine and 17-hydroxycorticoids. The completeness of collection may be gauged from the total creatinine excreted. The frozen urine, representing virtually all of 1 day's collection, is submitted for analysis. The quantity of aldosterone released at pH 1 from normal urine is 5[tg. to 15ttg. per day and represents approximately 10~b of the secreted hormone. Owing to various losses, many laboratories report a somewhat lower range of normal values; obviously, the result on the patient must be compared with the normal values from the laboratory making the analysis. Most patients with primary aldosteronism excrete from 20lag. to 9 1 rag. per day or more, but in a few patients the quantity may be within normal limits. This last finding does not exclude primary aldosteronism, but the discordant result should be noted and other related conditions not associated with high aldosterone output should be considered. The analysis should be repeated, as there is substantial day-to-day variation in the quantity of aldosterone secreted. It has been suggested that some patients with primary aldosteronism excrete a smaller than normal fraction of the secreted hormone; this may well occur in renal failure, but if it exists in other circumstances it is rare and not defined. Finally, some tumors appear to be under a degree of physiologic control, and thus the secretion rate of aldosterone may be reduced by potassium depletion. If such a patient is given large supplements of potassium (100 to 200 mEq. per day for 5 to 10 days) to rep l a c e his deficit, aldosterone secretion frequently rises above the normal range. Cortisol secretion, reflected in the level of 17-hydroxycorticoids, should be normal or only slightly increased; a high level should direct investigations toward possible causes (adrenal hyperplasia or tumor, or oat-cell carcinoma of lung or other organs) and other manifestations of Cushing's syndrome. Increased excretion of 17-ketosteroids is rare in primary aldosteronism and should stimulate further investigation. If all findings are compatible with primary aldosteronism, and if the patient's circulatory and renal function permits surgery, exploration of the adrenal glands should be undertaken. Prior to surgery, body potassium should be repleted. Administration of 25

potassium chloride (100-200 mEq. per day as enteric-coated tablets) should be accompanied by a low-sodium intake, which minimizes the effect of a high level of circulating aldosterone. The serum potassium concentration is a guide to the adequacy and effectiveness of therapy; the aim should be to approach normal values gradually and to repair the intracellular deficit. If the serum potassium fails to rise to normal, spironolactone may also be given in gradually increasing amounts. It is possible to induce hyperkalemia in sensitive patients by excessive or prolonged use of the above measures. When the serum potassium has become stabilized and all signs of neuromuscular difficulty have ceased, it is appropriate to proceed with bilateral exploration of the adrenal areas. It is ordinarily unnecessary to prepare patients with primary aldosteronism with large doses of cortisone such as are used in patients with Cushing's syndrome. In view of the uncertainties of surgery of the adrenals, however, the possibility of bilateral adrenalectomy must be borne in mind. It may be well to inject 100 rag. of cortisone acetate intramuscularly on the night before surgery and to repeat this dose on the morning of surgery. If an adenoma is found and removed, and if the other gland is intact, further corticosteroid therapy is given only if indicated by an abrupt fall in blood pressure or urine output (on adequate intravenous fluids). At surgery, both glands should be carefully exposed and palpated by an experienced surgeon. It may be difficult to find an adenoma attached by a small pedicle to the adrenal gland or to palpate a small tumor within the substance of the adrenal gland. Unfortunate instances have been recorded in which a normal adrenal gland was removed first, and bilateral adrenalectomy became necessary to remove a tumor involving much of the remaining gland. Hopefully, one adrenal will be a bit larger or thicker if the tumor is within the gland. Multiple or bilateral tumors have been reported; extra-adrenal tumor is extremely rare. Although malignancy is unlikely, a frozen section of any tissue should be made and examined during surgery. A part of the tumor should also be frozen for future analysis, if necessary. In most cases, a single adenoma is found and removed. If no tumor is found, it is probably best to proceed with the removal of 26

one adrenal and part of the other gland, as the metabolic problems may be relieved, at least temporarily. Blood pressure usually falls slowly after removal of a tumor, and the postoperative course may be uneventful. If there is rapid fall in blood pressure, vasopressor agents (metaraminol, angiotensin or norepinephrine) may be infused to permit a controlled fall. Urine output may be used as a guide to the adequacy of the circulation. Intravenous hydrocortisone is indicated if there is any suspicion of adrenal insufficiency or if the patient is unusually refractory to vasopressor drugs. It is difficult to predict the course of serum potassium postoperatively. The fall in blood pressure and renal blood flow may lead to a rise in serum potassium, especially if intravenous fluids containing potassium are given. Other patients with unrepaired deficits may show a fall; frequent measurements of the serum potassium level postoperatively are helpful in guiding fluid administration. Arterial pressure usually subsides gradually over a period of days to a month after removal of a tumor. Unfortunately, in about one third of cases, blood pressure does not return to normal, or rises again after an initial fall. If metabolic abnormalities and hyperaldosteronuria persist, one must consider what other sources of aldosteronism exist--a second adenoma or the remaining normal adrenal tissue stimulated by pathologic processes in the kidneys. More often, metabolic abnormalities and aldosteronuria disappear, confirming that the tumor was the primary cause of that disorder; but the elevated arterial pressure reflects an established pattern independent of the aldosteronism. The residual hypertension can be controlled by hypotensive drugs.

OTHER FORMS OF HYPERTENSION AND POTASSIUM DEFICIENCY ASSOCIATED WITH HIGH ALDOSTERONE SECRETION

Juvenile aldosteronism has been described in a number of infants, children and adolescents. The patient comes under observation because of headache, irritability, epistaxis, convulsions, nocturia with enuresis, polydipsla, polyuria or retarded develop27

ment--physical or mental. The problem often becomes manifest in early childhood and has been thought by some to be congenital; so far, no evidence of familial incidence has been recorded. Arterial pressure is found to be very high, even by adult standards. The severe and symptomatic hypertension, with cncephalopathy, vasospasm and papilledema, suggests "malignant hypertension"; but the condition may persist for many years, in contrast with the rapidly fatal course of arteriolar nephrosclerosis in adults. There is evidence of marked potassium deficiency, with electrocardiographic changes, muscle weakness or paralysis, and tetany associated with alkalosis. The typical renal findings of aldosteronism are present, complicated in some cases by nephrosclerosis or pyelonephritis. Aldosterone secretion is increased. Urinary 17-hydroxycortlcoids have been above normal in several cases. At surgery, bilateral adrenal hyperplasia or "normal adrenal glands" are found. Hyperplasia in several cases has been described as involving the zona fasciculata. One adrenal gland has been removed, or a subtotal adrenalectomy has been performed; in the latter case, adrenal insufficiency is possible and cortisol should be given. Postoperatively, there has been some fall in blood pressure and reduced secretion of adrenal hormones, together with a return of the metabolic abnormality to normal and with improvement of the cardiac, neuromuscular and renal manifestations of hypokalemia. In some instances, the blood pressure has not returned to normal and further administration of hypotensive agents has been necessary. In the differential diagnosis of aldosteronism in children, early onset and severe symptomatic hypertension suggest bilateral adrenal hyperplasia. A rare case of typical primary aldosteronism due to adenoma can also occur. The pathogenesis of juvenile aldosteronism is not clear. Further information is needed to establish a possible role of renin or angiotensin in the pathogenesis. Renal ischemia due ta obstruction o[ the renal artery leads to hypertension, which is frequently severe, symptomatic and runs an "accelerated" course. There is, however, a good deal of variation from case to case. Some patients have a more benign hypertension, and a few simulate primary aldosteronism. 28

In my series, a significant increase of aldosterone secretion and' excretion occurs in 40~b of patients with hypertension due to proved renal artery obstruction. In some cases of renal artery disease, aldosterone secretion may be as much as 1 rag. per day, higher than in the average patient with primary aldosteronism; but for an unexplained reason, there may be no evidence of potassium depletion. In a few instances, all of the usual findings of primary aldosteronism are present, including hypertension; severe potassium depletion due to loss through the kidneys, with its usual effects on neuromuscular, renal and cardiac function; alkalosis and normal or increased serum sodium concentration; and a high rate of aldosterone secretion. Such patients respond to spironolactone like a patient with primary aldostcronism, with potassium retention, sodium diuresis and a return of serum potassium concentration toward normal levels. It must be emphasized that the problem is not so much to rule out aldosteronism in cases with renal artery disease, but rather to avoid making an erroneous diagnosis of primary aldosteronism and removing normal adrenal glands from the unusual patient with renal artery disease whose symptoms and signs are those of aldosteronism. Some useful warning signs that aldosteronism is not primary are: a brief history or sudden onset of hypertension, which may be severe and symptomatic; the presence of severe vasospasm and papilledema on examination of the retina; or the" finding of a reduced concentration of sodium in the plasma. It has been reported that extracellular fluid and plasma volumes may not be increased as much and the postural fall in blood pressure may not be as large as the comparable changes observed in some cases of primary aldosteronism. Despite these possible differences, certain patients with unilateral renal artery disease may simulate primary aldosteronism so closely that they have been operated on and adrenal tissue has been removed under the impression that the patients had primary aldosteronism. It is therefore important to rule out renal artery disease in all patients with apparent "primary aldosteronism" before adrenal surgery is undertaken. The usual order of testing is, first, intravenous pyelography, performed in the special manner described above (see "Primary Aldosteronism," p. 20). If differences of renal perfusion are suggested by delayed opacification and dye 99

excretion, or by late hyperconcentration or by smaller size of the affected kidney, differential renal function tests may also be undertaken. The location of the arterial lesion can be defined most clearly by arteriography, which is also indicated if there is any suggestion that both renal arteries are involved. It is currently thought that renal ischemia causes hyperaldosteronism through the release of renin and angiotensin, but only a few patients with renal ischemia and resultant hypertension develop evidence of hyperaldosteronism. There is reason to believe that after an initial period of ischemia, rising arterial pressure improves the perfusion of the kidney with the obstructed artery, while the damaging effects of greatly increased blood pressure on the arteries of the contralateral kidney may later cause release of renin from the "normal" kidney; the situation may then be analogous to that seen in "malignant hypertension." More precise information on these questions is needed. The ideal treatment of aldosteronism and hypertension associated with unilateral renal artery obstruction is removal of the obstruction and repair or replacement of the renal artery. If this is not feasible, excision of the kidney with the obstructed renal artery is necessary. Following successful surgery, aldosteronism subsides. Removal of the adrenal glands is not indicated, as it can correct only the metabolic abnormality and does not result in a return of blood pressure to normal; on the contrary, an unstable and difficult therapeutic problem is created by adrenal insufficiency, Severe, accelerated, "'malignant" hypertension is frequently associated with increased aldosterone secretion. This syndrome is usually defined as a severe, symptomatic form of hypertension associated with headache, visual disturbance, encephalopathy, myocardial failure and progressive renal insufficiency. Retinal changes usually include papilledema, marked narrowing or obliteration of arteries, hemorrhages and exudates. Increased renin and angiotensin levels are believed to be associated with a seeondary rise in aldosterone secretion and excretion. Metabolic alterations, with hypokalemla, alkalosis, polyuria and other phenomena resembling aldosteronism are also seen in some cases. These phenomena are not regularly correlated with increased aldosterone output, and they may be improved when high blood pressure is controlled with hypotensive agents for 3 to 12 weeks. 30

When aldosterone hypersecretion exists, it is probably secondary to the changes in renal circulation. The failure of bilateral adrenalectomy to provide substantial benefit for patients with malignant hypertension suggests that increased adrenal secretions are not initiating the disorder. Differential diagnosis with primary aldosteronism does not ordinarily present a serious problem, since potassium deficiency is mild or absent in most patients with malignant hypertension, unless thiazide diuretics are used. The symptoms, retinopathy and malignant nephrosclerosis are more severe than is usual in primary aldosteronism. Hyponatremia, renal failure and acidosis are more common in malignant hypertension than in primary aldosteronism. Normal extracellular and plasma volumes or absence of the abnormal circulatory reflexes found in severe potassium depletion favors malignant hypertension; but abnormal resuits in these tests do not exclude malignant hypertension if heart failure is present. If the tendency for potassium wasting abates on control of the hypertension with drugs (other than diuretics), malignant hypertension is more likely. Taking these various statistical guides together, the probability of a correct differential diagnosis is high; but it must be frankly admitted that no definitive test exists. Benign, essential hypertension is not regularly associated with increased aldosterone secretion or excretion. In "severe and complicated" cases, aldosterone secretion may be definitely increased; in other cases, a more striking day-to-day variation with some high values is noted. Potassium depletion is rare unless diuretics are given. One patient with benign hypertension and all of t h e other characteristics of primary aldosteronism except an adrenal adenoma has been described. There does not seem to be any conclusive way to differentiate this rare picture from that of primary aldosteronism. Fortunately, this patient showed substantial improvement after subtotal adrenalectomy. Adenomatous hyperplasia o[ the adrenal cortex may also be associated with hypertension. Although one cannot speak with certainty, it seems likely that these changes are secondary to renal vascular disease, since similar changes in the adrenal cortex have been noted in other patients with long-standing, severe, secondary aldosteronism. 31

The use o[ oral thiazlde diuretics as popular and effective agents for the treatment of hypertension has created a problem in the detection of cases of possible primary aldosteronism, since these diuretics so frequently lead to lowering of serum potassium concentration. It is a good general rule that investigation o[ all hypertensive patients should precede therapy, with rare exceptions in aged or seriously ill patients. Hypertension, after all, is not a disease, but a manifestation of disease. There are curable forms, but the tests which we use to detect these cases are confused and rendered less reliable by the effects of treatment. Physicians and patients should consider the advantage of improved and earlier diagnosis of the patient with curable hypertension, masquerading as "essential hypertension." Late diagnosis may be futile if irreversible arterial, renal, myocardial or cerebral damage has already occurred. If the patient has already been given oral diuretics, however, we may still be able to take advantage of t h e opportunity to observe the consequences. If no reduction in serum potassium below the normal range has occurred, the diagnosis of primary aldosteronism is quite unlikely. Contrariwise, the development of severe, symptomatic hypokalemia soon after the institution of thiazide therapy should raise the question of aldosteronism-primary or secondary. The average hypertensive patient loses a small amount of potassium when thiazides are given, but this is rapidly made up, as is the deficit of sodium which occurs soon after taking these diuretics. Aldosterone levels in such patients are not regularly increased above the normal level, though scattered high values may occur. Different findings are observed in patients with marked aldosteronlsm, since a substantial deficit of potassium existed prior to the use of the oral diuretic, and potassium wasting is aggravated, with rapid decline of serum potassium into the symptomatic range. If the findings are intermediate between these extremes, i.e., a moderate and asymptomatic reduction in serum potassium is observed, the administration of thiazide should be stopped and the patient carefully followed. If the blood pressure rises, a different form of treatment may be instituted. Oral potassium supplements are given if the serum potassium does not rise quickly to normal. Hypokalemia solely due to oral diuretics is usually 32

associated with a relatively small deficit of total body potassium and is quickly repaired after giving as little as 100 to 200 mEq. of supplementary potassium. Other forms of potassium wasting, including aldosteronism, usually require heavier and more persistent replacement. If hypokalemia persists, the patient should be studied as a possible case of aldosteronism as outlined in previous sections. Potassium wasting due to renal disorders is not often associated with hypertension and increased aldosteronuria, since simple potassium depletion tends to lower arterial pressure and reduce aldosterone secretion. Thus, in simple renal potassium wasting, two of the principal findings of primary aldosteronism are lacking. In some cases, the sodium-losing tendency evokes a compensatory aldosterone hypersecretion which may become autonomous and could possibly lead to adenoma formation; but blood pressure usually remains within normal limits. In the later stages, however, renal failure or vascular disease may cause a rise in blood pressure and increased aldosterone secretion. Similar situations have been considered in earlier sections; here, too, there is no infallible test to distinguish between a late, complicated case of primary aldosteronism and one secondary to renal disease, unless it can be established from history and laboratory records that the renal disorder preceded the rise in blood pressure or that there are findings which cannot be attributed to aldosteronism. It should be clearly understood that most of the signs and laboratory changes o] "primary aIdosteronism" are those of potassium depletion due to renal wastage; the other distinctive signs of primary aldosteronism are hypertension, increased aldosterone secretion and extrarenal effects of aldosterone, e.g., on sweat and saliva. The responses to spironolactone and to sodium depletion may be different in primary renal disorders. Spironolactone acts most effectively when aldosterone levels are high; clear effects in primary aldosteronism have been described, but these are not seen in other forms of renal potassium loss, unless these are associated with sodium loss and secondary aldosteronism. A low-sodium diet, which minimizes potassium wasting and has a beneficial effect on primary aldosteronism, is not likely to benefit the patient with primary renal wasting whose sodium-losing tendency may cause serious sodium depletion. 33

Renal disease is suggested by the finding of azotemia, acidosis or hyponatremia; heavy proteinuria and~other urinary changes not usually seen in primary aldosteronism; and nephroealcinosis or lithiasis, hypoealeemia, rickets or osteitis fibrosa. The pathogenesis of renal potassium-wasting disorders is not always clear, but several causes have been noted frequently (see Table 3). In infants, Fanconi's syndrome or renal tubular acidosis may cause hypokalemia. In adults, cases of renal tubular acidosis, pyelonephritis and polycystic disease have been recorded. In these cases, other signs typical of the underlying disease are noted. There remain a number of cases of "cryptogenie" potassium wasting. Two brothers described by France had normal blood pressure, severe hypokalemia and normal aldosterone output. It is obvious that each ease presents individual features, but certain general principles are useful. Serious diagnostic problems may arise in the case of patients with far-advanced renal disease, hypertension and hypokalemia. This combination occurs in many patients with azotemla who suffer from severe nausea and malnutrition. In some cases, the history or the laboratory findings are very suggestive of primary aldosteronism, but the physician must decide whether it is justifiable to operate on far-advanced cases with little hope of survival and considerable uncertainty concerning diagnosis.

The syndrome o[ hyperplasia o[ the juxtagIomerular complex, described by Bartter and Gill, is another fascinating problem of hyperaldosteronism and potassium wasting in normotensive patients. This rare disorder, occurring in young children, perhaps as a congenital disorder, is characterized by normal blood pressure and signs of aldosteronism resulting from adrenal cortical hyperplasia. The overproduction of aldosterone could not be suppressed by sodium loading or by expansion of plasma volume. It was associated with hypokalemic alkalosis and vasopressln-resistant hyposthtenuria. In both subjects, the investigators were able to demonstrate increased amounts of circulating angiotensin, presumably due to increased release of renin from the hyperplastie juxtaglomerular cells. In both cases, angiotensin II infused intravenously produced smaller rises in blood pressure than occur in comparable doses of angiotensin given to normal subjects. The authors, therefore, conceive that this syndrome is due to a de34

fective vascular response to the pressor action of angiotensin, with compensatory overproduction of renin and angiotensin, stimulation of the adrenal cortex to secrete aldosterone and the consequent metabolic abnormalities.

CLINICAL CONDITIONS WITH FINDINGS SIMILAR TO PRIMARY ALDOSTERONISM, BUT WITH NORMAL OR LOW ALDOSTERONE SECRETION

A [amilial renal disorder simulating primary aldosteronism, but with negligible aldosterone secretion, has been described by Liddle. Seven of 11 siblings in the affected family showed hypertension, hypokalemia and renal potassium wasting, but aldosterone secretion rate was low. There was no response to spironolactone, and there was a normal salivary sodium and potassium content. Other known causes of hypertension and hypokalernie alkalosis were excluded. Renal function was normal, apart from the inappropriate high exchange of sodium for potassium in the renal tubules~ which occurred at unusually low levels of aldosterone secretion. Treatment with triamterene, an inhibitor of sodium and potassium exchange in the kidneys, was followed by improved sodium excretion and potassium conservation. The blood pressure also returned to normal when treatment with triamterene was continued. This situation must be considered in patients with apparent primary aldosteronism who show low or normal levels of aldosterone secretion and who fail to show a positive spironolactone test or evidence of increased aldosterone activity on extrarenal target organs. Exogenous mineraloeorticoids must be considered in the differential diagnosis. A history of ingestion of licorice, fludrocortisone or other agents producing mineralocorticoid effects must be sought. A very large intake of sodium bicarbonate may produce some similar effects. Excessive production o[ cortisol is usually not a problem in the diagnosis of the hypertensive patient, since other signs of Cushing's syndrome are present, while hypokalemic alkalosis is uncommon~ and aldosterone secretion is usually low or normal. Bub occasionally, adrenal tumors or hyperplastic glands will produce 35

a significant excess of both aldosterone and cortisol; in these mixed [orms o/hyperadrenoeortieism, either hormone may dominate the clinical and laboratory signs, or a mixed pattern may emerge. Anaplastic carcinoma, resembling oat-cell tumor of the lung, but arising in various organs, may contain and release into plasma a polypeptide with biologic effects like ACITH. Adrenal hyperplasia and secretion of very large quantities of cortisol result. These patients show some hypertension, as well as severe weakness, due in part to profound potassium depletion. Pigmentation of the skin is associated with increased melanocyte-stimulatlng activity. Many patients do not show other clinical signs of Clushing's syndrome which might be expected in patients secreting large amounts of cortisol. Aldosterone secretion is usually normal or reduced. Spironolactone administration does not produce a significant improvement in electrolyte balance. Plasma cortisol levels and urine 17-hydroxycorticoids are greatly increased. It is important to distinguish such cases from primary aldosteronism because of the marked differences in pathogenesis and prognosis. Removal of the primary tumor may be followed by temporary improvement of all signs, but metastases are usually present and the syndrome tends to recur. Management is largely supportive and palliative. Surgical adrenalectomy or chemical blocking of cortlsol biosynthesis may be indicated in special circumstances; but these measures do not arrest the progress of the underlying disease. Potassium zoasting due to renal disorders has been discussed in an earlier section. It is frequently associated with normal or low aldosterone secretion, unless sodium wasting, vascular disease or other stimuli are also present. ALDOSTERONE AND EDEMA

The first evidence of the existence of aldosterone in man was the finding of increased quantities of a sodinm-retaining factor in the urine of patients with heart failure, nephrosis or cirrhosis who were in positive sodium balance and were accumulating edema. Since these patients are more sensitive than normal men to the 36

sodium-retaining effect of aldosterone, the correlation of increased aldosterone with sodium retention could be demonstrated, and the significance of aldosterone in controlling sodium excretion was gradually appreciated. Aldosterone antagonists have been developed and have proved to be useful adjuvants in diuretic therapy. Aldosterone secretion can be assumed to be high only during periods when edema is being collected and urine sodium is quite low. During the stationary or diuretic phase of edema, aldosterone secretion is ordinarily normal or reduced. It is obvious, therefore, that one cannot equate edema with increased secretion of aldosterone. Furthermore, other factors can affect sodium excretion; for example, reduced glomerular filtration rate can limit the quantity of sodium filtered, and other factors acting on tubular transport of sodium may affect sodium excretion. It is necessary, therefore, to view the hypersecretion of aldosterone as one mechanism in a complex system. All patients with edema cannot be considered as cases of "secondary aldosteronism." Among the disorders which can lead to hypersecretion of aldosterone and edema are: the nephrotic syndrome, nutritional or idiopathic hypoalbuminemia, congestive heart failure, cirrhosis of the liver and idiopathic edema. Increased aldosterone secretion does not result directly from the presence of disease of tile kidneys or liver. The stimulus arises at the time that edema begins to form and is presumably another manifestation of the same process which causes the edema, i.e., increased venous pressure or reduced circulating albumin. In an effort to find a common factor and an adequate explanation for sodium retention, Peters postulated a fall in central plasma and blood volume, comparing the situation with that observed in normal man after hemorrhage, prolonged standing or blocking of venous return. These stimuli can also increase aldosterone secretion. The argument that aldosterone secretion is stimulated by reduced plasma volume is also supported by the effectiveness of concentrated human serum albumin in expanding plasma volume and lowering aldosterone secretion in some patients with the nephrotic syndrome. A possible mechanism for sensing decreased blood volume is the fall in renal blood flow, which can stimulate the juxtaglomerular cells to release renin, leading in turn to a higher circulating level of angiotcnsin and stimulating the hypersecretion of aldo37

sterone. The absence of hypertension may be explained by the reduced sensitivity of subjects with this type of "secondary aldosteronism" to the pressor effects of angiotensin, compared with normal subjects receiving an equivalent rate of infusion. It is possible to criticize and raise objections to this postulated sequence of events at several points, but it serves as a framework for current thinking and experimental testing. There is no increase in cortisol secretion in these disorders. It is therefore considered that endogenous pituitary corticotropin is not the stimulus to aldosteronism. A C T H may play a supportive role, however, and its suppression may help to reduce aldosterone in some instances. The regulation of aldosterone in patients with edema is abnormal in several respects. Secretion rate is abnormally high. Some part of the increase may be due to a low sodium intake, but it has also been observed that increased levels of aldosterone in edematous patients are difficult to suppress by sodium loading. These patients accumulate large volumes of edema before spontaneous suppression of the abnormal secretion of aldosterone Occurs,

There is also an abnormal response to aldosterone in the edematous patient, with increased sensitivity to mineralocorticoidinduced sodium retention and failure to "escape"; thus, edema is prone to accumulate in large amounts. Experimental study of this problem by Davis shows that increased sensitivity occurs in circumstances like those which increase aldosterone secretion, and that another humoral factor, as yet unidentified, may be involved. Potassium wasting is not evident so long as urine sodium remains low, but may appear when diuretics are given. There may be abnormalities in the metabolism of aldosterone. In cirrhosis of the liver, the removal of aldosterone from the circulating blood is greatly delayed. The association of this delay with hypersecretion of aldosterone leads to greatly increased blood levels. A similar impairment of aldosterone metabolism is also seen in patients with severe congestive heart failure, who may show an increased level of circulating aldosterone even when the secretion rate is normal or only slightly increased. High levels of aldosterone act not only on the kidneys but also on the content of sodium in sweat, saliva and stool. The normal 38

loss of sodium through sweat or stool is considerably decreased in patients with increased levels of aldosterone. If the stimulus to aldosteronism is sufficiently prolonged and intense, there may be alterations in the morphology of the adrenal glands. Adrenal hyperplasia, adenomatous changes and even the development of a clear-cut adenoma secreting aldosterone may ensue. This situation should be suspected in patients who maintain a high, fixed Output of aldosterone despite adequate therapy of the underlying disease to reduce the stimulus to hyperaldosteronism. Although adrenalectomy is not ordinarily considered in the management of such patients, there have been reported cases in which intractable hyperaldosteronism has been effectively corrected only after removal of hyperplastic or adenomatous adrenal tissue. lllanagement o[ the underlying disease and of its physiologic disturbances should receive equal consideration with the relief of symptoms and treatment of secondary aldosteronism. Obviously, the patient with liver disease will require specific attention directed toward improvement of his hepatocellular damage through rest, improved nutrition, abstention from ethanol or toxic substances and general supportive treatment. The patient with the nephrotic syndrome will require similar supportive management; and in the absence of contraindications, corticosteroids may be given to reduce the abnormal glomerular permeability to albumin and to halt theprogress of the glomerular lesion. The patient with congestive heart failure will require rest, digitalis and diuretic administration to relieve the burden on the failing heart; and certain forms of valvular deformity or abnormal communications may he corrected by surgery. Amelioration of the basic disorder offers a better prospect of lasting benefit than the temporary assistance obtained by relief of secondary aldosteronism. Idiopathic edema is a form of mild, dependent edema, occurring in women without signs of disease of heart, liver, kidneys, veins or thyroi& No relevant disorder is suggested by history or physical examination. There may be premenstrual aggravation of edema, but the problem is continuous. Some patients are intelligent and efficient individuals who are quite demanding of themselves and of others. Situational factors may play a part. Most of these patients are operating under stress, and some are danger39

ously close to hysterical or psychotic reaction; they must be managed cautiously to reduce nervous strain and to create a neutral environment. Edema usually disappears at bed rest or especially on hospitalization. Laboratory tests are not helpful except to rule out other possible causes of edema. In addition to the psychologic problems, postural changes are particularly important. Sodium excretion falls when the patient stands, and the normal orthostatic increase in aldosterone secretion is exaggerated and prolonged in the patient. Hepatic blood flow, falls on assuming the upright position, and this delays the removal of any excess aldosterone from the circulation. Most patients lose their edema overnight; but if the situation is aggravated, failure of the normal release of sodium and water during recumbency leads to persistent and cumulative retention of sodium. The pathogenesis of this abnormal state is not well understood. There is no clear evidence of increased venous resistance or abnormal capillary permeability in most cases. The demonstration of increased quantities of aldosterone in the urine of emotionally disturbed or tense individuals may be relevant to the problems which these patients show. There must also be some abnormality leading to unusual sensitivity and inadequate escape from sodium retention. The few patients who have received exogenous desoxycorticosterone have escaped from the sodium-retaining action but only after visible edema has accumulated. Treatment begins with rest and relaxation, resulting in clearing of edema in many patients; but few patients wish or are able to spend most of the day in bed for any period of time. Dietary sodium restriction, diuretic therapy, aldosterone antagonists, vasopressor agents and elastic support for the legs to minimize the accumulation of edema are helpful. An appropriate combination of these measures is usually successful and acceptable. A few reported cases of "idiopathic edema" have been associated with serious complications requiring radical therapy. The relation of these cases to the usual, chronic, benign form of the disorder is not clear. In the management o[ the edematous patient, the physician must take into account the effects of possible associated aldosteronism not only on the signs of disease but also in relation to therapy. Restriction of dietary sodium (3 to 5 Gm. NaCl per day) 40

avoids excessive intake. Severe reduction (below 1.8 Gm. NaCI, or 700 rag. Na or 30 mEq. per day) should be used only in especially difficult cases and for limited periods, since such a diet is deficient in other nutrients and predisposes to hyponatremia. Severe sodium restriction stimulates aldosterone secretion, but its immediate effect is a loss of sodium and water from the body. In some patients with heart failure, sodium restriction can decrease aldosterone secretion if reduced ventricular filling pressure and relief of pulmonary and hepatic congestion result in improved cardiac output. Diuretics generally decrease the reabsorption of sodium chloride in the renal tubules. The introduction of the thiazide diuretics has been especially helpful, since they can be taken by mouth, are well tolerated and have a low toxicity. Theophylline, mercurials, acidifying salts and acetazolamide also have their places. Each agent can cause specific undesired effects with which the physician must be familiar. After a certain period of administration, the patient may appear to become refractory to any one diuretic. The loss of effectiveness may be associated with increasing severity of the underlying disease, or with decreased volume or abnormal composition of body fluids, or with reduced glomerular filtration or with other problems which accompany the prolonged and continuous use of diuretics. Intermittent administration is o[ten more effective in stimulating diuresis and is less likely to lead to undesired effects than continuous administration o[ the same agent. When a strong stimulus to aldosterone secretion is present, oral diuretics may overcome increased sodium reabsorption in the proximal tubule without correcting the excessive exchange of potassium for sodium in the distal tubule, resulting in potassium wasting and inadequate sodium excretion. This problem is vet3, suggestive of secondary aldosteronism, whose effects can be reduced by an aldosterone antagonist. The first effective aldosterone antagonist available for clinical use was spironolactone (Aldactone 100-rag. pills). More recently, another preparation of the same basic agent (Aldaetone-A) has been released, which is claimed to be 4 times as active and is made up in pills containing 25 rag. of the active agent. The recommended initial dose is 3 to 6 pills per day; somewhat larger doses may be given if there is a strong indication. Toxic effects may 41

include drowsiness, tremor, weakness or other neurologic manifestations. Some patients develop a skin rash or other evidence of hypersensitivity. Other hormones and drugs may act as aldosterone antagonists but are not in general use for this purpose. Large doses of progesterone may partly block aldosterone-induced sodium retention, but substantial side effects are noted. Various diuretics have been promoted as aldosterone antagonists; but the term is generally reserved for agents which have no appreciable diuretic action in normal subjects on ordinary sodium intake and which cause sodium excretion only when aldosterone secretion is increased. Several adrenal cortical hormones, including cortisone and its analogues, have a biphasic action on excretion of sodium. Following an initial period of sodium retention, increased sodium excretion appears, leading to relief of edema in some patients. The mechanism of action is complex, including improved appetite and nutrition, expanded plasma volume, increased glomerular filtration rate, increased clearance of free water, possibly some suppression of aldosterone secretion and a modification of the sodium-retaining action of aldosterone. These nonspecific effects have been noted in various edematous patients, including the nephrotic syndrome, hepatic cirrhosis and heart failure; but benefit does not follow the use of cortisone-like hormones sufficiently regularly to justify their routine use. Cortisone derivatives may also have specific effects on the basic disorder--for example, in the nephrotic syndrome of children and the related syndrome in adults.

OTHER CONDITIONS ASSOCIATED WITH INCREASED ALDOSTERONE SECRETION

The causes and possible effects of increased aldosterone secretion in the following conditions are not well defined. It is premature to call them forms of "aldosteronism" if this term implies "an abnormal state caused by aldosterone." Nervous tension, anxiety and some psychoses may be associated with a variable and intermittent increase in aldosterone in urine. Causes which have been suggested include increased pituitary 42

A C T H release and inadequate food and sodium intake, among others. There is no current information to suggest that a high level of aldosterone causes the psychologic disturbance. Surgical operations and other procedures or trauma may increase aldosterone secretion by pituitary A C T H release, sodium depletion, blood loss and other factors. Aldosterone may play some part in the postoperative fall in sodium excretion, but its effect are neither crucial nor damaging, so far as is known. Pregnancy is regularly associated with increasing aldosterone secretion beginning around the fifteenth week and rising to very high levels in the last trimester. T h e average woman in late pregnancy secretes far more aldosterone each day than the average patient with primary aldosteronlsm, yet no deleterious effects are seen; early efforts to relate increased secretion to increased blood pressure, edema, renal disorders or "toxemia" of pregnancy were not successful. Other suggested causes of increased secretion are the positive sodium balance required to meet the needs of the fetus, fluids and circulation, or a response to high levels of progesterone, which tend to reduce the sodium-retalnlng action of aldosterone. It is not clear that aldosterone is in any way essential for normal pregnancy, judging from the reports of successful pregnancy in adrenalectomized women maintained on cortisone. T h e requirements for cortisone are not increased until the onset of delivery. There is also a change in the metabolism of aldosterone, in which a larger proportion is excreted as the acid-labile metabolite, ordinarily measured in clinical assay. This alteration in metabolism gives the impression of a greater increase in aldosterone secretion than actually exists. Similar alterations have been observed in patients receiving large doses of estrogenic and progestational hormones, as well as in certain patients with liver disease and cardiac failure. It remains to be determined whether the increased secretion and excretion of aldosterone in pregnancy serves a useful function or whether it is simply a part of the nonspecific change in hormonal balance. Familial periodic paralysis is an inherited disorder characterized by a chronic deficit of potassium and excess of sodium in muscle fibers and punctuated by episodes of paralysis, with critical fall in serum and cxtracellular potassium concentration due to shifts of potassium into muscle cells. Attacks are precipitated by rest, car43

bohydrate intake or "stress." The disease may become clinically apparent in thyrotoxic patients and be relieved when thyroid status returns to normal. A great deal of attention has been paid to the dramatic, intermittent attacks from which the patient seeks relief. Aldosterone excretion rises at this time, together with other corticosteroid metabolites. There is no evidence of renal potassium wasting; on the contrary, urine potassium falls with serum potassium during attacks. The attack is usually self-limited but may be shortened by giving oral or intravenous potassium salts. The patient can also be taught to avoid factors which precipitate attacks. Corticosteroids should not be prescribed without due consideration of possible precipitation of attacks. Muscle strength may be improved, and the frequency and severity of attacks can be reduced by treatment of the chronic abnormalities of muscle electrolytes. A low-sodium diet, increased potassium intake and aldosterone antagonists have been helpful in minimizing the chronic sodium excess and potassium deficiency of muscle and thus minimizing the fall in extracellular potassium which accompanies the reversion of muscle electrolytes toward normal during an attack. Since extracellular electrolytes are not usually abnormal in the interval between attacks, it is not possible to gauge accurately the efficacy of treatment by measurements of serum or urine electrolytes; but it may be well to observe the effects of treatment. SUMMARY

This review reports recent advances in the knowledge of (1) physiologic regulation of aldosterone secretion, (9) pathologic conditions associated with disturbances of aldosterone secretion, metabolism and effects and (3) other related conditions which must be considered in the differential diagnosis of possible aldosteronism. The reader's attention is drawn to changing concepts and usage of the terms "primary aldosteronism" and "secondary aldosteronism." The current trend is toward the use of these terms in a pathogenetic sense rather than to define specific clinical syndromes. 44

REFERENCES Three hundred original articles on aldosterone were published last year; the total bibliography runs into thousands. It is impossible to refer to all major contributions in a brief bibliography. This list has been selected to include some topics of particular interest to the clinician. Whenever possible, recent articles by active investigators have been selected. References to earlier work may be obtained from these reports. August, J. T., Nelson, D. tI., and Thorn~ G. W.: Response of normal subjects to large amounts of aldosterone, J. Clin. Invest. 37:1549, 1958. Bartter, F. C , Pronove, P., and Gill, J. R., Jr.: Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemie alkalosis, Am. J. Med. 33:811, 1962. Biglieri, E. G., Slaton, P. E., and Forsham, P. tI.: Useful parameters in the diagnosis of primary aldosteronism, J.A.M.A. 178: 19, 1961. Conn, J. W.: AIdosteron[sm in man, J.A.M.A. 183:871, 1963. Cope, 121.L., tIarwood, M., and Pearson, J.: Aldosterone secretion in hypertensive diseases, Brit. M. J. 1:659, 1962. Coppage, W. S., and Liddle, G. W.: Mode of action and clinical uses of aldosterone antagonists, Ann. New York Aead. Se. 88:815, 1960. Davis, J. O., Hartroft, P. M., et al.: The role of the renln-angiotensln system in the control of aldosterone secretion, J. Clin. Invest. 41:378, 1962. Eales, L., and Linder, G. C.: Potassium-loslng pyelonephritls and malignant hypertension: A ease report with balance studies~ Metabolism 8:445, 1959. Earle, D. P , et al.: Low potassium syndrome due to defective renal tubular mechanisms for handling potassium, Am. J. Med. 11 : 283, 1951. Edmonds, 13. J.: An aldosterone antagonist and diuretics in the treatment of chronic oedema and aseites, Lancet 1:509, 1960. Foye, L. V., Jr., and Feichtmeir, T. V.: Adrenal cortical carcinoma producing solely mlneraloeortieold effects Am. J. Med. 19:966, 1955. Genest~ J.: Anglotensin, aldosterone and human arterial hypertension, Canad. M. A. J. 84:403, 1961. Gifford, R. W., Jr., Mattox, V. R., el al.: Effect of thiazlde diuretles on plasma volume, body electrolytes, and excretion of aldosterone of hypertensive patients, Circulation 22:755~ 1960. Gowenlock~ A. tI., and Wrong, O.: Ityperaldosteronlsm secondary to renal isehemia, Quart. J. Med. 31:323, 1962. Greenough, W. B., III., et al.: Correction of hyperaldosteronism and of massive fluid retention of unknown cause by sympathomimetie agents, Am. J. Med. 33:603, 1962. Holten, 13., and Petersen~ V. P.: Malignant hypertension with increased secretion of aldosterone and depletion of potassium, Lancet 2:918, 1956. 45

Hudson, J. B., Chobanian, A. V., and Relman, A. S.: Hypoaldosteronism: A clinical study of a patient with an isolated adrenal mineraloeortlcold deficiency, resulting in hyperkalemla and Stokes-Adams attacks, New England J. Med. 257:529, 1957. Laidlaw, J. C., Yendt, E. R., and Gornall, A. G.: Hypertension caused by renal artery occlusion simulating primary aldosteronlsm, Metabolism 9:612, 1960. Landau, R. L., and Lugibihl, K.: Inhibition of the sodium-retalnlng influence of aldosterone by progesterone, J. Clin. Endocrinol. 18: 1237, 1958. Laragh, J. H.: Interrelationships between anglotensln, noreplnephrlne, epinephrine, aldosterone secretion, and electrolyte metabolism in man, Circulation 25:203, 1962. Luetscher, J. A., et al.: Observations on metabolism of aldosterone in man, Ann. Int. Med. 59:1, 1963. Mach, R. S., et al.: Oed~mes par r&ention de chlorure de sodium avec hyperaldost&onurie, Schweiz. reed. Wchnschr. 85:1229, 1955. Muller, A. F., Manning, E. L., and Riondel, A. M.: Influence of position and activity on the secretion of aldosterone, Lancet 1:711, 1958. ~fulrow, P. J., Ganong, ~,V. F., and Boryczka, A.: Further evidence for a role of the renin-anglotensin system in regulation of aldosterone secretion, Proe. Soc. Exper. Biol. & Med. 112:7, 1963. Peters, J. P.: The role of sodium in the production of edemas New England J. Med. 239:353, 1948. Schwartz, W. B.: Potassium and the kidney, New England J. Med. 253: 601, 1955. Skanse, B., and H6kfelt, B.: Hypoaldosteronlsm with otherwise intact adrenocortlcal function, resulting in a characteristic clinical entity, Acta endocrlnol. 28:29, 1958. Splnk, W. W., and Vick, J. A.: Reversal of experimental endotoxin shock with a combination of aldosterone and metaramlnol, Proc. Soc. Exper. Biol. & Med. 107:777, 1961. Talt, J. F., et al.: The metabolic clearance rate of aldosterone in pregnant and nonpregnant subjects estimated by both slngle-injection and constant-infusion methods, J. Glin. Invest. 41:2093, 1962. Thorn, G. W., et al.: Clinical studies on bilateral complete adrenalectomy in patients with severe hypertensive vascular disease, Ann. Int. Med. 37:972, 1952. Toblan, L.: Interrelationships of electrolytes, juxtaglomerular cells, and hypertension, Physiol. Rev. 40:280, 1960. Venning, E. H., Dyrenfurth, I., and Giroud, C. J. P.: Aldosterone excretion in healthy persons, J. Clin. Endocrinol. 16:1326, 1956. Watanabe, M., et al.: Secretion rate of aldosterone in normal pregnancy, J. C1in. Invest. 42:1619, 1963. Wright, R. D.: Control of secretion of aldosterone, Brit. M. Bull. 18:159, 1962. 46