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Disorders of Antidiuretic Hormone Secretion
Disorders of Antidiuretic Hormone Secretion ROBERT D. UTIGER, M.D.*
The proper functioning of mechanisms designed to maintain normal water balance in man is of utmost importance in maintaining homeostasis. Abnormalities of such mechanisms lead to the development of several dramatic and potentially life-threatening disorders. It is the purpose of the present paper to review the factors responsible for the maintenance of normal water balance, describe the clinical syndromes resulting when these mechanisms are impaired and, lastly, to discuss the diagnosis and management of such disorders.
ANTIDIURETIC HORMONE SECRETION Although antidiuretic hormone-hereafter referred to by its chemical name, arginine vasopressin (AVP)-is secreted from the neurohypophysis, it is now recognized that this is only the final step of a complicated neurosecretory process?! The neurohypophyseal system consists of neurons whose cell bodies are grouped together in the supraoptic and paraventricular nuclei of the anterior hypothalamus. The axons of these neurons pass from the hypo thalamus and through the pituitary stalk and then terminate in swellings next to capillaries in the posterior pituitary gland (Fig. 1). These neuronal cell bodies and their axons contain characteristic dense granules about 0.1 to 0.3 J1- in diameter, which are referred to as neurosecretory granules (NSG). These granules are apparent by light microscopy in aggregated form as neurosecretory material (NSM). Since alterations of both NSG and NSM in the neurohypophyseal system can be correlated with the hormone content of the posterior pituitary and the state of hydration of the animal, it is presumed that they contain AVP and oxytocin, in association with some carrier protein. There is now considerable evidence that AVP and oxytocin and, indeed, the neurosecretory granules, are formed within the cell bodies in the hypo thalamic nuclei. The formed polypeptide hormone is transported down the axons of the neurohypophyseal tract to storage sites in the nerve endings in the posterior pituitary. These concepts have been established by several types of data. Histological studies after stalk section indicate accumulation of NSG on the proximal side of the severed neurons and thus indicate that the flow of NSG is from hypothalamus to pituitary. NSM and A VP disappear from the portions of the neurosecretory system distal to such lesions. Furthermore, a series of elegant studies 'Metabolism Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
Medical Clinics of North America- Vo!. 52, No. 2, March, 1968
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Third Ventricle
Posterror plfultary Anteflor pituitary
Figure 1.
Schematic drawing of the neurohypophyseal system.
by Sachs and his associates 21l have indicated that, when 35S-cys teine Ca structural component of AVP) is infused into the third ventricle of a dog, the AVP isolated from the hypothalamus has a specific activity several times greater than that found in the posterior pituitary. Also it has been shown that in vitro hypo thalamic tissue will incorporate :15S-cysteine into AVP, whereas the distal parts of the neurohypophyseal system will not. Hence there is both morphological and biochemical evidence that AVP is produced within the hypothalamus and then is transported to the posterior pituitary, from which it is secreted. What factors regulate the secretion of AVP into the plasma? The central role of AVP in the regulation of osmotic pressure in the extracellular fluid has been recognized since the experiments of Verney.28 There are osmoreceptors sensitive to changes in extracellular fluid CECF) osmolality, located by Jewell and Verney'" somewhere in the distribution of the internal carotid artery. These osmoreceptors are sufficiently sensitive that increases in plasma osmolality of as little as 2 per cent are sufficient to increase AVP secretion and initiate antidiuresis. In man, Aubry and co-workers2 have recently shown that the threshold above which AVP secretion is stimulated is about 288 to 290 mOsm. per liter. Conversely, reduction in plasma osmolality rapidly decreases AVP secretion. Another major regulator of AVP secretion is ECF volume: reduced ECF volume results in increased AVP secretion, whereas increased ECF volume inhibits it. It has been shown by Share 24 that reduction in blood volume of as little as 10 per cent results in increased secretion of AVP. The location of the volume receptors mediating this response is unclear; evidence for atrial, aortic and carotid receptors has been obtained. 24 It appears that regulation of AVP secretion by volume changes takes precedence over control by osmoreceptor stimulation, since plasma hypo-osmolality does not diminish the stimulation of AVP release induced by volume depletion. Although these are the major physiological regulators of AVP secretion, other stimuli such as stress, pain and a variety of pharmacological agents such as ether, nicotine and other drugs are also known to stimulate AVP release.
METABOLISM AND ACTION OF AVP Most data concerning plasma levels of AVP have been obtained by bioassay procedures, the most satisfactory of which measures the antidiuretic activity of plasma or extracts therefrom in the rat. From such studies it appears that the concentration of AVP in plasma of normally hydrated subjects is about 1 ]LU. per ml. Studies employing such methods have confirmed suspicions from indirect measurements that AVP in-
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creases rapidly in response to plasma hyperosmolality or volume reduction. For example, Czaczkes and co-workers 8 reported plasma A VP concentrations of 2 to 4 ILU. per ml. after 3 to 4 hours of dehydration; the AVP concentration increased to 10 ILU. per ml. after 16 hours and to 18 ILU. per ml. after 24 hours of dehydration. Similar results have been reported by others.t.30 Furthermore, plasma AVP activity declines even more rapidly after rehydration. s In addition, studies on the disappearance of both endogenous AVP after administration of an acute water load or exogenously administered AVP indicate a rapid turnover (plasma half-time of 10 to 15 minutes), which is more rapid when dehydration is present and plasma AVP concentrations are higher. 7 The major biological action of AVP is to promote the formation of a concentrated urine. Normally, some 80 per cent of the glomerular filtrate is reabsorbed in the proximal tubule. In the loop of Henle, sodium, chloride and, to a lesser extent, water are reabsorbed. Thus, urine reaching the distal tubule is hypotonic. AVP acts on the distal tubule and perhaps the collecting duct to increase the permeability of these parts of the nephron to water. This increase in permeability allows movement of water into the hypertonic renal medullary interstitial space. In the absence of AVP, these segments of the nephron remain impermeable to water; thus large volumes of dilute urine are excreted. While there is evidence that A VP may also reduce cutaneous, salivary and gastrointestinal water secretion,2!' the importance of these effects is not clear. Virtually all of the homeostatic effects of A VP and the abnormalities related to its deficiency may be explained on the basis of its renal action. Finally, though AVP also has vasopressor activity, this is demonstrable only after administration of pharmacologic quantities. While the overall renal effects of AVP are well understood today, much remains to be learned about its biochemical mode of action. Current evidence favors the hypothesis that it increases the quantity of adenosine 3',5'-phosphate (cyclic 3' ,5' -AMP) in the renal tubular cell by enhancing its formation from ATP by the enzyme adenylcyclase. w Cyclic 3',5'-AMP has been shown to produce virtually all of the biological effects of AVP and, furthermore, appears to be the mechanism by which a number of hormones exert their effects in other tissues. How changes in cell content of this nucleotide produce physical changes resulting in increased cellular water permeability remains obscure.
POLYURIC SYNDROMES A number of pathophysiological abnormalities may be responsible for a persistent increase in urine flow. These may be generally divided into polyuric syndromes due to diminished secretion of AVP and those due to impaired ability of the kidney to respond to AVP. The disorders that may be responsible for polyuria are outlined in Table 1. Any lesion which damages the neurohypophyseal system can result in diabetes insipidus. However, since certain of the hypothalamicneurohypophyseal tract fibers terminate in the pituitary stalk (Fig. 1), lesions involving just the posterior pituitary may leave a sufficient number of inta~t nerve fibers to permit normal storage and release of
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Table 1.
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Classification of Polyu fie Syndromes
Poly"ria rill" to r.. d"ced prodllctio/l o/AVP
Diseases involving the hypothalamic-neurohypophyseal system (diabetes insipidus) Reduced secretion of A VP secondary to increased thirst (psychogenic polydipsia)
Pol!Jllria cllle to structural or dynamic renal a/marmalities
Disease in which there is impaired renal tubular responsiveness to AVP Congenital nephrogenic diabetes insipidus Multiple renal tubular functional abnormalities (Fanconi's syndrome) Acquired tubular lesions (hypokalemia, hypercalcemia) Diseases producing an osmotic diuresis (diabetes mellitus, chronic renal insufficiency) Disease producing reduced renal medullary tonicity so that the osmotic gradient across the distal tu bule is reduced (psychogenic polydipsia, renal arterial disease, sickle cell anemia)
AVP. Studies in animals with lesions of the neurohypophyseal tract indicate that severe diabetes insipidus does not occur until about 90 per cent of the cells in the hypothalamic nuclei are destroyed. There are many causes of diabetes insipidus in man (Table 2). They include a variety of systemic and intracranial diseases. s Increasingly common is diabetes insipidus as a consequence of hypophysectomy, pituitary stalk section or other procedures designed to ablate pituitary function. Most series also include a considerable number (30 to 45 per cent) of cases of idiopathic diabetes insipidus,5.2H a small proportion of which occur in a familial pattern. In the few of these patients examined pathologicallyH only loss of cells or neuronal degeneration in the hypothalamic nuclei has been found. It is possible, however, that some of these cases are due to genetic defects in hormone synthesis such that a polypeptide is produced with an amino acid substitution, which thus has no antidiuretic activity. Immunological methods now becoming available may help to answer such questions.17 The onset of polyuria in spontaneous diabetes insipidus is characteristically abrupt. Urine volumes generally range from 4 to 8liters daily, Table 2.
Causes of Diabetes Insipidus
Intracranial Lesions
Pituitary tumor Primary brain tumor Metastatic tumor-leukemia Trauma Cerebral vascular disease
Systemic Dis()rtlf'}"s
Histiocytosis Sarcoidosis Infectious diseases
Iatrogenic
Hypophysectomy Pituitary stalk section C ryohypophysectomy Implantation of radioactive materials into the sella turcica
Idiopathic
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but larger volumes occasionally occur, and on occasion the diagnosis may be made when the urine volume is only 3 to 4 liters per day. Presumably such patients can secrete some AVP, but not normal quantities. Accompanying the polyuria are associated signs of nocturia and frequent urination. Less significant polyuria will occur when there is anterior pituitary insufficiency. Detailed observations are now available concerning the several patterns of polyuria that may occur after surgical procedures in and about the pituitary region. 18 In some patients polyuria lasts only a few days and then urine-concentrating ability returns to normal. Presumably in such patients there is minor damage to the neurohypophyseal system with full recovery thereafter. Other patients have immediate postoperative polyuria, followed by a period (usually lasting 4 to 7 days) in which urine volumes are normal; only then do they develop permanent polyuria. The development of this interphase characterized by normal urinary output is thought to represent release of AVP from the denervated posterior lobe of the pituitary. Thus, after the stored hormone is liberated, permanent polyuria ensues. Finally, some patients develop permanent polyuria immediately after operation. In them, presumably, the neurohypophyseal tract has been completely destroyed and the posterior pituitary removed. Thirst is a vital compensatory mechanism in polyuric patients. Considerable evidence indicates that there is a hypothalamic thirst center located near or at least closely connected to the hypothalamicneurohypophyseal system. It is activated by the same type of stimuliincreased plasma osmolality or reduced extracellular fluid volume - that stimulate the secretion of AVP. Increased thirst or polydipsia, then, is the mechanism by which patients with various polyuric syndromes compensate for their excessive water loss. Characteristic of the polydipsia of diabetes insipidus is the preference for water, rather than other beverages, and the desire for ice water.26 So long as such patients are able to gratify their thirst, dehydration and its consequences do not occur. In normal circumstances the only inconvenience of a polyuric syndrome is the requirement for frequent water ingestion and urination. When, however, thirst cannot be gratified, serious dehydration may result. This can occur when consciousness is altered by anesthetic agents or trauma. The mucous membranes become dry, skin turgor is poor and evidence of circulatory collapse develops. Inadequate compensation of a polyuric syndrome is present whenever hypernatremia (and thus hyperosmolality) is found. Usually such patients will be quite ill, and the hypernatremia is a result of inadequate water replacement by the physician in the patient who cannot express or satisfy his thirst. Occasional patients have been encountered, however, with marked hypernatremia, a normal state of consciousness and little or no increase in thirst.;),2:1 This situation, usually accompanied by diabetes insipidus, is generally a result of extensive hypothalamic disease. Presumably the hyperosmolar state is well tolerated in such patients because its onset has been gradual. The alterations in cell membrane permeability which allow such a patient to appear normal have not been defined.
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DIAGNOSIS OF POLYURIC DISORDERS Usually a careful history, physical examination and selected laboratory tests will readily allow the proper diagnosis in these patients. Polyuria due to hypercalcemia, hypokalemia and renal disease is usually mild; its presence is not volunteered by the patient, but must be sought by the clinician. These disorders usually impair maximal concentrating ability rather than leading to elaboration of persistently hypotonic urine. The three Ipajor polyuric syndromes which must be differentiated are diabetes insipidus, psychogenic polydipsia (or compulsive water drinking) and congenital hereditary nephrogenic diabetes insipidus. The latter is an X-linked disorder with onset usually very shortly after birth. The clinical differences between patients with diabetes insipidus and those with psychogenic polydipsia have been nicely pointed out by de Wardener.9 Patients with the latter disorder are usually females with a long history of psychosomatic and other complaints and do not complain of thirst and polyuria. However, it does occur in association with severe organic disease. 25 A large number of diagnostic procedures have been devised to further evaluate patients with polyuria, since measurements of plasma A VP are not available. The purpose of these procedures is to determine whether urine concentration can occur following an osmotic load and, if not, to determine whether this defect in urinary concentration is due to failure of A VP secretion or to failure of its action on the kidney. First, it should be pointed out that measurement of plasma osmolality in the basal state may provide useful information.!) Normally plasma osmolality is quite closely maintained between 275 and 290 mOsm. per liter. If osmolality measurements are unavailable, plasma osmolality may be closely approximated by doubling the plasma sodium concentration and adding 10 (in the absence of abnormal amounts of glucose or urea). In a patient with hypophyseal or nephrogenic diabetes insipidus, plasma osmolality may be high, since the primary event is loss of water, and compensation through increased thirst may not be complete. On the other hand, in psychogenic polydipsia the plasma osmolality may be decreased. WATER DEPRIVATION. The classic provocative test is the restriction of water intake. Since prolonged dehydration may lead to serious sequelae in the severely polyuric patient, this test is best performed in the daytime, when careful supervision is possible, and water deprivation should not be continued after 3 to 5 per cent of body weight has been lost. Normally urine flow will fall to less than 1 ml. per min. and urine osmolality will rise to over 600 mOsm. per liter after 6 hours of water deprivation. Plasma osmolality should not increase. In contrast, urine flow rates remain high, plasma osmolality increases and urine osmolality rises little in patients with diabetes insipidus. Typical results of water deprivation testing in a patient with diabetes insipidus recently studied at Barnes Hospital are shown in Figure 2. In certain patients greater reduction in urine flow and urine osmolality values of 400 to 500 mOsm. per liter may be found when severe dehydration has occurred. Such
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t Water
Figure 2. Changes in urine flow, plasma and serum osmolality and body weight in a patient with diabetes insipidus during a period of water deprivation. Basal 24hour fluid intake and urine output volumes in this patient ranged from 3'12 to 5 liters daily.
WEIGHT (/bs)
122
OSMOLALITY Plasma Urine ( mOsm/Ll
287
200
U R I NE VOLUME (ml/hr)
Deprivation Begun
118~ 306
3i9
~
100
°0L-~~2--L-~4--L-~6L-~-8L-~
HOURS
patients may be said to have partial neurohypophyseal insufficiency. While most patients with psychogenic polydipsia will respond normally to such osmotic stress, occasional patients may not. This may be a result of chronic suppression of AVP release or vasopressin resistanceprobably due to the reduction of renal medullary hypertonicity that is caused by chronic polydipsia and polyuria. SALINE INFUSION. The alternative means of increasing plasma osmolality to attempt to stimulate AVP release is by the infusion of hypertonic saline. As formulated by Hickey and Hare,!2 0.25 m!. of 2.5 per cent sodium chloride per kg. per minute is infused over a 45-minute period in a previously well-hydrated patient. Measurements of urine volume at 15-minute intervals and frequent measurements of urine and plasma osmolality should be made, the latter to ensure that plasma osmolality has increased sufficiently above the threshold required (to at least 295 mOsm. per lit er) to produce AVP secretion normally.!5 As after water deprivation, normal subjects and those with psychogenic polydipsia should have a 75 per cent or more fall in urine flow rate and a prompt increase in urine osmolality. If these tests do not elicit an antidiuretic response, the ability of the renal tubule to respond to AVP must then be examined. Since the responses to single doses of AVP are variable and may be transitory, it is wise to infuse AVP at a rate of 5 mU. per minute for 60 minutes. In diabetes insipidus or psychogenic polydipsia there will be a prompt fall in urine volume and a rise in urine osmolality. Furthermore, thirst will usually dramatically decrease. Alternatively, 5 U. of pitressin tannate in oil may be given at bedtime. Urine testing the following day should reveal maximal antidiuresis. The patient may well comment that for the first time in months he did not awaken to urinate and drink water.
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Diabetes insipidus may be managed by intranasal insufflation of posterior pituitary powder, pitressin nasal spray or subcutaneous injection of pitressin tannate in oil. Commercially available pitressin is a partially purified mixture of porcine and bovine pituitary powders; it thus contains lysine and arginine vasopressin. Patients with mild cases often may not require any therapy. There are no fixed dosage rules; treatment is generally given in 0.5 to 1 U. doses intranasally and 5 U. doses parenterally and repeated when thirst and polyuria recur. Intranasal therapy is generally required two to four times daily, and, especially with the powder, may produce an aggravating rhinitis. Parenteral therapy need be given only once every 2 to 4 days; care should be taken that the solution is warmed and well mixed before injection to ensure correct dosage. Synthetic lysine vasopressin has been used intranasally and found both effective and free of the side effects of other intranasal preparations. l1 • \4 It should become available in the near future. While development of antibody to lysine vasopressin during treatment has been reported/ 9 its presence has not been shown to increase replacement requirements.
INAPPROPRIATE SECRETION OF ANTIDIURETIC HORMONE In 1957, a syndrome of hyponatremia with increased urinary sodium excretion was recognized in several patients with carcinoma of the lung by Schwartz and associates. 22 Since then many additional cases have been recognized and a similar syndrome has been reported in patients with non-neoplastic disorders, usually involving the central nervous system .. The major findings in such patients consist of (1) hypo-osmolality of the serum, primarily due to reduction in plasma sodium and chloride concentrations (the concentration of other plasma electrolytes is usually normal); (2) the presence of significant amounts of sodium in the urine; (3) clinical signs of normal or perhaps increased hydration; (4) urine that is hypertonic in relation to the plasma; and (5) normal renal, cardiac and adrenal function. The symptoms of this syndrome are quite variable. If the plasma sodium concentration is above 120 mEq. per lit er, there may be none. When the plasma sodium is lower, symptoms such as anorexia, nausea and vomiting, and central nervous system signs such as apathy, confusion and ultimately coma, may occur. This syndrome should be suspected in any patient with significant hyponatremia and hypo-osmolality. Most patients with moderate or severe hyponatremia will, if adrenal and renal salt-retaining mechanisms are intact, elaborate a virtually sodium-free urine. Only in patients inappropriately secreting AVP and those with adrenal or salt-wasting renal disease will the urine contain appreciable amounts of sodium. The latter causes of hyponatremia are usually associated with signs of extracellular fluid deficit and, in addition, may be confirmed by simple laboratory tests. The pathogenesis of the syndrome of inappropriate secretion of anti-
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diuretic hormone may be outlined as follows (Table 3). When fluid intake is unrestricted, secretion of AVP leads to water retention, resulting in increased extracellular fluid volume and thus dilution of the plasma with hypo-osmolality, hyponatremia and hypochloremia. The resultant hypervolemia leads to reduction in aldosterone secretion by the adrenal gland, increased glomerular filtration rate and increased production of "third factor." This latter material is a postulated hormone of currently unknown origin. Its elaboration at times of ECF volume surfeit is thought to be responsible for the diminution of proximal tubular sodium reabsorption known to occur at such times.lO Natriuresis may result from all three phenomena. Since aldosterone secretion and excretion rates are normal, and not depressed, and glomerular filtration is not markedly increased in these patients, the "third factor" effect is probably the more important in producing the sodium diuresis. In general, net sodium deficit is. not present, although when hyponatremia is severe in a patient who is not extremely overhydrated, sodium loss probably has occurred. However, therapeutic administration of sodium usually leads simply to its prompt appearance in the urine and only a transient rise in plasma sodium concentration. The therapy of choice in this situation is water restriction. Following its institution, body weight falls and plasma sodium concentration rises rapidly. Serial measurements of plasma and urine sodium and osmolality, and the response to water restriction, in such a patient with carcinoma of the lung studied at Barnes Hospital are shown in Figure 3. 27 The most frequent cause of inappropriate secretion of AVP is malignant neoplasms of nonendocrine tissue. Most, but not all, of the cases reported have been in patients with carcinoma of the lung, usually of the oat-cell or anaplastic type. In a number of these patients, AVP has Table 3.
Physiology of the Syndrome of Inappropriate Secretion of Antidiuretic Hormone H 2 0 ingestion
+ Increased secretion of AVP
t
Enhanced renal water reabsorption
/
Expansi on of ECF volume
~ Urine hypertonic to plasma
~{DiminiShed ~
aldosterone secretion } Increased glomerular filtration rate Increased secreti on of "thi rd factor"
Plasma hypoosmolality (Hyponatremial
Natri uresi s
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FLUID INTAKE SURGERY LIMITED
t t
OSMOLALITY Plasma Urine (mOsm/U
264 95
265 241 604 514
URINE NO""
57
103
(meq/doy)
93
140
Figure 3. Serial plasma and urine osmolality and sodium data in a patient with an AVP-secreting carcinoma of the lung. Note the response to fluid restriction. (Reproduced from Utiger.")
PLASMA NoT 120-/-~ (meq/U
~ 100 L-~I__~__~__L-~I__- k__-L__L 4
12
20
HOSPITAL DAY
28
been identified by biological or immunological techniques in the tumor tissue, and increased serum or urine levels of AVP have also been occasionally found. Also, in the tumor studied here,27 electron microscope studies showed material in the tumor cells similar to neurohypophyseal neurosecretory granules. Other causes of this syndrome include a variety of central nervous disorders, such as meningitis, trauma, brain tumors and acute intermittent porphyria, and disorders such as myxedema, pulmonary tuberculosis and other lung lesions. 4 These lesions probably lead to excessive secretion of AVP from the hypothalamicneurohypophyseal system, perhaps by altering normal neuronal inflow into the system or by direct stimulation of it. In any event, the clinical picture is similar to that of patients with AVP-secreting nonendocrine tumors and the therapy of the fluid and electrolyte abnormalities per se is the same.
REFERENCES J. F.: Increased plasma arginine vasopressin in clinical adrenocortical insufficiency and its inhibition by glucosteroids. J. Clin. Invest., 46:111, 1967. Aubry, R. H., Nankin, H. R., Moses, A. M., and Streeten, D. H. P.: Measurement of the osmotic threshold for vasopressin release in human subjects, and its modification by cortisol. J. Clin. Endocrinol., 25:1481, 1965. Avioli, L. V., Earley, L. E., and Kashima, H. K.: Chronic and sustained hypernatremia, absence of thirst, diabetes insipidus, and adrenocorticotropin insufficiency resulting from widespread destruction of the hypothalamus. Ann. Int. Med., 56: 131, 1962. Bartter, F. C., and Schwartz, W. B.: The syndrome of inappropriate secretion of antidiuretic hormone. Amer. J. Med., 42:790,1967. Blotner, H.: Diabetes insipidus. In Christian, H. A., ed.: Oxford Medicine. New York, Oxford University Press, 1950, Vol. 4, p. 179.
1. Ahmed, A. B. J., George, B. C., Gonzalez-Auvert, C., and Dingman,
2. 3. 4. 5.
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6. Braverman, L. K, Mancini, J. P., and McGoldrick, D. M.: Hereditary idiopathic diabetes insipidus. Ann. Int. Med., 63:503, 1965. 7. Czaczkes, J. W., and Kleeman, C. R.: The effect of various states of hydration and the plasma concentration on the turnover of antidiuretic hormone in mammals. J. Clin. Invest., 43:1649,1964. 8. Czaczkes, J. W., Kleeman, C. R., and Koenig, M.: Physiologic studies of antidiuretic hormone by its direct measurement in human plasma. J. Clin. Invest., 43:1625,1964. 9. de Wardener, H. P.: Polyuria. J. Chron. Dis., 11:199, 1960. 10. de Wardener, H. E., Mills, I. H., Clapham, W. F., and Hayter, C. J.: Studies on the efferent mechanism of the sodium diuresis which follows the administration of intra venous saline in the dog. Clin. Sci., 21 :249, 1961. 1l. Dingman, J. F., and Hauger-Klevene, J. H.: Treatment of diabetes insipidus with synthetic lysine vasopressin. J. Clin. Endocrinol., 24:550, 1964. 12. Hickey, R. C., and Hare, K: The renal excretion of chloride and water in diabetes insipidus. J. Clin. Invest., 23:768, 1944. 13. Jewell, P. A., and Varney, E. B.: An experimental attempt to determine the site of the neurohypophyseal osmoreceptors in the dog. Phil. Trans. Ray. Soc. London, 240: 197, 1957. 14. Moses, A. M.: Synthetic lysine vasopressin nasal spray in treatment of diabetes insipidus. Clin. Pharmacol. and Therap., 5:422, 1964. 15. Moses, A. M., Streeten, D. H. P.: Differentiation of polyuric states by measurement of responses to changes in plasma osmolality induced by hypertonic saline infusions. Amer. J. Med., 42:368, 1967. 16. Orloff, J., and Handler, J.: The role of adenosine-3',5'-phosphate in the action of antidiuretic hormone. Amer. J. Med., 42:757, 1967. 17. Permutt, M. A., Parker, C. W., and Utiger, It D.: Immunochemical studies with lysine vasopressin. Endocrinology, 78:809, 1966. 18. Randall, R. V., Jr., Clark, E. C., Dodge, H. W., Jr., and Love, J G.: Polyuria after operation for tumors in the region of the hypophysis and hypothalamus. J. Clin. Endocrinol., 20: 1614, 1960. 19. Roth, J., Glick, S. M., Klein, Le A., and Peterson, M. J.: Specific antibody to vasopressin in man. J. Clin. Endocrinol., 26:671, 1966. 20. Sachs, H.: Biosynthesis and release of vasopressin. Amer. J Med., 42:687, 1967. 2l. Scharrer, E., and Scharrcr, B.: Hormones produced by neurosecretory cells. Rec. Progr. Hormone Res., 10:183, 1954. 22. Schwartz, W. B., Bennett, W., Curelop, S., and Bartter, F. C.: A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. Amer. J. Med., 23:529, 1957. 23. Segar, W. E.: Chronic hyperosmolality. Amer. J. Dis. Child., 112:318,1966. 24. Share, L.: Vasopressin, its bioassay and the physiological control of its release. Amer. J. Med., 42:701, 1967. 25. Sitprija, V., Pochanugool, C., Benyajati, C., and Suwanwela, C.: Polydipsia and polyuria associated with quadriplegia. Ann. Int. Med., 65:62, 1966. 26. Thomas, W. C., Jr.: Diabetes insipidus. J. Clin. Endocrinol., 17:565, 1957. 27. Utiger, R. D.: Inappropriate antidiuresis and carcinoma of the lung: Detection of arginine vasopressin in tumor extracts by immunoassay. J. Clin. Endocrinol., 26:970, 1966. 28. Vcrney, E. B.: The antidiuretic hormone and the factors which determine its release. Proc. Roy. Soc. Med., 135:25, 1947. 29. Wakim, K G.: Reassessment of the source, mode and locus of action of antidiuretic hormone. Amer. J. Med., 42:394, 1967. 30. Yoshida, S., Motohashi, K, Ibayashi, H., and Okinaka, S.: Method for the assay of antidiuretic hormone in plasma with a note on the antidiuretic titer of human plasma. J. Lab. Clin. Med., 62:279, 1963. 660 S. Euclid Avenue St. Louis, Missouri 63110
The proper functioning of mechanisms designed to maintain normal water balance in man is of utmost importance in maintaining homeostasis. Abnormalities of such mechanisms lead to the development of several dramatic and potentially life-threatening disorders. It is the purpose of the present paper to review the factors responsible for the maintenance of normal water balance, describe the clinical syndromes resulting when these mechanisms are impaired and, lastly, to discuss the diagnosis and management of such disorders.
ANTIDIURETIC HORMONE SECRETION Although antidiuretic hormone-hereafter referred to by its chemical name, arginine vasopressin (AVP)-is secreted from the neurohypophysis, it is now recognized that this is only the final step of a complicated neurosecretory process?! The neurohypophyseal system consists of neurons whose cell bodies are grouped together in the supraoptic and paraventricular nuclei of the anterior hypothalamus. The axons of these neurons pass from the hypo thalamus and through the pituitary stalk and then terminate in swellings next to capillaries in the posterior pituitary gland (Fig. 1). These neuronal cell bodies and their axons contain characteristic dense granules about 0.1 to 0.3 J1- in diameter, which are referred to as neurosecretory granules (NSG). These granules are apparent by light microscopy in aggregated form as neurosecretory material (NSM). Since alterations of both NSG and NSM in the neurohypophyseal system can be correlated with the hormone content of the posterior pituitary and the state of hydration of the animal, it is presumed that they contain AVP and oxytocin, in association with some carrier protein. There is now considerable evidence that AVP and oxytocin and, indeed, the neurosecretory granules, are formed within the cell bodies in the hypo thalamic nuclei. The formed polypeptide hormone is transported down the axons of the neurohypophyseal tract to storage sites in the nerve endings in the posterior pituitary. These concepts have been established by several types of data. Histological studies after stalk section indicate accumulation of NSG on the proximal side of the severed neurons and thus indicate that the flow of NSG is from hypothalamus to pituitary. NSM and A VP disappear from the portions of the neurosecretory system distal to such lesions. Furthermore, a series of elegant studies 'Metabolism Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
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Third Ventricle
Posterror plfultary Anteflor pituitary
Figure 1.
Schematic drawing of the neurohypophyseal system.
by Sachs and his associates 21l have indicated that, when 35S-cys teine Ca structural component of AVP) is infused into the third ventricle of a dog, the AVP isolated from the hypothalamus has a specific activity several times greater than that found in the posterior pituitary. Also it has been shown that in vitro hypo thalamic tissue will incorporate :15S-cysteine into AVP, whereas the distal parts of the neurohypophyseal system will not. Hence there is both morphological and biochemical evidence that AVP is produced within the hypothalamus and then is transported to the posterior pituitary, from which it is secreted. What factors regulate the secretion of AVP into the plasma? The central role of AVP in the regulation of osmotic pressure in the extracellular fluid has been recognized since the experiments of Verney.28 There are osmoreceptors sensitive to changes in extracellular fluid CECF) osmolality, located by Jewell and Verney'" somewhere in the distribution of the internal carotid artery. These osmoreceptors are sufficiently sensitive that increases in plasma osmolality of as little as 2 per cent are sufficient to increase AVP secretion and initiate antidiuresis. In man, Aubry and co-workers2 have recently shown that the threshold above which AVP secretion is stimulated is about 288 to 290 mOsm. per liter. Conversely, reduction in plasma osmolality rapidly decreases AVP secretion. Another major regulator of AVP secretion is ECF volume: reduced ECF volume results in increased AVP secretion, whereas increased ECF volume inhibits it. It has been shown by Share 24 that reduction in blood volume of as little as 10 per cent results in increased secretion of AVP. The location of the volume receptors mediating this response is unclear; evidence for atrial, aortic and carotid receptors has been obtained. 24 It appears that regulation of AVP secretion by volume changes takes precedence over control by osmoreceptor stimulation, since plasma hypo-osmolality does not diminish the stimulation of AVP release induced by volume depletion. Although these are the major physiological regulators of AVP secretion, other stimuli such as stress, pain and a variety of pharmacological agents such as ether, nicotine and other drugs are also known to stimulate AVP release.
METABOLISM AND ACTION OF AVP Most data concerning plasma levels of AVP have been obtained by bioassay procedures, the most satisfactory of which measures the antidiuretic activity of plasma or extracts therefrom in the rat. From such studies it appears that the concentration of AVP in plasma of normally hydrated subjects is about 1 ]LU. per ml. Studies employing such methods have confirmed suspicions from indirect measurements that AVP in-
DISORDERS OF ANTIDIURETIC HORMONE SECRETION
383
creases rapidly in response to plasma hyperosmolality or volume reduction. For example, Czaczkes and co-workers 8 reported plasma A VP concentrations of 2 to 4 ILU. per ml. after 3 to 4 hours of dehydration; the AVP concentration increased to 10 ILU. per ml. after 16 hours and to 18 ILU. per ml. after 24 hours of dehydration. Similar results have been reported by others.t.30 Furthermore, plasma AVP activity declines even more rapidly after rehydration. s In addition, studies on the disappearance of both endogenous AVP after administration of an acute water load or exogenously administered AVP indicate a rapid turnover (plasma half-time of 10 to 15 minutes), which is more rapid when dehydration is present and plasma AVP concentrations are higher. 7 The major biological action of AVP is to promote the formation of a concentrated urine. Normally, some 80 per cent of the glomerular filtrate is reabsorbed in the proximal tubule. In the loop of Henle, sodium, chloride and, to a lesser extent, water are reabsorbed. Thus, urine reaching the distal tubule is hypotonic. AVP acts on the distal tubule and perhaps the collecting duct to increase the permeability of these parts of the nephron to water. This increase in permeability allows movement of water into the hypertonic renal medullary interstitial space. In the absence of AVP, these segments of the nephron remain impermeable to water; thus large volumes of dilute urine are excreted. While there is evidence that A VP may also reduce cutaneous, salivary and gastrointestinal water secretion,2!' the importance of these effects is not clear. Virtually all of the homeostatic effects of A VP and the abnormalities related to its deficiency may be explained on the basis of its renal action. Finally, though AVP also has vasopressor activity, this is demonstrable only after administration of pharmacologic quantities. While the overall renal effects of AVP are well understood today, much remains to be learned about its biochemical mode of action. Current evidence favors the hypothesis that it increases the quantity of adenosine 3',5'-phosphate (cyclic 3' ,5' -AMP) in the renal tubular cell by enhancing its formation from ATP by the enzyme adenylcyclase. w Cyclic 3',5'-AMP has been shown to produce virtually all of the biological effects of AVP and, furthermore, appears to be the mechanism by which a number of hormones exert their effects in other tissues. How changes in cell content of this nucleotide produce physical changes resulting in increased cellular water permeability remains obscure.
POLYURIC SYNDROMES A number of pathophysiological abnormalities may be responsible for a persistent increase in urine flow. These may be generally divided into polyuric syndromes due to diminished secretion of AVP and those due to impaired ability of the kidney to respond to AVP. The disorders that may be responsible for polyuria are outlined in Table 1. Any lesion which damages the neurohypophyseal system can result in diabetes insipidus. However, since certain of the hypothalamicneurohypophyseal tract fibers terminate in the pituitary stalk (Fig. 1), lesions involving just the posterior pituitary may leave a sufficient number of inta~t nerve fibers to permit normal storage and release of
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Table 1.
D.
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Classification of Polyu fie Syndromes
Poly"ria rill" to r.. d"ced prodllctio/l o/AVP
Diseases involving the hypothalamic-neurohypophyseal system (diabetes insipidus) Reduced secretion of A VP secondary to increased thirst (psychogenic polydipsia)
Pol!Jllria cllle to structural or dynamic renal a/marmalities
Disease in which there is impaired renal tubular responsiveness to AVP Congenital nephrogenic diabetes insipidus Multiple renal tubular functional abnormalities (Fanconi's syndrome) Acquired tubular lesions (hypokalemia, hypercalcemia) Diseases producing an osmotic diuresis (diabetes mellitus, chronic renal insufficiency) Disease producing reduced renal medullary tonicity so that the osmotic gradient across the distal tu bule is reduced (psychogenic polydipsia, renal arterial disease, sickle cell anemia)
AVP. Studies in animals with lesions of the neurohypophyseal tract indicate that severe diabetes insipidus does not occur until about 90 per cent of the cells in the hypothalamic nuclei are destroyed. There are many causes of diabetes insipidus in man (Table 2). They include a variety of systemic and intracranial diseases. s Increasingly common is diabetes insipidus as a consequence of hypophysectomy, pituitary stalk section or other procedures designed to ablate pituitary function. Most series also include a considerable number (30 to 45 per cent) of cases of idiopathic diabetes insipidus,5.2H a small proportion of which occur in a familial pattern. In the few of these patients examined pathologicallyH only loss of cells or neuronal degeneration in the hypothalamic nuclei has been found. It is possible, however, that some of these cases are due to genetic defects in hormone synthesis such that a polypeptide is produced with an amino acid substitution, which thus has no antidiuretic activity. Immunological methods now becoming available may help to answer such questions.17 The onset of polyuria in spontaneous diabetes insipidus is characteristically abrupt. Urine volumes generally range from 4 to 8liters daily, Table 2.
Causes of Diabetes Insipidus
Intracranial Lesions
Pituitary tumor Primary brain tumor Metastatic tumor-leukemia Trauma Cerebral vascular disease
Systemic Dis()rtlf'}"s
Histiocytosis Sarcoidosis Infectious diseases
Iatrogenic
Hypophysectomy Pituitary stalk section C ryohypophysectomy Implantation of radioactive materials into the sella turcica
Idiopathic
DISORDERS OF ANTIDIURETIC HORMONE SECRETION
385
but larger volumes occasionally occur, and on occasion the diagnosis may be made when the urine volume is only 3 to 4 liters per day. Presumably such patients can secrete some AVP, but not normal quantities. Accompanying the polyuria are associated signs of nocturia and frequent urination. Less significant polyuria will occur when there is anterior pituitary insufficiency. Detailed observations are now available concerning the several patterns of polyuria that may occur after surgical procedures in and about the pituitary region. 18 In some patients polyuria lasts only a few days and then urine-concentrating ability returns to normal. Presumably in such patients there is minor damage to the neurohypophyseal system with full recovery thereafter. Other patients have immediate postoperative polyuria, followed by a period (usually lasting 4 to 7 days) in which urine volumes are normal; only then do they develop permanent polyuria. The development of this interphase characterized by normal urinary output is thought to represent release of AVP from the denervated posterior lobe of the pituitary. Thus, after the stored hormone is liberated, permanent polyuria ensues. Finally, some patients develop permanent polyuria immediately after operation. In them, presumably, the neurohypophyseal tract has been completely destroyed and the posterior pituitary removed. Thirst is a vital compensatory mechanism in polyuric patients. Considerable evidence indicates that there is a hypothalamic thirst center located near or at least closely connected to the hypothalamicneurohypophyseal system. It is activated by the same type of stimuliincreased plasma osmolality or reduced extracellular fluid volume - that stimulate the secretion of AVP. Increased thirst or polydipsia, then, is the mechanism by which patients with various polyuric syndromes compensate for their excessive water loss. Characteristic of the polydipsia of diabetes insipidus is the preference for water, rather than other beverages, and the desire for ice water.26 So long as such patients are able to gratify their thirst, dehydration and its consequences do not occur. In normal circumstances the only inconvenience of a polyuric syndrome is the requirement for frequent water ingestion and urination. When, however, thirst cannot be gratified, serious dehydration may result. This can occur when consciousness is altered by anesthetic agents or trauma. The mucous membranes become dry, skin turgor is poor and evidence of circulatory collapse develops. Inadequate compensation of a polyuric syndrome is present whenever hypernatremia (and thus hyperosmolality) is found. Usually such patients will be quite ill, and the hypernatremia is a result of inadequate water replacement by the physician in the patient who cannot express or satisfy his thirst. Occasional patients have been encountered, however, with marked hypernatremia, a normal state of consciousness and little or no increase in thirst.;),2:1 This situation, usually accompanied by diabetes insipidus, is generally a result of extensive hypothalamic disease. Presumably the hyperosmolar state is well tolerated in such patients because its onset has been gradual. The alterations in cell membrane permeability which allow such a patient to appear normal have not been defined.
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DIAGNOSIS OF POLYURIC DISORDERS Usually a careful history, physical examination and selected laboratory tests will readily allow the proper diagnosis in these patients. Polyuria due to hypercalcemia, hypokalemia and renal disease is usually mild; its presence is not volunteered by the patient, but must be sought by the clinician. These disorders usually impair maximal concentrating ability rather than leading to elaboration of persistently hypotonic urine. The three Ipajor polyuric syndromes which must be differentiated are diabetes insipidus, psychogenic polydipsia (or compulsive water drinking) and congenital hereditary nephrogenic diabetes insipidus. The latter is an X-linked disorder with onset usually very shortly after birth. The clinical differences between patients with diabetes insipidus and those with psychogenic polydipsia have been nicely pointed out by de Wardener.9 Patients with the latter disorder are usually females with a long history of psychosomatic and other complaints and do not complain of thirst and polyuria. However, it does occur in association with severe organic disease. 25 A large number of diagnostic procedures have been devised to further evaluate patients with polyuria, since measurements of plasma A VP are not available. The purpose of these procedures is to determine whether urine concentration can occur following an osmotic load and, if not, to determine whether this defect in urinary concentration is due to failure of A VP secretion or to failure of its action on the kidney. First, it should be pointed out that measurement of plasma osmolality in the basal state may provide useful information.!) Normally plasma osmolality is quite closely maintained between 275 and 290 mOsm. per liter. If osmolality measurements are unavailable, plasma osmolality may be closely approximated by doubling the plasma sodium concentration and adding 10 (in the absence of abnormal amounts of glucose or urea). In a patient with hypophyseal or nephrogenic diabetes insipidus, plasma osmolality may be high, since the primary event is loss of water, and compensation through increased thirst may not be complete. On the other hand, in psychogenic polydipsia the plasma osmolality may be decreased. WATER DEPRIVATION. The classic provocative test is the restriction of water intake. Since prolonged dehydration may lead to serious sequelae in the severely polyuric patient, this test is best performed in the daytime, when careful supervision is possible, and water deprivation should not be continued after 3 to 5 per cent of body weight has been lost. Normally urine flow will fall to less than 1 ml. per min. and urine osmolality will rise to over 600 mOsm. per liter after 6 hours of water deprivation. Plasma osmolality should not increase. In contrast, urine flow rates remain high, plasma osmolality increases and urine osmolality rises little in patients with diabetes insipidus. Typical results of water deprivation testing in a patient with diabetes insipidus recently studied at Barnes Hospital are shown in Figure 2. In certain patients greater reduction in urine flow and urine osmolality values of 400 to 500 mOsm. per liter may be found when severe dehydration has occurred. Such
387
DISORDERS OF ANTIDIURETIC HORMONE SECRETION
t Water
Figure 2. Changes in urine flow, plasma and serum osmolality and body weight in a patient with diabetes insipidus during a period of water deprivation. Basal 24hour fluid intake and urine output volumes in this patient ranged from 3'12 to 5 liters daily.
WEIGHT (/bs)
122
OSMOLALITY Plasma Urine ( mOsm/Ll
287
200
U R I NE VOLUME (ml/hr)
Deprivation Begun
118~ 306
3i9
~
100
°0L-~~2--L-~4--L-~6L-~-8L-~
HOURS
patients may be said to have partial neurohypophyseal insufficiency. While most patients with psychogenic polydipsia will respond normally to such osmotic stress, occasional patients may not. This may be a result of chronic suppression of AVP release or vasopressin resistanceprobably due to the reduction of renal medullary hypertonicity that is caused by chronic polydipsia and polyuria. SALINE INFUSION. The alternative means of increasing plasma osmolality to attempt to stimulate AVP release is by the infusion of hypertonic saline. As formulated by Hickey and Hare,!2 0.25 m!. of 2.5 per cent sodium chloride per kg. per minute is infused over a 45-minute period in a previously well-hydrated patient. Measurements of urine volume at 15-minute intervals and frequent measurements of urine and plasma osmolality should be made, the latter to ensure that plasma osmolality has increased sufficiently above the threshold required (to at least 295 mOsm. per lit er) to produce AVP secretion normally.!5 As after water deprivation, normal subjects and those with psychogenic polydipsia should have a 75 per cent or more fall in urine flow rate and a prompt increase in urine osmolality. If these tests do not elicit an antidiuretic response, the ability of the renal tubule to respond to AVP must then be examined. Since the responses to single doses of AVP are variable and may be transitory, it is wise to infuse AVP at a rate of 5 mU. per minute for 60 minutes. In diabetes insipidus or psychogenic polydipsia there will be a prompt fall in urine volume and a rise in urine osmolality. Furthermore, thirst will usually dramatically decrease. Alternatively, 5 U. of pitressin tannate in oil may be given at bedtime. Urine testing the following day should reveal maximal antidiuresis. The patient may well comment that for the first time in months he did not awaken to urinate and drink water.
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Diabetes insipidus may be managed by intranasal insufflation of posterior pituitary powder, pitressin nasal spray or subcutaneous injection of pitressin tannate in oil. Commercially available pitressin is a partially purified mixture of porcine and bovine pituitary powders; it thus contains lysine and arginine vasopressin. Patients with mild cases often may not require any therapy. There are no fixed dosage rules; treatment is generally given in 0.5 to 1 U. doses intranasally and 5 U. doses parenterally and repeated when thirst and polyuria recur. Intranasal therapy is generally required two to four times daily, and, especially with the powder, may produce an aggravating rhinitis. Parenteral therapy need be given only once every 2 to 4 days; care should be taken that the solution is warmed and well mixed before injection to ensure correct dosage. Synthetic lysine vasopressin has been used intranasally and found both effective and free of the side effects of other intranasal preparations. l1 • \4 It should become available in the near future. While development of antibody to lysine vasopressin during treatment has been reported/ 9 its presence has not been shown to increase replacement requirements.
INAPPROPRIATE SECRETION OF ANTIDIURETIC HORMONE In 1957, a syndrome of hyponatremia with increased urinary sodium excretion was recognized in several patients with carcinoma of the lung by Schwartz and associates. 22 Since then many additional cases have been recognized and a similar syndrome has been reported in patients with non-neoplastic disorders, usually involving the central nervous system .. The major findings in such patients consist of (1) hypo-osmolality of the serum, primarily due to reduction in plasma sodium and chloride concentrations (the concentration of other plasma electrolytes is usually normal); (2) the presence of significant amounts of sodium in the urine; (3) clinical signs of normal or perhaps increased hydration; (4) urine that is hypertonic in relation to the plasma; and (5) normal renal, cardiac and adrenal function. The symptoms of this syndrome are quite variable. If the plasma sodium concentration is above 120 mEq. per lit er, there may be none. When the plasma sodium is lower, symptoms such as anorexia, nausea and vomiting, and central nervous system signs such as apathy, confusion and ultimately coma, may occur. This syndrome should be suspected in any patient with significant hyponatremia and hypo-osmolality. Most patients with moderate or severe hyponatremia will, if adrenal and renal salt-retaining mechanisms are intact, elaborate a virtually sodium-free urine. Only in patients inappropriately secreting AVP and those with adrenal or salt-wasting renal disease will the urine contain appreciable amounts of sodium. The latter causes of hyponatremia are usually associated with signs of extracellular fluid deficit and, in addition, may be confirmed by simple laboratory tests. The pathogenesis of the syndrome of inappropriate secretion of anti-
DISORDERS OF ANTIDIURETIC HORMONE SECRETION
389
diuretic hormone may be outlined as follows (Table 3). When fluid intake is unrestricted, secretion of AVP leads to water retention, resulting in increased extracellular fluid volume and thus dilution of the plasma with hypo-osmolality, hyponatremia and hypochloremia. The resultant hypervolemia leads to reduction in aldosterone secretion by the adrenal gland, increased glomerular filtration rate and increased production of "third factor." This latter material is a postulated hormone of currently unknown origin. Its elaboration at times of ECF volume surfeit is thought to be responsible for the diminution of proximal tubular sodium reabsorption known to occur at such times.lO Natriuresis may result from all three phenomena. Since aldosterone secretion and excretion rates are normal, and not depressed, and glomerular filtration is not markedly increased in these patients, the "third factor" effect is probably the more important in producing the sodium diuresis. In general, net sodium deficit is. not present, although when hyponatremia is severe in a patient who is not extremely overhydrated, sodium loss probably has occurred. However, therapeutic administration of sodium usually leads simply to its prompt appearance in the urine and only a transient rise in plasma sodium concentration. The therapy of choice in this situation is water restriction. Following its institution, body weight falls and plasma sodium concentration rises rapidly. Serial measurements of plasma and urine sodium and osmolality, and the response to water restriction, in such a patient with carcinoma of the lung studied at Barnes Hospital are shown in Figure 3. 27 The most frequent cause of inappropriate secretion of AVP is malignant neoplasms of nonendocrine tissue. Most, but not all, of the cases reported have been in patients with carcinoma of the lung, usually of the oat-cell or anaplastic type. In a number of these patients, AVP has Table 3.
Physiology of the Syndrome of Inappropriate Secretion of Antidiuretic Hormone H 2 0 ingestion
+ Increased secretion of AVP
t
Enhanced renal water reabsorption
/
Expansi on of ECF volume
~ Urine hypertonic to plasma
~{DiminiShed ~
aldosterone secretion } Increased glomerular filtration rate Increased secreti on of "thi rd factor"
Plasma hypoosmolality (Hyponatremial
Natri uresi s
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FLUID INTAKE SURGERY LIMITED
t t
OSMOLALITY Plasma Urine (mOsm/U
264 95
265 241 604 514
URINE NO""
57
103
(meq/doy)
93
140
Figure 3. Serial plasma and urine osmolality and sodium data in a patient with an AVP-secreting carcinoma of the lung. Note the response to fluid restriction. (Reproduced from Utiger.")
PLASMA NoT 120-/-~ (meq/U
~ 100 L-~I__~__~__L-~I__- k__-L__L 4
12
20
HOSPITAL DAY
28
been identified by biological or immunological techniques in the tumor tissue, and increased serum or urine levels of AVP have also been occasionally found. Also, in the tumor studied here,27 electron microscope studies showed material in the tumor cells similar to neurohypophyseal neurosecretory granules. Other causes of this syndrome include a variety of central nervous disorders, such as meningitis, trauma, brain tumors and acute intermittent porphyria, and disorders such as myxedema, pulmonary tuberculosis and other lung lesions. 4 These lesions probably lead to excessive secretion of AVP from the hypothalamicneurohypophyseal system, perhaps by altering normal neuronal inflow into the system or by direct stimulation of it. In any event, the clinical picture is similar to that of patients with AVP-secreting nonendocrine tumors and the therapy of the fluid and electrolyte abnormalities per se is the same.
REFERENCES J. F.: Increased plasma arginine vasopressin in clinical adrenocortical insufficiency and its inhibition by glucosteroids. J. Clin. Invest., 46:111, 1967. Aubry, R. H., Nankin, H. R., Moses, A. M., and Streeten, D. H. P.: Measurement of the osmotic threshold for vasopressin release in human subjects, and its modification by cortisol. J. Clin. Endocrinol., 25:1481, 1965. Avioli, L. V., Earley, L. E., and Kashima, H. K.: Chronic and sustained hypernatremia, absence of thirst, diabetes insipidus, and adrenocorticotropin insufficiency resulting from widespread destruction of the hypothalamus. Ann. Int. Med., 56: 131, 1962. Bartter, F. C., and Schwartz, W. B.: The syndrome of inappropriate secretion of antidiuretic hormone. Amer. J. Med., 42:790,1967. Blotner, H.: Diabetes insipidus. In Christian, H. A., ed.: Oxford Medicine. New York, Oxford University Press, 1950, Vol. 4, p. 179.
1. Ahmed, A. B. J., George, B. C., Gonzalez-Auvert, C., and Dingman,
2. 3. 4. 5.
DISORDERS OF ANTIDIURETIC HORMONE SECRETION
391
6. Braverman, L. K, Mancini, J. P., and McGoldrick, D. M.: Hereditary idiopathic diabetes insipidus. Ann. Int. Med., 63:503, 1965. 7. Czaczkes, J. W., and Kleeman, C. R.: The effect of various states of hydration and the plasma concentration on the turnover of antidiuretic hormone in mammals. J. Clin. Invest., 43:1649,1964. 8. Czaczkes, J. W., Kleeman, C. R., and Koenig, M.: Physiologic studies of antidiuretic hormone by its direct measurement in human plasma. J. Clin. Invest., 43:1625,1964. 9. de Wardener, H. P.: Polyuria. J. Chron. Dis., 11:199, 1960. 10. de Wardener, H. E., Mills, I. H., Clapham, W. F., and Hayter, C. J.: Studies on the efferent mechanism of the sodium diuresis which follows the administration of intra venous saline in the dog. Clin. Sci., 21 :249, 1961. 1l. Dingman, J. F., and Hauger-Klevene, J. H.: Treatment of diabetes insipidus with synthetic lysine vasopressin. J. Clin. Endocrinol., 24:550, 1964. 12. Hickey, R. C., and Hare, K: The renal excretion of chloride and water in diabetes insipidus. J. Clin. Invest., 23:768, 1944. 13. Jewell, P. A., and Varney, E. B.: An experimental attempt to determine the site of the neurohypophyseal osmoreceptors in the dog. Phil. Trans. Ray. Soc. London, 240: 197, 1957. 14. Moses, A. M.: Synthetic lysine vasopressin nasal spray in treatment of diabetes insipidus. Clin. Pharmacol. and Therap., 5:422, 1964. 15. Moses, A. M., Streeten, D. H. P.: Differentiation of polyuric states by measurement of responses to changes in plasma osmolality induced by hypertonic saline infusions. Amer. J. Med., 42:368, 1967. 16. Orloff, J., and Handler, J.: The role of adenosine-3',5'-phosphate in the action of antidiuretic hormone. Amer. J. Med., 42:757, 1967. 17. Permutt, M. A., Parker, C. W., and Utiger, It D.: Immunochemical studies with lysine vasopressin. Endocrinology, 78:809, 1966. 18. Randall, R. V., Jr., Clark, E. C., Dodge, H. W., Jr., and Love, J G.: Polyuria after operation for tumors in the region of the hypophysis and hypothalamus. J. Clin. Endocrinol., 20: 1614, 1960. 19. Roth, J., Glick, S. M., Klein, Le A., and Peterson, M. J.: Specific antibody to vasopressin in man. J. Clin. Endocrinol., 26:671, 1966. 20. Sachs, H.: Biosynthesis and release of vasopressin. Amer. J Med., 42:687, 1967. 2l. Scharrer, E., and Scharrcr, B.: Hormones produced by neurosecretory cells. Rec. Progr. Hormone Res., 10:183, 1954. 22. Schwartz, W. B., Bennett, W., Curelop, S., and Bartter, F. C.: A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. Amer. J. Med., 23:529, 1957. 23. Segar, W. E.: Chronic hyperosmolality. Amer. J. Dis. Child., 112:318,1966. 24. Share, L.: Vasopressin, its bioassay and the physiological control of its release. Amer. J. Med., 42:701, 1967. 25. Sitprija, V., Pochanugool, C., Benyajati, C., and Suwanwela, C.: Polydipsia and polyuria associated with quadriplegia. Ann. Int. Med., 65:62, 1966. 26. Thomas, W. C., Jr.: Diabetes insipidus. J. Clin. Endocrinol., 17:565, 1957. 27. Utiger, R. D.: Inappropriate antidiuresis and carcinoma of the lung: Detection of arginine vasopressin in tumor extracts by immunoassay. J. Clin. Endocrinol., 26:970, 1966. 28. Vcrney, E. B.: The antidiuretic hormone and the factors which determine its release. Proc. Roy. Soc. Med., 135:25, 1947. 29. Wakim, K G.: Reassessment of the source, mode and locus of action of antidiuretic hormone. Amer. J. Med., 42:394, 1967. 30. Yoshida, S., Motohashi, K, Ibayashi, H., and Okinaka, S.: Method for the assay of antidiuretic hormone in plasma with a note on the antidiuretic titer of human plasma. J. Lab. Clin. Med., 62:279, 1963. 660 S. Euclid Avenue St. Louis, Missouri 63110