Case Based Pediatrics For Medical Students and Residents
Department of Pediatrics, University of Hawaii John A. Burns School of Medicine
Chapter XV.5. Antidiuretic Hormone
Daniel C. H. Kidani, MD
May 2003

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This is a 1 year old male who presents to the office with a chief complaint of increased urination and thirst. Over the past month, he has been wetting an increasing number of diapers, >15 per day which is associated with increased fluid consumption. He always has a bottle or training cup in his hand, and his parents feel that this is abnormal.

Exam: VS are normal. Weight is at the 75th percentile. He is alert and active, in no distress. He is slightly large for age. No abnormalities are detected on physical examination. No ketosis is detected and he exhibits no signs of dehydration.

Labs: UA is normal. Urine specific gravity is 1.005. No glycosuria is noted. CBC WBC 8.0, Hgb 16.5, Hct 48.7, Platelet count 324,000. Chemistry: Na 149, K 4.4, Cl 99, CO2 22, Glucose 102.

How would you work this patient up?

Antidiuretic hormone (ADH) is a short peptide also known as 8-arginine-vasopressin (AVP) (1). It is synthesized in the supraoptic and paraventricular nuclei of the anterior hypothalamus and is subsequently transported via neurons to the posterior pituitary gland where it is stored as granules and released into the systemic circulation through the cavernous sinus and superior vena cava (2).

The main biologic effect of ADH is to reduce the rate of urine flow by increasing the reabsorption of solute-free water from the filtrate in the distal tubules and collecting ducts of nephrons (1). This response is mediated by specific V2 receptors located on the basolateral surface of the principle cells of collecting ducts to induce water reabsorption. In their resting state, V2 receptors are inactive, and the distal tubules and collecting ducts are impermeable to water (2). Once V2 receptors are activated by ADH, a G-protein-coupled adenylcyclase is activated which converts ATP to cAMP which then activates a protein kinase. This protein kinase induces vesicles containing water channels, made up of the protein aquaporin-2 (2), to migrate to the apical cell membrane resulting in increased permeability to free water. Water is reabsorbed into the cell and passes through the freely permeable basolateral membrane into the peritubular capillaries (1). As a result of the increased permeability, most of the water in the diluted filtrate that reaches the distal nephron back diffuses down the osmotic gradient created by the hypertonic milieu of the surrounding renal medulla. This back diffusion of water in the absence of solute increases urine concentration and reduces urine flow by an amount proportional to the level of ADH. ADH also increases NaCl reabsorption in the thick ascending loop of Henle. These effects of ADH result in tubular conservation of water, increased urine osmolality, decreased plasma osmolality, and negative free water clearance without significant alteration in solute excretion. However, ADH is rapidly reversible once plasma levels decline as its half-life is between 5 and 15 minutes (1).

ADH also acts on V1 receptors located in smooth muscle and can cause contraction of the GI tract as well as all parts of the vascular bed (vasoconstriction), especially the small arterioles and venules (hence, its other name, vasopressin) (1). This effect on the contractile elements are neither antagonized by adrenergic blocking agents nor prevented by vascular denervation.

Granules of ADH are released when hypothalamic osmoreceptors sense an increase in serum osmolality, even as little as 1% above normal. The threshold range for ADH secretion is 280-290 mOsm/liter. Once the threshold range is exceeded, there is a steep rise in the release of ADH, resulting in a decrease in serum osmolality back toward normal while increasing the osmolality of urine (1).

Regulation of ADH secretion is mediated by osmoreceptors that are thought to be located in the anteromedial hypothalamus near the neurohypophyseal cell bodies in the supraoptic nucleus. These osmoreceptors are normally sensitive to small changes in effective osmotic pressure such that a decrease in plasma osmolality as small as 1% to 2% rapidly suppresses ADH secretion to levels that permit a maximum water diuresis. Above this set-point, plasma ADH rises steeply in direct proportion to plasma osmolality and reaches a level sufficient to produce a maximum antidiuresis before plasma osmolality or serum sodium exceed the normal range; typically 275 to 295 mOsm/lit in a healthy individual. However, the sensitivity and the slope of the ADH response varies widely between individuals, and is thought to be genetically determined. This set-point is reduced during pregnancy and the luteal phase of the menstrual cycle (hence, more fluid retention), but increased in the elderly (hence, less fluid retention) (2).

Non-osmotic variables can also influence ADH secretion. Reductions in blood volume or arterial pressure of more than 10% to 20% stimulate release of ADH. This is thought to be due to lowering the set-point of the osmoregulatory system, mediated by neural pathways that originate in stretch receptors in the walls of the left atrium and large arteries. These pathways project via the vagal and glossopharyngeal nerves to the brain stem and eventually to the hypothalamus where they interact via an as of yet unknown way with input from osmoreceptors. Under normal conditions, this pathway seems to have little or no influence on ADH secretion; however, in conditions such as severe congestive heart failure, adrenal insufficiency, and other diseases associated with large reductions in blood pressure or blood volume, this pathway may have a profound effect (2).

ADH released via this pathway is released in concentrations 10-1000 times greater than normal. At these high concentrations, ADH acts as a vasoconstrictor, especially at the outer renal cortex. This is mediated by activation of V1 receptors which exist on vascular smooth muscle, glomerular mesangial cells, and the vasa recta and is mediated through the phosphatidyl-inositol pathway (1). Thus, hypovolemia-induced secretion of ADH is a more potent stimulant for ADH release than is serum osmolality and contributes to the SIADH (fluid retention, hypoosmolality, and hyponatremia) seen in postoperative patients (1).

Nausea is another potent stimulus for ADH release under pathologic conditions (e.g., vasovagal reactions, emotional stress with a vasovagal reaction, hyperemesis gravidum, diabetic ketoacidosis, chemotherapy, motion sickness). Even if transient and unassociated with emesis or changes in blood pressure, nausea can result in rapid 20- to 500-fold increases in plasma ADH levels (2).

The function of ADH is to decrease water loss; however, its ability to do so is limited because it cannot reduce the rate of urine output below the amount required to excrete a given solute load and cannot eliminate insensible losses such as the evaporation of water from the skin and lungs. Thus, another mechanism to replace this water loss must exist. This vital function is carried out by the thirst mechanism (2).

Thirst is regulated primarily by hypothalamic osmoreceptors; however, these osmoreceptors are less sensitive than those for ADH release. The osmotic threshold at which thirst begins is about 5 to 10 mOsm/kg higher than the threshold for ADH release (2).

Diabetes insipidus is an uncommon syndrome characterized clinically by increased fluid intake and the excretion of abnormally large volumes of urine of low specific gravity. It is caused by a deficiency of or a resistance to ADH (3). The most common cause is a primary deficiency of ADH secretion, usually referred to as pituitary, neurogenic, neurohypophyseal, cranial, or central diabetes insipidus. It is almost always the result of irreversible destruction of more than 80% of ADH-producing magnocellular neurons secondary to acquired, congenital, or genetic diseases (2).

Congenital causes include septo-optic dysplasia, cleft lip and palate, other midline craniofacial defects, holoprosencephalic syndromes, and agenesis/hypogenesis of the pituitary. Primary central diabetes insipidus can also be caused by head trauma, primary tumors (craniopharyngiomas, adenomas, meningiomas, dysgerminoma), and metastatic (breast, lung) tumors, lymphomas, granulocytic leukemias, neurosarcoid, histiocytosis, xanthoma disseminatum, chronic meningitis, viral encephalitis, toxoplasmosis, autoimmune conditions (lymphocytic infundibuloneurohypophysitis, scleroderma, Wegener's granulomatosis, SLE), Sheehan's syndrome, carotid aneurysms, hypoxic encephalopathy, snake venom, as well as idiopathic causes.

The most common genetic form of central diabetes insipidus is transmitted in a completely penetrant autosomal dominant fashion and involves the AVP-NPII gene on chromosome 20. The AVP (ADH) deficiency is not present at birth but develops several months to years later and may gradually progress from partial to severe (>95%). It is hypothesized that the mutant AVP-NPII gene produces a defective AVP prohormone which cannot be secreted, and thus accumulates within neurons and leads to neuronal death. A much rarer form of congential central diabetes insipidus is transmitted in an autosomal recessive mode which also involves the AVP-NPII gene, but unlike its autosomal dominant counterpart, leads to the production of a mutant AVP with little or no antidiuretic effect (2).

A primary deficiency of plasma ADH can also occur during pregnancy and is known as gestational diabetes insipidus. In this case, the deficiency is a result of degradation of ADH by a vasopressinase produced in the placenta. Polyuria, thirst, and polydipsia typically occur during the third trimester which usually remits 3 to 6 weeks after delivery (3).

Decreased ADH is not always the cause of diabetes insipidus. Rather, a deficiency in the responsiveness of ADH at its site of action may also cause polyuria. This form of diabetes insipidus is termed nephrogenic. These patients have normal secretion of AVP and are unresponsive to exogenous vasopressin. The abnormality lies in a defective expression of vasopressin V2 receptors or vasopressin-sensitive water channels (3).

The most common form of genetic nephrogenic diabetes insipidus is transmitted in an X-linked recessive mode. It is congenital and often results in repeat episodes of hypernatremic dehydration during the first 2 years of life. It is refractory to the antidiuretic effect of normal to modestly increased levels of plasma ADH, but it may respond to high pharmacologic doses of deamino-D-arginine vasopressin (DDAVP, a synthetic vasopressin) (2).

Less common forms of congenital nephrogenic diabetes insipidus are transmitted in autosomal dominant and autosomal recessive modes. These conditions are caused by mutations in the coding region of one or both aquaporin-2 genes and usually result in severe or complete resistance to ADH (2).

Acquired forms of nephrogenic diabetes insipidus are usually less severe than genetic forms. It is seen in pyelonephritis, renal amyloidosis, myeloma, potassium depletion, Sjogren's syndrome, sickle cell anemia, hypercalcemia, sarcoma, and neurosarcoid of the kidney. Acute tubular necrosis may also be associated with a transient nephrogenic diabetes insipidus. Glucocorticoids, diuretics, demeclocycline, lithium, foscarnet, and methicillin may all cause nephrogenic diabetes insipidus (2).

The pathophysiology that underlies central, gestational, and nephrogenic diabetes insipidus are similar. In all three, the kidneys are unable to concentrate urine resulting in a diuresis that results in a slight (1% to 2%) decrease in body water and an increase in basal plasma osmolality and sodium. Increased serum osmolality stimulates thirst and a compensatory increase in water intake, preventing further dehydration. Thus, unless the thirst mechanism is damaged or the patient is unable to increase fluid intake, water and osmolar homeostasis are maintained.

In all types of chronic diabetes insipidus, the maximum urinary concentrating capacity is reduced and is proportional to the severity of the diabetes insipidus. It is thought that this may be the result of washout of the medullary concentration gradient or inhibition of aquaporin-2 synthesis. However, it usually corrects within 24 to 72 hours if polyuria is eliminated (2).

The hallmarks of diabetes insipidus are polyuria (2-20 liters per day) and increased fluid intake (3). Polyuria results in symptoms of urinary frequency, nocturia, incontinence, or enuresis. Fatigue may be an associated complaint resulting from frequent disruption of sleep. Polyuria is always accompanied by a proportionate polydipsia that is usually, but not always, attributable to increased thirst (2).

Physical exam findings including vital signs and routine laboratory studies are usually unremarkable. However, dehydration and hypernatremia may be present especially after hypothalamic damage secondary to shock or anoxia (3). Neurologic symptoms may be present depending on the etiology of the DI, such as hyperphagia, visual field defects, anosmia, weight loss, etc. (2).

Evaluation for DI should include a 24-hour urine collection for volume, glucose, and creatinine as well as serum studies for glucose, urea nitrogen, calcium, uric acid, potassium, and sodium (3).

There is no single diagnostic test to make the diagnosis of diabetes insipidus. The diagnosis is made mainly on clinical grounds with some laboratory supportive evidence. However, hyperuricemia implicates central diabetes insipidus as decreased V1 stimulation decreases urate clearance. If diabetes insipidus is suspected, a supervised vasopressin challenge test should be administered. Desmopressin acetate (DDAVP, a vasopressin analogue) which has a long duration of action and an antidiuretic/pressor factor of approximately 3000 when compared to AVP (4), is given in an initial dose of subcutaneously, or intravenously, with measurements of urine osmolality obtained 12 hours prior and 12 hours after administration. If basal plasma ADH is low, or if the osmolality of urine collected 1 or 2 hours after subcutaneous injection of DDAVP is more than 50% greater than the pretreatment value, the patient has central diabetes insipidus. The dosage of desmopressin is doubled if the response is marginal. Patients with central diabetes insipidus notice a marked decrease in polyuria and polydipsia (2). In contrast, if basal plasma ADH is elevated, or if the administration of DDAVP results in little or no increase in urine concentration, the patient has severe nephrogenic diabetes insipidus. A two day trial of DDAVP with ad lib fluid intake can also help to distinguish between central and nephrogenic diabetes insipidus (2).

Magnetic resonance imaging of the brain with and without gadolinium contrast may also be useful in determining the type and etiology of the diabetes insipidus. It cannot differentiate between central and nephrogenic diabetes insipidus, but it may be able to differentiate diabetes insipidus from primary polydipsia (2).

Central diabetes insipidus must be distinguished from other causes of polyuria. Therefore, Cushing's syndrome as well as glucocorticoid therapy, diabetes mellitus, drugs (carbamazepine, lithium), psychogenic polydipsia, central nervous system sarcoidosis, as well as intravenous fluid administration must be considered (3). Psychogenic water drinking can be extremely difficult to distinguish from DI. Withholding water from such patients will often result in anxiety, but withholding water from patients with DI, is dangerous. Thus, until the diagnosis can be confirmed, an evaluation for DI in uncertain cases, must often be done as an inpatient to establish the diagnosis. In theory, psychogenic water drinkers should not have hypernatremia.

The signs and symptoms of diabetes insipidus can be eliminated completely by replacing the AVP deficiency with DDAVP. DDAVP is a synthetic analogue of vasopressin but is more resistant to degradation, has less of a pressor effect, and can be given by mouth, nasal spray, or injection (4). The dose required to normalize the 24-hour urine volume and concentration varies from patient to patient and must be determined empirically. The typical requirements in adults are 50 to 200 mcg by mouth two to three times a day, 5 to 20 mcg by nasal spray two to three times a day, or 1 to 2 mcg by subcutaneous injection once or twice a day. Patients rarely develop water intoxication due to homeostatic mechanisms; however, patients on DDAVP should be advised to drink only when truly thirsty (2). Adverse reactions to DDAVP include nasal irritation, agitation, and erythromelalgia (throbbing and burning pain in the skin often precipitated by exertion or heat). Hyponatremia is rare if the patient is placed on the minimum effective dose and thirst is allowed to occur periodically (3).

The signs and symptoms of nephrogenic diabetes insipidus are completely unaffected by standard doses of DDAVP unless the process is partial in which case tenfold higher doses are effective. The expense and inconvenience of this treatment, however, make this regimen impractical. If hypokalemia, hypercalcemia, or the use of lithium is present, the correction of the underlying problem may correct the diabetes insipidus (lithium can cause nephrogenic DI); however, in many cases this is difficult to accomplish. Treatment usually consists of a low sodium diet coupled with an empirically determined combination of chlorothiazide, hydrochlorothiazide, amiloride, or indomethacin. Patient's typically experience a 50% to 70% decrease in urine volume (2).

The syndrome of inappropriate ADH secretion (SIADH) is a disorder characterized elevated levels of ADH which hinders the ability of the kidneys to dilute urine resulting in water intoxication with hypotonicity and hyponatremia (4). In pediatrics, SIADH is most commonly encountered in patients with bacterial meningitis. A urine sodium should be immediately obtained once hyponatremia is identified. A low urine sodium (coupled with hyponatremia) is abnormal and indicative of SIADH.

Patients may develop symptoms of hyponatremia ranging from mild headaches, anorexia, and confusion to nausea, vomiting, coma, convulsions, and death (2). However, hyponatremia may be asymptomatic if it has developed gradually. Symptomatic hyponatremia has a mortality of 10 to 15%, and the mortality rate is higher when the serum sodium level is below 110 mEq/L (4).

Patients may experience weight gain because of water retention; however, edema is not present because the retained water is distributed among both extracellular and intracellular compartments. Signs of congestive heart failure, cirrhosis, nephrosis, or hypovolemia are also absent (2).

Acute water retention causes neurologic symptoms by rapidly increasing the intracellular volumes of brain cells and thus inducing cerebral edema. It is probable that chronic hyponatremia is less symptomatic because there is time for activation of compensatory volume-regulatory mechanisms in the central nervous system. Brain cells compensate for volume gain by activating ion transport processes that pump out intracellular KCl and NaCl. This compensation has therapeutic importance, because rapid correction of hyponatremia by infusion of hypertonic saline produces a transient hypertonic encephalopathy as water is drawn out of the already contracted intracellular space. This can cause permanent neurologic damage, for example central pontine myelinolysis and death (4).

In most patients with SIADH, the defect in urinary dilution is caused by ectopic production, exogenous administration, or osmotically inappropriate neurohypophyseal secretion of ADH. Associated conditions (not necessarily etiologies) include brain malformations, midline defects, ectopic secretion from neoplasms (e.g., small cell lung cancer), other cancer conditions, drugs, severe neurological conditions (meningitis, severe head trauma, encephalitis, coma, etc.), severe pneumonia, respiratory failure (with mechanical ventilation), etc. (4).

ADH is synthesized as a prohormone of 166 amino acids that is processed to produce three peptides: the mature octapeptide hormone, a midregion 10,000-molecular-weight peptide with vasopressin-binding activity called neurophysin II, and a C-terminal glycopeptide. Both the vasopressin (ADH) and the neurophysin are packaged within the neurosecretory granule (4).

Neuroendocrine tumor cells produce ADH in a similar fashion, secreting both vasopressin and neurophysin II. However, vasopressin's sister peptide oxytocin together with its binding protein, neurophysin I, are also commonly secreted. The proximity of the genes for vasopressin and oxytoxin, less than 12kb within the human genome, is thought to explain this phenomenon as a single transcription factor could activate both promoters (4).

Water retention leads to expansion of both the extra and intracellular compartments. The expansion of extracellular fluid volume (likely secondary to suppression of aldosterone and increased atrial natriuretic peptide release) leads to natriuresis (sodium excretion) and a reduction in fluid volume in patients with an adequate sodium intake.

Plasma AVP and AVP analogues do not significantly lower serum sodium unless total water intake (dietary plus insensible) exceeds total output (urinary plus insensible). When such imbalance occurs, the excess water cannot be excreted as quickly as is normal because urinary concentration cannot decrease sufficiently to permit a fully compensatory water diuresis. Consequently, water is retained in the extracellular and intracellular compartments; the concentration of sodium and other solutes in body fluids is diluted; plasma urea, uric acid, rennin and aldosterone activities are reduced; and urinary sodium excretion increases as an appropriate response to the expansion of plasma and extracellular volume, via ANP (4). The natriuresis aggravates the dilutional hyponatremia but partially offsets the extracellular volume expansion, preventing edema or other signs of hypervolemia. The rate at which these abnormalities develop varies widely depending on the magnitude of the imbalance between the total rate of water intake and excretion by renal and extrarenal routes. If the defect in urinary dilution is minor or if insensible loss of water is abnormally high, even markedly increased rates of water intake may be insufficient to induce hyponatremia. On the other hand, if urinary concentration is fixed at a high level and insensible loss is low, even an apparently normal basal rate of fluid intake may be sufficient to produce the syndrome (2).

SIADH is generally diagnosed by finding a low serum osmolality in conjunction with a relatively high urine osmolarity. This is abnormal since the urine should be very dilute if the plasma is hypo-osmolar. Checking the serum and urine sodium levels are often sufficient since hyponatremia in conjunction with an elevated urine sodium is similarly abnormal, although this can also be caused by diuretics, mineralocorticoid deficiency (Addisonian crisis) and salt losing nephropathy.

The clinical presentation of SIADH can vary appreciably owing to differences in the type of osmoregulatory defect present. The most striking and potentially confusing variant is that caused by downward resetting of the osmostat. In this type of defect, plasma AVP and urine concentration continue to be osmoregulated and can still be maximally suppressed if fluid intake is great enough to lower plasma osmolality/sodium to the new threshold or set point. Consequently, patients with this variant of SIADH may present with hyponatremia and maximum urinary dilution, leading to the false conclusion that polydipsia alone was responsible for the fluid-electrolyte imbalance. If the measurements of urine osmolality are repeated during therapeutic fluid restriction, the true cause becomes apparent because urinary concentration begins long before serum sodium rises to normal. Close monitoring of urine output and serum sodium is important for effective clinical management in all variants of SIADH because the abnormal AVP secretion of any type can suddenly remit, allowing a brisk water diuresis that raises the serum sodium more rapidly than may be safe. Such remissions are relatively common in SIADH because it is usually an acute self-limited disorder that lasts only a few days or weeks (2).

The SIADH must be differentiated from hypervolemic, hypovolemic, and other forms of euvolemic hyponatremia. These distinctions can usually be made on the basis of the clinical history, physical examination, and routine laboratory tests. Hypervolemic hyponatremia occurs in patients with severe congestive failure, cirrhosis, or nephrosis, and is always associated with edema. The osmotic suppression of plasma AVP and urinary dilution are also impaired, but, in this case, the defect is caused by a reduction in effective blood volume, which stimulates AVP release via the baroregulatory system. Because of this effective hypovolemia, plasma urea, uric acid, renin activity, and aldosterone are also usually elevated, and the urinary excretion of salt and water is decreased.

Hypovolemic hyponatremia occurs in conditions such as diuretic abuse, mineralocorticoid deficiency, or gastroenteritis, which result in excessive loss of sodium and water. The resultant depletion of intravascular and interstitial fluid results in physical signs of hypovolemia, such as tachycardia and postural hypotension. It also increases plasma AVP and urine concentration and decreases renal perfusion. Consequently, plasma urea, uric acid, renin activity, and aldosterone are elevated, whereas urinary excretion of salt and water are reduced (unless a diuretic or sodium-losing nephropathy is responsible).

In addition to SIADH, euvolemic hyponatremia can result from isolated cortisol deficiency or emesis. The pathophysiology and clinical characteristics of the latter two forms of euvolemic hyponatremia are identical to SIADH, with the exception that they are associated with hypocortisolemia or a history of nausea and vomiting and can be corrected completely by treatment with cortisol or antiemetics (2).

In some patients, SIADH can be cured by eliminating the tumor, drug, or disease responsible for the syndrome. In others, it is an acute self-limited disorder that remits spontaneously within 2 to 3 weeks. The most common therapy used to treat SIADH is fluid restriction. This reduces free water retention and allows the hyponatremia to resolve gradually. If the hyponatremia is severe, or accompanied by symptoms such as nausea, vomiting, coma, or seizures, it may be desirable to correct part of it more rapidly by combining fluid restriction with a slow intravenous infusion of hypertonic (3%) saline. Hypertonic saline infusion is dangerous, requiring close monitoring and frequent stat sodium measurements (a turnaround time of 1 hour is not fast enough since the sodium may have risen to excessive levels before then). When infused at a rate of approximately 0.05 mL/kg/min, 3% saline raises serum sodium by about 2 mEq/L per hour. With this therapy and all other methods of treatment, urine output and fluid intake should be monitored closely because SIADH can remit spontaneously at any time, and, when it does, the resultant water diuresis may raise serum sodium too fast or too far if water intake is not allowed to increase. The objective should be to raise serum sodium no faster than 24 mEq/L in 24 hours and to a final level no greater than 135 mEq/L. Although this issue is not yet settled, raising the serum sodium faster or farther may cause acute osmotic demyelinization, a serious complication characterized by severe neurologic abnormalities, including quadriparesis, mutism, pseudobulbar palsy, seizures, behavioral disturbances, and movement disorders (2).

Chronic SIADH usually cannot be controlled by fluid restriction alone because thirst is also increased inappropriately; however, the hyponatremia may be corrected or prevented by treatment with demeclocycline (induces nephrogenic diabetes insipidus) or fludrocortisone (mineralocorticoid with aldosterone-like activity). When given at doses ranging from 150 to 300 mg two to four times a day, demeclocycline increases urinary free water excretion by interfering with the antidiuretic action of AVP. This effect may not occur for several weeks and is usually reversible when treatment is stopped. Demeclocycline may also cause photosensitivity, azotemia, or other signs of nephrotoxicity, but these side effects are usually also reversible. Treatment with fludrocortisone in doses of 0.1 to 0.3 mg twice a day can also be effective, presumably because it promotes sodium retention; however, it may also act in part by inhibiting thirst and fluid intake. The abnormalities in AVP secretion and AVP action are not affected by fludrocortisone. The principal side effects are hypokalemia and hypertension, which may necessitate potassium supplementation or reduction of the dose. AVP antagonists may also prove to be effective treatment for chronic SIADH in the future (2).


1. What is actions does ADH have?

2. What clinical manifestations might one see in a case of diabetes insipidus?

3. How might one distinguish nephrogenic from central diabetes insipidus?

4. Are levels of ADH under regulatory control in SIADH?

5. What is the most common neoplastic cause of SIADH?

6. If hyponatremia is found, what is the most useful next test to determine the etiology of the hyponatremia.

7. True/False: 3% sodium chloride solution (hypertonic saline) can be used safely to raise the serum sodium level in SIADH.


1. Sladen RN. Chapter 18. In: Miller RD (ed). Anesthesia, 5th edition. 2000, Philadelphia: Churchill Livingstone, Inc., pp. 679-680.

2. Robertson GL. Antidiuretic Hormone: Normal and Disordered Function. Endocrinol Metabol Clin 2001;30(3): 671-694.

3. Fitzgerald PA. Ch. 26 - Endocrinology. In: Tierney, Lawrence M, et al (eds). Current Medical Diagnosis and Treatment, 39th ed. 2000, New York: Lange Medical Books/McGraw-Hill, pp. 1086-1088.

4. Strewler GJ. Chapter 36 - Humoral Manifestations of Malignancy. In: Wilson JD, et al (eds). Williams Textbook of Endocrinology, 9th edition. 1998, Philadelphia: W. B. Saunders Company, pp. 1697-1710.

5. Okuda T, et al. Chapter 21 - Fluid and Electrolyte Disorders. In: Tierney LM, et al (eds). Current Medical Diagnosis and Treatment, 39th edition. 2000, New York: Lange Medical Books/McGraw-Hill, pp. 861-865.

Answers to questions

1. The main biologic actions of ADH are to reduce the rate of urine flow by increasing the reabsorption of solute-free water from the filtrate in the distal tubules and collecting ducts of nephrons. This occurs via V2 receptors. When ADH acts on V1 receptors it causes vasoconstriction and contraction of smooth muscle elements.

2. Besides polyuria and polydipsia, physical exam and lab studies are typically within normal limits. However, in severe cases, signs and symptoms of hypernatremia and dehydration may be present.

3. Vasopressin challenge test: polyuria and polydipsia are corrected in central diabetes insipidus, but not corrected with standard doses in nephrogenic diabetes insipidus.

4. Yes and No. There are 4 types, only one is regulated by osmolality; however, the osmostat is reset to a lower osmolality.

5. Small cell lung cancer

6. The urine sodium is the test that should be done next. If the urine sodium is low, then the hyponatremia is due to total body sodium depletion. If the urine sodium is high, then the hyponatremia is due to SIADH, Addisonian crisis, diuretics, or salt losing nephropathy.

7. False. Hypertonic saline infusion is dangerous.

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