Chapter 374: Disorders of the Neurohypophysis

The neurohypophysis, or posterior pituitary, is formed by axons that originate in large cell bodies in the supraoptic and paraventricular nuclei of the hypothalamus. It produces two hormones: (1) arginine vasopressin (AVP), also known as antidiuretic hormone, and (2) oxytocin. AVP acts on the renal tubules to reduce water loss by concentrating the urine. Oxytocin stimulates postpartum milk letdown in response to suckling. A deficiency of AVP secretion or action causes diabetes insipidus (DI), a syndrome characterized by the production of large amounts of dilute urine. Excessive or inappropriate AVP production impairs urinary water excretion and predisposes to hyponatremia if water intake is not reduced in parallel with urine output.

SYNTHESIS AND SECRETION

AVP is a nonapeptide composed of a six-member disulfide ring and a tripeptide tail (Fig. 374-1). It is synthesized via a polypeptide precursor that includes AVP, neurophysin, and copeptin, all encoded by a single gene on chromosome 20. After preliminary processing and folding, the precursor is packaged in neurosecretory vesicles, where it is transported down the axon; further processed to AVP, neurophysin, and copeptin; and stored in neurosecretory vesicles until released by exocytosis into peripheral blood.

AVP secretion is regulated primarily by the “effective” osmotic pressure of body fluids. This control is mediated by specialized hypothalamic cells known as osmoreceptors, which are extremely sensitive to small changes in the plasma concentration of sodium and its anions but normally are insensitive to other solutes such as urea and glucose. The osmoreceptors appear to include inhibitory as well as stimulatory components that function in concert to form a threshold, or set point, control system. Below this threshold, plasma AVP is suppressed to levels that permit the development of a maximum water diuresis. Above it, plasma AVP rises steeply in direct proportion to plasma osmolarity, quickly reaching levels sufficient to effect a maximum antidiuresis. The absolute levels of plasma osmolarity/sodium at which minimally and maximally effective levels of plasma AVP occur, vary appreciably from person to person, apparently due to genetic influences on the set and sensitivity of the system. However, the average threshold, or set point, for AVP release corresponds to a plasma osmolarity or sodium of about 280 mosmol/L or 135 meq/L, respectively; levels only 2–4% higher normally result in maximum antidiuresis.

Although it is relatively stable in a healthy adult, the set point of the osmoregulatory system can be lowered by pregnancy, the menstrual cycle, estrogen, and relatively large, acute reductions in blood pressure or volume. Those reductions are mediated largely by neuronal afferents that originate in transmural pressure receptors of the heart and large arteries and project via the vagus and glossopharyngeal nerves to the brainstem, from which postsynaptic projections ascend to the hypothalamus. These pathways maintain a tonic inhibitory tone that decreases when blood volume or pressure falls by >10–20%. This baroregulatory system is probably of minor importance in the physiology of AVP secretion because the hemodynamic changes required to affect it usually do not occur during normal activities. However, the baroregulatory system undoubtedly plays an important role in AVP secretion in patients with disorders that produce large, acute disturbances of hemodynamic function. AVP secretion also can be stimulated by nausea, acute hypoglycemia, glucocorticoid deficiency, smoking, and, possibly, hyperangiotensinemia. The emetic stimuli are extremely potent since they typically elicit immediate, 50- to 100-fold increases in plasma AVP even when the nausea is transient and is not associated with vomiting or other symptoms. They appear to act via the emetic center in the medulla and can be blocked completely by treatment with antiemetics such as fluphenazine. There is no evidence that pain or other noxious stresses have any effect on AVP unless they elicit a vasovagal reaction with its associated nausea and hypotension.

ACTION

The most important, if not the only, physiologic action of AVP is to reduce water excretion by promoting concentration of urine. This antidiuretic effect is achieved by increasing the hydroosmotic permeability of cells that line the distal tubule and medullary collecting ducts of the kidney (Fig. 374-2). In the absence of AVP, these cells are impermeable to water and reabsorb little, if any, of the relatively large volume of dilute filtrate that enters from the proximal nephron. The lack of reabsorption results in the excretion of very large volumes (as much as 0.2 mL/kg per min) of maximally dilute urine (specific gravity and osmolarity ~1.000 and 50 mosmol/L, respectively), a condition known as water diuresis. In the presence of AVP, these cells become selectively permeable to water, allowing the water to diffuse back down the osmotic gradient created by the hypertonic renal medulla. As a result, the dilute fluid passing through the tubules is concentrated and the rate of urine flow decreases. The magnitude of this effect varies in direct proportion to the plasma AVP concentration and the rate of solute excretion. At maximum levels of AVP and normal rates of solute excretion, it approximates a urine flow rate as low as 0.35 mL/min and a urine osmolarity as high as 1200 mosmol/L. This effect is reduced by a solute diuresis such as glucosuria in diabetes mellitus.

At high concentrations, AVP also causes contraction of smooth muscle in blood vessels in the skin and gastrointestinal tract, induces glycogenolysis in the liver, and potentiates adrenocorticotropic hormone (ACTH) release by corticotropin-releasing factor. These effects are mediated by V_1a or V_1b receptors that are coupled to phospholipase C. Their role, if any, in human physiology/pathophysiology is uncertain.

METABOLISM

AVP distributes rapidly into a space roughly equal to the extracellular fluid volume. It is cleared irreversibly with a half-life (t _1/2) of 10–30 min. Most AVP clearance is due to degradation in the liver and kidneys. During pregnancy, the metabolic clearance of AVP is increased three- to fourfold due to placental production of an N-terminal peptidase.

Because AVP cannot reduce water loss below a certain minimum level obligated by urinary solute load and evaporation from skin and lungs, a mechanism for ensuring adequate intake is essential for preventing dehydration. This vital function is performed by the thirst mechanism. Like AVP, thirst is regulated primarily by an osmostat that is situated in the anteromedial hypothalamus and is able to detect very small changes in the plasma concentration of sodium and its anions. The thirst osmostat appears to be “set” about 3% higher than the AVP osmostat. This arrangement ensures that thirst, polydipsia, and dilution of body fluids do not occur until plasma osmolarity/sodium starts to exceed the defensive capacity of the antidiuretic mechanism.

Oxytocin is also a nonapeptide that differs from AVP only at positions 3 and 8 (Fig. 374-1). However, it has relatively little antidiuretic effect and seems to act mainly on mammary ducts to facilitate milk letdown during nursing. It also may help initiate or facilitate labor by stimulating contraction of uterine smooth muscle, but it is not clear if this action is physiologic or necessary for normal delivery.

DIABETES INSIPIDUS

Clinical Characteristics

A decrease of 75% or more in the secretion or action of AVP usually results in DI, a syndrome characterized by the production of abnormally large volumes of dilute urine. The 24-h urine volume exceeds 40 mL/kg body weight, and the osmolarity is <300 mosmol/L. The polyuria produces symptoms of urinary frequency, enuresis, and/or nocturia, which may disturb sleep and cause mild daytime fatigue or somnolence. It also results in a slight rise in plasma osmolarity that stimulates thirst and a commensurate increase in fluid intake (polydipsia). Overt clinical signs of dehydration are uncommon unless thirst and/or the compensatory increase of fluid intake are also impaired.

Etiology

A primary deficiency of AVP secretion usually results from agenesis or irreversible destruction of the neurohypophysis. It is referred to variously as neurohypophyseal DI, neurogenic DI, pituitary DI, cranial DI, or central DI. It can be caused by a variety of congenital, acquired, or genetic disorders, but in about one-half of all adult patients, it is idiopathic (Table 374-1). Pituitary DI caused by surgery in or around the neurohypophysis usually appears within 24 h. After a few days, it may transition to a 2- to 3-week period of inappropriate antidiuresis, after which the DI may or may not recur permanently. Five genetic forms of pituitary DI are now known. By far, the most common is transmitted in an autosomal dominant mode and is caused by diverse mutations in the coding region of one allele of the AVP–neurophysin II (or AVP-NPII) gene. All the mutations alter one or more amino acids known to be critical for correct processing and/or folding of the prohormone, thus interfering with its trafficking through the endoplasmic reticulum. The misfolded mutant precursor accumulates and interferes with production of AVP by the normal allele, eventually destroying the magnocellular neurons in which it is produced. The AVP deficiency and DI are usually not present at birth but develop gradually over a period of several months to years, progressing from partial to severe at different rates depending on the mutation. Once established, the deficiency of AVP is permanent, but for unknown reasons, the DI occasionally improves or remits spontaneously in late middle age. The parvocellular neurons that make AVP and the magnocellular neurons that make oxytocin appear to be unaffected. There are also rare autosomal recessive forms of pituitary DI. One is due to an inactivating mutation in the AVP portion of the gene; another is due to a large deletion involving the majority of the AVP gene and regulatory sequences in the intergenic region. A third form is caused by mutations of the WFS 1 gene responsible for Wolfram’s syndrome (DI, diabetes mellitus, optic atrophy, and neural deafness [DIDMOAD]). An X-linked recessive form linked to a region on Xq28 has also been described but the causative gene has not yet been identified.

A primary deficiency of plasma AVP also can result from increased metabolism by an N-terminal aminopeptidase produced by the placenta. It is referred to as gestational DI because the signs and symptoms manifest during pregnancy and usually remit several weeks after delivery.

Secondary deficiencies of AVP secretion result from inhibition by excessive intake of fluids. They are referred to as primary polydipsia and can be divided into three subcategories. One of them, dipsogenic DI, is characterized by inappropriate thirst caused by a reduction in the set of the osmoregulatory mechanism. It sometimes occurs in association with multifocal diseases of the brain such as neurosarcoid, tuberculous meningitis, and multiple sclerosis but is often idiopathic. The second subtype, psychogenic polydipsia, is not associated with thirst, and the polydipsia seems to be a feature of psychosis or obsessive compulsive disorder. The third subtype, iatrogenic polydipsia, results from recommendations to increase fluid intake for its presumed health benefits.

Primary deficiencies in the antidiuretic action of AVP result in nephrogenic DI. The causes can be genetic, acquired, or drug induced (Table 374-1). The most common genetic form is transmitted in a semirecessive X-linked manner. It is caused by mutations in the coding region of the V₂ receptor gene that impair trafficking and/or ligand binding of the mutant receptor. There are also autosomal recessive or dominant forms of nephrogenic DI. They are caused by AQP2 gene mutations that result in complete or partial defects in trafficking and function of the water channels that mediate antidiuresis in the distal and collecting tubules of the kidney.

Secondary deficiencies in the antidiuretic response to AVP result from polyuria per se. They are caused by washout of the medullary concentration gradient and/or suppression of aquaporin function. They usually resolve 24–48 h after the polyuria is corrected but can complicate interpretation of some acute tests used for differential diagnosis.

Pathophysiology

In pituitary, gestational, or nephrogenic DI, the polyuria results in a small (1–2%) decrease in body water and a commensurate increase in plasma osmolarity and sodium that stimulates thirst and a compensatory increase in water intake. As a result, hypernatremia and other overt physical or laboratory signs of dehydration do not develop unless the patient also has a defect in thirst or fails to increase fluid intake for some other reason.

In pituitary and nephrogenic DI, the severity of the defect in AVP secretion or action varies significantly from patient to patient. In some, the defect is so severe that it cannot be overcome by even an intense stimulus such as nausea or severe dehydration. In others, the defect in AVP secretion or action is incomplete, and a modest stimulus such as a few hours of fluid deprivation, smoking, or a vasovagal reaction can raise urine osmolarity as high as 800 mosmol/L. However, even when the defects are partial, the relation of urine osmolarity to plasma AVP in patients with nephrogenic DI (Fig. 374-3A) or of plasma AVP to plasma osmolarity and sodium in patients with pituitary DI (Fig. 374-3B) is subnormal.

In primary polydipsia, the pathogenesis of the polydipsia and polyuria is the reverse of that in pituitary, nephrogenic, and gestational DI. In primary polydipsia, an abnormality in cognition or thirst causes excessive intake of fluids and an increase in body water that reduces plasma osmolarity/sodium, AVP secretion, and urinary concentration. Dilution of the urine, in turn, results in a compensatory increase in urinary free-water excretion that usually offsets the increase in intake and stabilizes plasma osmolarity/sodium at a level only 1–2% below basal. Thus, hyponatremia or clinically appreciable overhydration is uncommon unless the polydipsia is very severe or the compensatory water diuresis is impaired by a drug or disease that stimulates or mimics the antiduretic effect of endogenous AVP. A rise in plasma osmolarity and sodium produced by fluid deprivation or hypertonic saline infusion increases plasma AVP normally. However, the resultant increase in urine concentration is often subnormal because polyuria per se temporarily reduces the capacity of the kidney to concentrate the urine. Thus, the maximum level of urine osmolarity achieved during fluid deprivation is often indistinguishable from that in patients with partial pituitary or partial nephrogenic DI.

Differential Diagnosis

When symptoms of urinary frequency, enuresis, nocturia, and/or persistent thirst are present in the absence of glucosuria, the possibility of DI should be evaluated by collecting a 24-h urine on ad libitum fluid intake. If the osmolarity is <300 mosmol/L and the volume >50 mL/kg per day, the patient has DI and should be evaluated further to determine the type and select appropriate therapy. If the volume and osmolarity are not concordant, the possibility of inaccurate collection can be evaluated by determining if total urinary creatinine is normal for the size of the patient (20–30 mg/kg/day).

The type of DI can sometimes be inferred from the clinical setting or medical history. Often, however, such information is lacking, ambiguous, or misleading, and other approaches to differential diagnosis are needed. If basal plasma osmolarity and sodium are within normal limits, the traditional approach is to determine the effect of fluid deprivation and injection of antidiuretic hormone on urine osmolarity. This approach suffices for differential diagnosis if fluid deprivation raises plasma osmolarity and sodium above the normal range without inducing concentration of the urine. In that event, primary polydipsia and partial defects in AVP secretion and action are excluded, and the effect on urine osmolarity of injecting 2 μg of the AVP analogue, desmopressin indicates whether the patient has severe pituitary DI or severe nephrogenic DI. However, this approach is of little or no diagnostic value if fluid deprivation results in concentration of the urine because the increases in urine osmolarity achieved both before and after the injection of desmopressin are similar in patients with partial pituitary DI, partial nephrogenic DI, and primary polydipsia. These disorders can be differentiated by measuring plasma AVP during fluid deprivation and relating it to the concurrent level of plasma and urine osmolarity (Fig. 374-3). However, this approach does not always differentiate clearly between partial pituitary DI and primary polydipsia unless the measurement is made when plasma osmolarity and sodium are at or above the normal range. This level is difficult to achieve by fluid deprivation alone once urinary concentration occurs. Therefore, it is usually necessary to give a short infusion of 3% saline condition (0.1 mL/kg body weight per minute for 60–90 min) and repeat the measurement of plasma AVP. This approach is highly reliable for differential diagnosis but it is often stressful for the patient and requires special facilities and staff to perform safely and accurately.

A simpler, and less stressful, but equally reliable way to differentiate between pituitary DI, nephrogenic DI, and primary polydipsia is to start by measuring basal plasma AVP and urine osmolarity under conditions of unrestricted fluid intake (Fig. 374-4). If AVP is normal or elevated (>1 pg/mL) and the concurrent urine osmolarity is low (<300 mosm/L), the patient has nephrogenic DI and the only additional evaluation required is to determine the cause. If, however, basal plasma AVP is low or undetectable (<1 pg/mL), nephrogenic DI is very unlikely and MRI of the brain can be performed to differentiate pituitary DI from primary polydipsia. In most healthy adults and children, the posterior pituitary emits a hyperintense signal visible in T1-weighted midsagittal images. This “bright spot” is almost always present in patients with primary polydipsia but is always absent or abnormally small in patients with pituitary DI, even if their AVP deficiency is partial. The MRI is also useful in searching for pathology responsible for pituitary DI or the dipsogenic form of primary polydipsia (Fig. 374-2). The principal caveat is that MRI is not reliable for differential diagnosis of DI in patients with empty sella because they typically lack a bright spot even when their AVP secretion and action are normal. MRI also cannot be used to differentiate pituitary from nephrogenic DI because many patients with nephrogenic DI also lack a posterior pituitary bright spot, probably because they have an abnormally high rate of AVP secretion and turnover.

If MRI and/or AVP assays with the requisite sensitivity and specificity are unavailable and a fluid deprivation test is impractical or undesirable, a third way to differentiate between pituitary DI, nephrogenic DI, and primary polydipsia is a trial of desmopressin therapy. Such a trial should be conducted with very close monitoring of serum sodium as well as urine output, preferably in hospital, because desmopressin will produce hyponatremia in 8–24 h if the patient has primary polydipsia.

TREATMENT

HYPODIPSIC HYPERNATREMIA

An increase in plasma osmolarity/sodium above the normal range (hypertonic hypernatremia) can be caused by either a decrease in total body water or an increase in total body sodium. The former results from a failure to drink enough to replace normal or increased urinary and insensible water loss. The deficient intake can be due either to water deprivation or a lack of thirst (hypodipsia). The most common cause of an increase in total body sodium is primary hyperaldosteronism (Chap. 379). Rarely, it can also result from ingestion of hypertonic saline in the form of sea water or incorrectly prepared infant formula. However, even in these forms of hypernatremia, inadequate intake of water also contributes. This chapter focuses on hypodipsic hypernatremia, the form of hypernatremia due to a primary defect in the thirst mechanism.

Clinical Characteristics

Hypodipsic hypernatremia is a syndrome characterized by chronic or recurrent hypertonic dehydration. The hypernatremia varies widely in severity and usually is associated with signs of hypovolemia such as tachycardia, postural hypotension, azotemia, hyperuricemia, and hypokalemia due to secondary hyperaldosteronism. Muscle weakness, pain, rhabdomyolysis, hyperglycemia, hyperlipidemia, and acute renal failure may also occur. Obtundation or coma may be present but are often absent. Despite inappropriately low levels of plasma AVP, DI usually is not evident at presentation but may develop during rehydration as blood volume, blood pressure, and plasma osmolarity/sodium return toward normal, further reducing plasma AVP.

Etiology

Hypodipsia is usually due to hypogenesis or destruction of the osmoreceptors in the anterior hypothalamus that regulate thirst. These defects can result from various congenital malformations of midline brain structures or may be acquired due to diseases such as occlusions of the anterior communicating artery, primary, or metastatic tumors in the hypothalamus, head trauma, surgery, granulomatous diseases such as sarcoidosis and histiocytosis, AIDS, and cytomegalovirus encephalitis. Because of their proximity, the osmoreceptors that regulate AVP secretion also are usually impaired. Thus, AVP secretion responds poorly or not at all to hyperosmotic stimulation (Fig. 374-6) but, in most cases, increases normally to nonosmotic stimuli such as nausea or large reductions in blood volume or blood pressure, indicating that the neurohypophysis is intact.

Pathophysiology

Hypodipsia results in a failure to drink enough water to replenish obligatory renal and extrarenal losses. Consequently, plasma osmolarity and sodium rise often to extremely high levels before the disorder is recognized. In most cases, urinary loss of water contributes little, if any, to the dehydration because AVP continues to be secreted in the small amounts necessary to concentrate the urine. In some patients this appears to be due to hypovolemic stimulation and/or incomplete destruction of AVP osmoreceptors because plasma AVP declines and DI develops during rehydration (Fig. 374-6). In others, however, plasma AVP does not decline during rehydration even if they are overhydrated. Consequently, they develop a hyponatremic syndrome indistinguishable from inappropriate antidiuresis. This suggests that the AVP osmoreceptors normally provide inhibitory and stimulatory input to the neurohypophysis and the patients can no longer osmotically stimulate or suppress tonic secretion of the hormone because both inputs have been totally eliminated by the same pathology that destroyed the osmoregulation of thirst. In a few patients, the neurohypophysis is also destroyed, resulting in a combination of chronic pituitary DI and hypodipsia that is particularly difficult to manage.

Differential Diagnosis

Hypodipsic hypernatremia usually can be distinguished from other causes of inadequate fluid intake (e.g., coma, paralysis, restraints, absence of fresh water) by the clinical history and setting. Previous episodes and/or denial of thirst and failure to drink spontaneously when the patient is conscious, unrestrained, and hypernatremic are virtually diagnostic. The hypernatremia caused by excessive retention or intake of sodium can be distinguished by the presence of thirst as well as the physical and laboratory signs of hypervolemia rather than hypovolemia.

TREATMENT

HYPONATREMIA DUE TO INAPPROPRIATE ANTIDIURESIS

A decrease in plasma osmolarity/sodium below the normal range (hypotonic hyponatremia) can be due to any of three different types of salt and water imbalance: (1) an increase in total body water that exceeds the increase in total body sodium (hypervolemic hyponatremia); (2) a decrease in body sodium greater than the decrease in body water (hypovolemic hyponatremia); or (3) an increase in body water with little or no change in body sodium (euvolemic hyponatremia) (Chap. 49). All three forms are associated with a failure to fully dilute the urine and mount a water diuresis in the face of hypotonic hyponatremia. However, the disorders with which they are associated and the types of salt and water imbalance that result differ. The hypervolemic form typically occurs in disorders like severe congestive heart failure or cirrhosis in which water is retained in excessive of sodium. The hypovolemic form typically occurs in disorders such as severe diarrhea, diuretic abuse, or mineralocorticoid deficiency in which sodium is lost in excess of water. Euvolemic hyponatremia, however, is due mainly to expansion of total body water caused by excessive intake in the face of a failure to dilute the urine in response to excessive water intake. The impaired dilution is usually caused by a defect in the osmotic suppression of AVP that can have either of two causes. One is a nonhemodynamic stimulus such as nausea or a cortisol deficiency, which can be corrected quickly by treatment with antiemetics or cortisol. The other is a primary defect in osmoregulation caused by another disorder such as malignancy, stroke, or pneumonia that cannot be easily or quickly corrected. The latter is commonly known as the syndrome of inappropriate antidiuretic hormone (SIADH). Much less often, euvolemic hyponatremia can also result from AVP-independent activation of renal V₂ receptors, a variant known as nephrogenic inappropriate antidiuresis or NSIAD. Both of the latter will be discussed in this chapter.

Clinical Characteristics

Antidiuresis of any cause decreases the volume and increases the concentration of urine. If not accompanied by a commensurate reduction in fluid intake or an increase in insensible loss, the reduction in urine output results in excess water retention which expands and dilutes body fluids. If the hyponatremia develops gradually or has been present for more than a few days, it may be largely asymptomatic. However, if it develops acutely, it is usually accompanied by symptoms and signs of water intoxication that may include mild headache, confusion, anorexia, nausea, vomiting, coma, and convulsions. Severe acute hyponatremia may be lethal. Other clinical signs and symptoms vary greatly, depending on the type of hyponatremia. The hypervolemic form is characterized by generalized edema and other signs of marked volume expansion. The opposite is evident in the hypovolemic form. However, overt signs of volume expansion or contraction are absent in SIADH, SIAD, NSIAD, and other forms of euvolemic hyponatremia.

Etiology

In SIADH, the inappropriate secretion of AVP can have many different causes. They include ectopic production of AVP by lung cancer or other neoplasms; eutopic release induced by various diseases or drugs; and exogenous administration of AVP, DDAVP, or large doses of oxytocin (Table 374-2). The ectopic forms result from abnormal expression of the AVP-NPII gene by primary or metastatic malignancies. The eutopic forms occur most often in patients with acute infections or strokes but have also been associated with many other neurologic diseases and injuries. The mechanisms by which these diseases interfere with osmotic suppression of AVP are not known. The defect in osmoregulation can take any of four distinct forms (Fig. 374-6). In one of the most common (reset osmostat), AVP secretion remains fully responsive to changes in plasma osmolarity/sodium, but the threshold, or set point, of the osmoregulatory system is abnormally low. These patients differ from those with the other types of SIADH in that they are able to maximally suppress plasma AVP and dilute their urine if their fluid intake is high enough to reduce their plasma osmolarity and/or sodium to the lower set point. In most patients, SIADH is self-limited and remits spontaneously within 2–3 weeks, but about 10% of cases are chronic. Another, smaller subgroup (~10% of the total) has inappropriate antidiuresis without a demonstrable defect in the osmoregulation of plasma AVP (Fig. 374-6). In some of them, all young boys, the inappropriate antidiuresis has been traced to a constitutively activating mutation of the V₂ receptor gene. This unusual variant may be referred to as familial nephrogenic SIAD (NSIAD) to distinguish it from other possible causes of the syndrome. The inappropriate antidiuresis in these patients appears to be permanent, although the hyponatremia is variable owing presumably to individual differences in fluid intake.

Pathophysiology

Impaired osmotic suppression of antidiuresis results in excessive retention of water and dilution of body fluids only if water intake exceeds insensible and urinary losses. The excess intake is sometimes due to an associated defect in the osmoregulation of thirst (dipsogenic) but can also be psychogenic or iatrogenic, including excessive IV administration of hypotonic fluids. In SIADH and other forms of euvolemic hyponatremia, the decrease in plasma osmolarity/sodium and the increase in extracellular and intracellular volume are proportional to the amount of water retained. Thus, an increase in body water of 10% (~4 L in a 70-kg adult) reduces plasma osmolarity and sodium by ~10% (~28 mosmol/L or 14 meq/L). An increase in body water of this magnitude is rarely detectable on physical examination but will be reflected in a weight gain of about 4 kg. It also increases glomerular filtration and atrial natriuretic hormone and suppresses plasma renin activity, thereby increasing urinary sodium excretion. The resultant reduction in total body sodium decreases the expansion of extracellular volume but aggravates the hyponatremia and further expands intracellular volume. The latter increases brain swelling and intracranial pressure, which probably produces most of the symptoms of acute water intoxication. Within a few days, this swelling may be counteracted by inactivation or elimination of intracellular solutes, resulting in the remission of symptoms even though the hyponatremia persists.

In type I (hypervolemic) or type II (hypovolemic) hyponatremia, osmotic suppression of AVP secretion appears to be counteracted by a hemodynamic stimulus resulting from a large reduction in cardiac output and/or effective blood volume. The resultant antidiuresis is enhanced by decreased distal delivery of glomerular filtrate that results from increased reabsorption of sodium in proximal nephron. If the reduction in urine output is not associated with a commensurate reduction in water intake or an increase in insensible loss, body fluids are expanded and diluted, resulting in hyponatremia despite an increase in body sodium. Unlike SIADH and other forms of euvolemic hyponatremia, however, glomerular filtration is reduced and plasma renin activity and aldosterone are elevated. Thus, the rate of urinary sodium excretion is low (unless sodium reabsorption is impaired by a diuretic), and the hyponatremia is usually accompanied by edema, hypokalemia, azotemia, and hyperuricemia. In type II (hypovolemic) hyponatremia, sodium and water are also retained as an appropriate compensatory response to the severe depletion.

Differential Diagnosis

SIADH is a diagnosis of exclusion that usually can be made from the history, physical examination, and basic laboratory data. If hyperglycemia is present, its contribution to the reduction in plasma sodium can be estimated either by measuring plasma osmolarity for a more accurate estimate of the true “effective” tonicity of body fluids or by correcting the measured plasma sodium for the reduction caused by the hyperglycemia using the simplified formula

where P_na = plasma sodium in meq/L and P_glu = plasma glucose in mg/dL.

If the plasma osmolarity and/or corrected plasma sodium are below normal limits, hypotonic hyponatremia is present and further evaluation to determine the type should be undertaken in order to administer safe and effective treatment. This differentiation is usually possible by evaluating standard clinical indicators of the extracellular fluid volume (Table 374-3). If these findings are ambiguous or contradictory, measuring plasma renin activity or the rate of urinary sodium excretion may be helpful provided that the hyponatremia is not in the recovery phase or is due to a primary defect in renal conservation of sodium, diuretic abuse, or hyporeninemic hypoaldosteronism. The latter may be suspected if serum potassium is elevated instead of low, as it usually is in types I and II hyponatremia. Measurements of plasma AVP are currently of no value in differentiating SIADH from the other types of hyponatremia since the plasma levels are elevated similarly in all. In patients who fulfill the clinical criteria for type III (euvolemic) hyponatremia, morning plasma cortisol should also be measured to exclude secondary adrenal insufficiency. If it is normal and there is no history of nausea/vomiting, the diagnosis of SIADH is confirmed, and a careful search for occult lung cancer or other common causes of the syndrome (Table 374-2) should be undertaken.

SIAD due to an activating mutation of the V₂ receptor gene should be suspected if the hyponatremia occurs in a child or several members of the family or is refractory to treatment with a vaptan (see below). In that case, plasma AVP should be measured to confirm that it is appropriately suppressed while the hyponatremia and antidiuresis are present, and the V₂ receptor gene should be sequenced, if possible.

TREATMENT

GLOBAL PERSPECTIVES

The incidence, clinical characteristics, etiology, pathophysiology, differential diagnosis, and treatments of fluid and electrolyte disorders in tropical and nonindustrialized countries differ in some respects from those in the United States and other industrialized parts of the world. Hyponatremia, for example, appears to be more common and is more likely to be due to infectious diseases such as cholera, shigellosis, and other diarrheal disorders. In these circumstances, hyponatremia is probably due to gastrointestinal losses of salt and water (hypovolemia type II), but other abnormalities, including undefined infectious toxins, also may contribute. The causes of DI are similar worldwide except that malaria and venoms from snake or insect bites are much more common in some tropical climates.