Diagnostic Considerations
The differential diagnoses of the syndrome of inappropriate antidiuretic hormone secretion.(SIADH) include other hyponatremic conditions, which can be divided into those that cause impairment in urinary water excretion and those in which renal handling of water is normal. All patients with hyponatremia should have a plasma osmolality measured to confirm hypo-osmolality.
Conditions in which renal water handling is impaired include the following:
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Effective circulating volume depletion - GI losses (eg, diarrhea, vomiting), renal losses (eg, diuretic therapy, adrenal insufficiency, primary renal salt wasting), skin losses, edematous disorders (congestive heart failure, cirrhosis with portal hypertension, severe nephrotic syndrome)
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Renal failure - Acute kidney injury (AKI) or chronic kidney disease (CKD)
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Other states of ADH excess - Cortisol deficiency, hypothyroidism, exogenous ADH (eg, deamino-D-arginine-vasopressin, vasopressin, oxytocin)
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Decreased solute intake
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Nephrogenic syndrome of inappropriate anti-diuresis (NSIAD)
Disorders with normal water excretion include the following:
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Primary polydipsia
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Reset osmostat
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Cerebral salt wasting
Pseudohyponatremia
Extreme elevations in plasma lipids or proteins can increase the plasma volume and can reduce the measured plasma Na+ concentration. Na+ is contained in the aqueous phase of plasma; the proteins and lipids cause an increase in the nonaqueous phase of plasma, leading to an overall increase in plasma volume without an actual decrease or dilution of Na+ in the aqueous phase. This was more of an issue in the past in the United States, when the conventional method of measuring Na+ (ie, flame-emission spectrophotometry) measured the aqueous and nonaqueous phases of plasma. The correction factors are as follows:
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Plasma triglycerides (g/L) x 0.002 = mEq/L decrease in Na +
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Plasma protein level - 8 (g/L) x 0.025 = mEq/L decrease in Na +
The newer method (using ion-specific Na+ electrodes) measures the Na+ in the aqueous phase only, thus avoiding the error of pseudohyponatremia. Pseudohyponatremia should be suspected when the measured plasma osmolality is normal in the presence of hyponatremia. Pseudohyponatremia may continue to be a problem in parts of the world where flame photometry is still used to measure Na+.
Hyperglycemia
Elevated glucose levels decrease the measured serum Na+ levels by 1.6 mEq/L for every 100 mg/dL increase in glucose. This results from the osmotic effect of glucose drawing water into the intravascular space. Plasma osmolality is high in this situation. This is a form of transient hyponatremia that corrects itself as hyperglycemia is reversed. [18] A similar form of hyponatremia can occur with any osmotically active substance in plasma, such as mannitol or dextran.
Exercise-induced hyponatremia
Exercise-induced hyponatremia has been reported during prolonged exercise such as in marathon runners and triathletes, usually in warmer climates, which can lead to severe hyponatremia associated with neurological symptoms. [23] The syndrome appears to arise because of excessive water consumption during the physical exercise coupled with loss of sodium chloride in sweat and nonosmotic stimulation of AVP secretion (from stress, volume contraction, nausea, and nonsteroidal anti-inflammatory drugs [NSAIDs]). Some athletes with cerebral edema also develop noncardiogenic pulmonary edema. [16]
Cerebral salt wasting
The term cerebral salt wasting (CSW) was introduced in the 1950s to describe an entity seen with certain cerebral disorders that can impair the ability of the kidneys to conserve Na+, with resultant salt wasting and polyuria. CSW is defined as the renal loss of Na+ with intracranial disease, which leads to hyponatremia and a decrease in extracellular fluid volume. [24, 25]
Vasopressin-resistant polyuria with hyponatremia, particularly in the setting of cerebral injury or cerebral disease or when accompanied by dehydration, should prompt consideration of CSW in the differential diagnosis. CSW must be distinguished from SIADH because management of these 2 conditions differs significantly.
The differences and similarities in findings for CSW and SIADH are itemized as follows:
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Hyponatremia - Present in both CSW and SIADH
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Urine Na - Increased in both CSW and SIADH
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Volume - Reduced in CSW and normal or increased in SIADH
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Salt wasting - Gross in CSW and self-limited in SIADH
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Urine output - Polyuria in CSW and variable in SIADH
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Hypouricemia - Occasional in CSW and frequent in SIADH
Over the years, much debate has been focused on the existence of this entity. The evidence in favor of CSW rests on the following points:
- The presence of a negative salt balance
- The development of volume contraction (by definition, patients with SIADH are euvolemic)
- The fact that patients with CSW respond to salt and volume replacement rather than to fluid restriction
Various mechanisms have been postulated, including the roles of natriuretic peptides and neural regulatory mechanisms. Measurement of AVP or atrial natriuretic peptide levels is not helpful because they have been known to vary even in persons with SIADH.
CSW is treated with Na+ replacement, which is diametrically opposite to that for SIADH. Na+ administration in persons with CSW corrects the hyponatremia and the fluid loss; however, in patients with SIADH, the effect is temporary. The mineralocorticoid fludrocortisone has been used as part of the treatment of CSW. [25]
Adrenal insufficiency
Cortisol has a negative feedback effect on ADH and corticotropin-releasing hormone. The absence of cortisol thus removes this inhibitory effect, increasing the release of ADH.
Renal disease
With declining renal function, the ability to excrete free water decreases, and the more advanced the reduction in glomerular filtration rate (GFR), the easier it is for patients to become hyponatremic with unrestricted fluid intake. In patients on long-term dialysis with no urine output, fluid intake no greater than insensible losses leads to a predictable fall in serum Na, which, however, is not sustained because of regular maintenance dialysis.
Reset osmostat
Persons with this entity have a normal response to changes in osmolality, but their threshold for ADH release is reduced. Therefore, they have a lower, but stable, plasma Na+ concentration. Some individuals probably carry a nonsynonymous polymorphism (P19S) in the transient receptor potential vanilloid 4 (TRPV4) channel, part of the osmoreceptor system, since this mutation has been shown to be associated with hyponatremia. [26]
The reset osmostat has been observed in pregnant women. Increased human chorionic gonadotropin levels have been implicated in this condition. The serum Na+ concentration falls by approximately 5 mEq/L in the first 2 months of pregnancy and remains stable until after delivery, when it returns to normal levels. Recognizing this entity is important because it does not require treatment.
Psychogenic polydipsia
This condition is characterized by an increase in water intake attributed to a defect in the thirst mechanism. In some patients, the osmotic threshold for thirst is reset below the reset for release of ADH. This disorder is mostly observed in patients with psychosis.
Water excretion is normal in these patients, and water restriction corrects the hyponatremia. In a patient on a normal diet and an average solute (protein and salts) intake, a substantial amount of water must be imbibed for hyponatremia to develop. Consider an individual who has 700 mOsm (primarily consisting of urea, Na+, potassium, and chloride) to excrete per day. Ordinarily, these individuals can vary their urine osmolality between 50 and 1400 mOsm/L and thus can excrete the osmotic load in a minimum of 500 mL and a maximum of 14 L. As long as their fluid intake is between these extremes, they adjust urine osmolality to excrete the load. To become hyponatremic, such an individual must drink more than 14 L a day.
Decreased solute intake
This disorder is observed in persons who drink hyponatremic fluids without adequate food intake. The condition is described in individuals who drink beer (beer potomania) and thrive on little else and thus have substantially reduced protein and salt intake. The daily solute intake directly influences the osmotic load to be excreted. With poor nutritional intake, the osmotic load may be as little as 200 mOsm; in this situation, it can be excreted in a maximum of 4 L. Ingestion of a larger quantity of solute-free fluids without other avenues for water loss can result in the development of hyponatremia.
Diuretics and hyponatremia
Diuretics can cause mild-to-severe hyponatremia. Thiazide diuretics cause hyponatremia more often than loop diuretics. This is related to the different sites of action of these agents.
Loop diuretics act in the medullary thick ascending limb and prevent Na+ absorption in the medullary thick ascending limb. This interferes with the concentrating ability by diminishing medullary osmolality. The Na+ can be reabsorbed once it reaches the distal tubule and the collecting duct.
The thiazide diuretics prevent Na+ absorption in the distal tubule and do not interfere with the medullary concentrating ability or the effect of ADH. However, the distal tubule is the diluting segment of the nephron, and diminished Na+ absorption here increases urine osmolality and prevents the excretion of hypotonic urine. In patients who are susceptible to this effect, hyponatremia is usually observed within 2 weeks. After that, a new steady state is reached and further changes in serum Na+ only occur with an added stimulus such as vomiting and diarrhea.
Nephrogenic syndrome of inappropriate antidiuresis
NSIAD is a rare X-linked recessive genetic disease arising from gain-of-function mutations in the V2 receptor, resulting in a spontaneously active receptor and unregulated water reabsorption. The laboratory features are identical to those of SIADH, with euvolemic hyponatremia, plasma hypo-osmolality, and increased urinary osmolality. The disease is likely to present in early infancy, although some adults have been described with this disorder. [27, 28] If AVP levels are measured, they are predicted to be low.
Hypervolemic hyponatremia
Other conditions to consider in the differential diagnosis of hyponatremia are those that are associated with hypervolemia in which the baroreceptors perceive reduced effective circulating volume and stimulate AVP secretion. These conditions include congestive heart failure, cirrhosis, and nephrotic syndrome. These should be evident on clinical examination because of the presence of peripheral edema with elevated jugular venous pressure, pulmonary rales, ascites, or stigmata of advanced liver disease.
Differential Diagnoses
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Cerebral salt wasting
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Exercise induced hyponatremia
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Psychogenic Polydipsia
