When the serum sodium level is unexpectedly low, one must determine whether it is due to false (artifactual) hyponatremia, sodium depletion, hemodilution, the IADH syndrome, or the reset osmostat syndrome. The first step is to rule out artifactual causes. The serum sodium tests should be repeated and blood redrawn if necessary, avoiding areas receiving IV infusions. Then, other causes for artifact, such as hyperlipemia or myeloma protein (if a flame photometer is being used), should be excluded. Next, iatrogenic causes should be considered, including sodium-poor IV fluids (producing dilution) and diuretics (producing sodium depletion). If none of these possibilities is the cause, measurement of urine sodium excretion and serum or urine osmolality may be useful.

Urine sodium. In hyponatremia, the kidney normally attempts to conserve sodium, so that the urine sodium level is low (<20 mEq/L, usually <10 mEq/L). If the patient has hyponatremia and is not receiving IV fluids containing sodium, and if the urine sodium concentration is normal or high (e.g., early morning random urine sodium >20 mEq/L), this suggests inappropriate sodium loss through the kidneys. Possible etiologies are (1) acute or chronic renal failure, such as diffuse, bilateral, renal tissue injury (blood urea nitrogen [BUN] and serum creatinine levels confirm or eliminate this possibility); (2) effect of diuretics or osmotic diuresis; (3) Addison’s disease; (4) IADH syndrome; and (5) the reset osmostat syndrome.

A low urine sodium concentration is a normal response to a low serum sodium level and suggests (1) nonrenal sodium loss (sweating or GI tract loss), (2) the reset osmostat syndrome, and (3) ECF dilution. Presence of edema favors ECF dilutional etiology (e.g., cirrhosis, congestive heart failure, nephrotic syndrome). Measurement of certain relatively stable constituents of blood, such as hemoglobin and total protein, may provide useful information. However, one must have previous baseline values to assist interpretation. A significant decrease in hemoglobin and total protein levels possibly in other substances such as serum creatinine and uric acid suggests hemodilution. Similar changes in several blood constituents are more helpful than a change in only one, since any constituent could change due to disease that is independent of vascular fluid shifts. A significant increase in hemoglobin level and other blood constituents suggests nonrenal sodium loss with accompanying dehydration.

The best way to determine hemodilution or hemoconcentration is by plasma volume measurement, most often by using albumin tagged with radioactive iodine. However, the diagnosis usually can be made in other ways.

Serum and urine osmolality. Osmolality is the measurement of the number of osmotically active particles in a solution. It is determined by either the degree of induced freezing point change or measurement of vapor pressure in special equipment. Units are milliosmoles per liter of water. Therefore, osmolality depends not only on the quantity of solute particles but also on the amount of water in which they are dissolved. Sodium is by far the major constituent of serum osmolality. Plasma proteins have little osmotic activity and normally are essentially noncontributory to serum osmolality. Serum (or plasma) osmolality may be calculated from various formulas, such as:

mOs m/L = 2Na + BG/20 + BUN/3

where blood glucose (BG) and BUN are in mg/100 ml and Na (sodium) is in mEq/L. The adult reference range is 275-300 mOsm/L. The ratio of serum sodium concentration to serum osmolality (Na/Osm) is normally 0.43-0.50.

Increased serum osmolality. Increased serum osmolality may be caused by loss of hypotonic (sodium-poor) water producing dehydration. Some etiologies include diabetes insipidus, fluid deprivation without replacing the daily insensible water loss of 0.5-1.0 L, and hypotonic fluid loss from skin, GI tract, or osmotic diuresis. It may also be caused by sodium overload, hyperglycemia (100 mg of glucose/100 ml increases osmolality about 5.5 mOsm/L), uremia (10 mg of urea/100 ml increases osmolality about 3.5 mOsm/L), unknown metabolic products, or various drugs or chemicals, especially ethyl alcohol. Ethanol is one of the more common causes for increased serum osmolality. Each 100 mg of ethanol/100 ml (equivalent to a serum concentration of 0.1%) raises serum osmolality about 22 mOsm/L. An “osmolal gap” (the difference between the calculated and the measured osmolality) of more than 10 mOsm/L provides a clue to the presence of unusual solutes. Osmolality is one of the criteria for diagnosis of hyperosmolar nonketotic acidosis and of the IADH syndrome (discussed previously). Renal dialysis units sometimes determine the osmolality of the dialysis bath solution to help verify that its electrolyte composition is within acceptable limits.

Decreased serum osmolality. Serum osmolality is usually decreased (or borderline low) in true noncomplicated hyponatremia. Hyponatremia with definitely normal or elevated serum osmolality can be due to (1) artifactual hyponatremia, due to interference by hyperlipidemia or elevated protein with flame photometer methods; (2) the presence of abnormal quantities of normal hyperosmolar substances, such as glucose or urea; or (3) the presence of abnormal hyperosmolar substances, such as ethanol, methanol, lactic acid or other organic acids, or unknown metabolic products. In categories 2 and 3, measured osmolality is more than 10 mOsm/L above calculated osmolality (alcohol does not produce this osmolal gap when the vapor pressure technique is used). Most of the hyperosmolar substances listed here, with the exception of ethanol, are associated with metabolic acidosis and will usually produce an elevated anion gap.

An appreciable minority of patients with hyponatremia (especially of mild degree) have serum osmolality results in the low-normal range, although theoretically the osmolality value should be decreased. Some of these patients may be dehydrated; others may have cardiac, renal, or hepatic disease. These diseases characteristically reduce the Na/Osm ratio, this being partially attributed to the effects of increased blood glucose, urea, or unknown metabolic substances. Especially in uremia, osmolality changes cannot always be accounted for by the effects of BUN alone. Patients in shock may have disproportionately elevated measured osmolality compared with calculated osmolality; again, this points toward circulating metabolic products. Besides elevating osmolality, these substances displace a certain amount of sodium from serum, thus lowering sodium levels.

Urine osmolality. In patients with hyponatremia, urine osmolality is most helpful in diagnosis of the IADH syndrome (discussed previously). Otherwise, urine osmolality values parallel the amount of sodium excreted, except that osmolality values may be disproportionately increased when large quantities of hyperosmotic substances (glucose, urea, ethanol, etc.) are also being excreted, causing an increased urine osmolality gap.

Summary of laboratory findings in hyponatremia

1. When hyponatremia is secondary to exogenous hemodilution from excess sodium-deficient fluid (e.g., excess IV fluids or polydipsia), serum osmolality is low, urine osmolality is low, and the urine sodium level is low. There may be other laboratory evidence of hemodilution.

2. When hyponatremia is secondary to endogenous hemodilution in cirrhosis, nephrotic syndrome, or congestive heart failure, serum osmolality is decreased and the urine sodium concentration is low. There may be other laboratory evidence to suggest hemodilution. The patient may have visible edema. The underlying condition (e.g., cirrhosis) may be evident.

3. When hyponatremia is due to sodium loss not involving the kidney (skin or GI tract), serum osmolality is usually decreased (or low normal due to dehydration if there is water intake that is inadequate). The degree of dehydration would influence the serum osmolality value. The urine sodium concentration is low. There may be other laboratory and clinical evidence of dehydration.

4. When hyponatremia is due to sodium loss through the kidneys (diuretics, renal failure, Addison’s disease), there is low serum osmolality and the urine sodium concentration is increased. Both BUN and serum creatinine levels are elevated in chronic renal disease (although they can be elevated from prerenal azotemia with normal kidneys).

5. In IADH syndrome, serum osmolality is low, urine osmolality is normal or increased, and urine sodium concentration is normal or high. Serum AVP (ADH) level is elevated.

6. In false hyponatremia due to marked serum protein or triglyceride elevation, serum sodium concentration is mildly decreased, serum osmolality is normal, and urine sodium concentration is normal.

7. In hyponatremia secondary to marked hyperglycemia, serum osmolality is increased; this suggests the presence of hyperosmotic substances, of which glucose can be confirmed by a blood glucose measurement.

The laboratory findings described earlier and summarized above apply to untreated classic cases. Diuretic or fluid therapy, or therapy with various other medications, may alter fluid and electrolyte dynamics and change the typical laboratory picture, or may even convert one type of hyponatremia into another. There is also a problem when two conditions coexist, for example, depletional hyponatremia from GI tract loss (which should produce dehydration and low urine sodium concentration) in a patient with poor renal function (whose kidneys cannot conserve sodium and who thus continues to excrete normal amounts of sodium into the urine despite dehydration).

Certain other test results or clinical findings suggest certain diseases. Hyperkalemia with hyponatremia raises the possibility of renal failure or Addison’s disease. If the patient’s hyponatremia is at least moderate in degree and is asymptomatic, it may reflect chronic hyponatremia rather than acute. If the patient has the reset osmostat syndrome, water restriction does not correct the hyponatremia, whereas water restriction would correct the hyponatremia of the IADH syndrome. If the serum osmolality is well within reference range in a patient with hyponatremia, and the sodium assay was done using flame photometry, serum total protein measurement and examination of the serum for the creamy appearance of hypertriglyceridemia can point toward pseudohyponatremia. If ion selective electrodes were used to assay sodium, and serum osmolality is normal or elevated in hyponatremia, calculation of the osmolal gap can point toward the presence of unexpected hyperosmolal substances.