Diagnostic evaluation of adults with hyponatremia

INTRODUCTION — Hyponatremia, defined as a serum sodium concentration below 135 mEq/L, is usually caused by a failure to excrete water normally [1,2]. In healthy individuals, the ingestion of water does not lead to hyponatremia because suppressed release of antidiuretic hormone (ADH), also called vasopressin, allows excess water to be excreted in a dilute urine (figure 1).

Renal water excretion is impaired in most patients who develop hyponatremia, usually due to an inability to suppress ADH secretion. An uncommon exception occurs in psychotic patients with primary polydipsia who drink such large quantities of fluid that, despite appropriately suppressed ADH release, the excretory capacity of the kidney is overwhelmed.

The diagnostic approach to the patient with hyponatremia will be reviewed here. Many patients with hyponatremia have a single cause, but multiple factors sometimes contribute to the fall in plasma sodium. As an example, when a patient infected with HIV becomes hyponatremic, volume depletion, the syndrome of inappropriate ADH secretion (SIADH), and adrenal insufficiency all may be present. (See "Electrolyte disturbances with HIV infection".)

The causes and treatment of hyponatremia are discussed separately:

●(See "Causes of hypotonic hyponatremia in adults".)

●(See "Causes of hyponatremia without hypotonicity (including pseudohyponatremia)".)

●(See "Overview of the treatment of hyponatremia in adults".)

●(See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat".)

OVERVIEW OF THE DIAGNOSTIC APPROACH — The evaluation of hyponatremia should follow a logical progression, answering several key questions. The first step is to determine if the patient has pseudohyponatremia, hypertonic hyponatremia, or isotonic hyponatremia, rather than hypotonic hyponatremia. (See 'Patients with potentially normal or elevated plasma tonicity' below.)

Once it has been determined that the patient has hypotonic hyponatremia (as is usually the case), the next step is to determine its cause. (See 'Patients with hypotonic hyponatremia' below.)

Because most patients with hypotonic hyponatremia are unable to excrete water normally, the cause of impaired water excretion should be evaluated:

●Is the glomerular filtration rate (GFR) severely reduced? (See 'Patients with severely reduced GFR' below.)

●Is the patient taking a thiazide diuretic? (See 'Patients taking thiazides' below.)

●Does the patient have an edematous state (eg, heart failure, cirrhosis)? (See 'Patients with edema and/or ascites' below.)

●Does the patient have true hypovolemia, and, if so, what is the cause? (See 'Apparent hypovolemia' below.)

●Does the patient have the syndrome of inappropriate antidiuretic hormone (ADH) secretion (SIADH) and, if so, why? (See 'High urine sodium and osmolality' below.)

If, despite hyponatremia, urine osmolality is found to be maximally dilute (<100 mosmol/kg water), four possibilities should be considered (see 'Low urine sodium and osmolality' below):

●Was there massive water intake, thereby overwhelming a normal ability to excrete water?

●Was the diet deficient in protein, severely limiting urine solute secretion?

●Was urine osmolality measured after the cause of increased ADH release had already resolved?

●Does the patient have a reset osmostat?

The answers to these questions are provided by a focused history and physical examination supplemented by laboratory data.

This topic presents an algorithmic clinical approach to determining the cause of hyponatremia in adults (algorithm 1). A physiologic approach to determining the cause of hyponatremia, categorized by the ability to dilute the urine and by whether ADH is suppressed, is presented in a table and discussed in detail in a different topic (table 1). (See "Causes of hypotonic hyponatremia in adults".)

If acute hyponatremia is suspected or if the patient has neurologic symptoms, therapy may be required before completing the diagnostic algorithm. (See "Overview of the treatment of hyponatremia in adults".)

THE INITIAL EVALUATION — The initial diagnostic approach to the adult patient with hyponatremia consists of a directed history and physical examination as well as selected laboratory tests (see 'History and physical examination' below and 'Tests that are often initially available' below). When hyponatremia is first discovered, some elements of the history, key features of the physical exam, and the results of several helpful laboratory tests are usually already available, and these guide the subsequent diagnostic approach (algorithm 1).

If hyperglycemia is present, the serum sodium concentration should be corrected for the effect of glucose to exclude hypertonic hyponatremia.

In addition, other patients whose history and initial laboratory studies suggest one of the following should be evaluated for possible isotonic or hypertonic hyponatremia:

●Patients who have had recent surgery utilizing large volumes of electrolyte-poor irrigation fluid (eg, prostate or intrauterine procedures)

●Patients treated with mannitol, glycerol, or intravenous immune globulin

●Patients with lipemic serum

●Patients with obstructive jaundice

●Patients with a known plasma cell dyscrasia

Patients who do not have hyperglycemia or one of these other features associated with isotonic or hypertonic hyponatremia are likely to have hypotonic hyponatremia. (See 'Patients with hypotonic hyponatremia' below.)

History and physical examination — The key aspects of the history and physical examination directed toward determining the cause of hyponatremia (table 1) are as follows [2-4]:

●A history of electrolyte-rich fluid loss (due, for example, to vomiting, diarrhea, or diuretic therapy) that may indicate hypovolemia or, on examination, signs of extracellular volume depletion, such as decreased skin turgor, a low jugular venous pressure, or orthostatic or persistent hypotension, although none of these are diagnostic of hypovolemia. (See "Etiology, clinical manifestations, and diagnosis of volume depletion in adults".)

●A history of low protein intake and/or high fluid intake. (See "Causes of hypotonic hyponatremia in adults", section on 'Low dietary solute intake'.)

●A history consistent with malignancy, central nervous system disease, pulmonary disease, HIV infection, heart failure, hepatic failure, or a plasma cell dyscrasia. (See "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)" and "Electrolyte disturbances with HIV infection" and "Hyponatremia in patients with heart failure" and "Hyponatremia in patients with cirrhosis".)

●Use of medications associated with hyponatremia, such as thiazide and thiazide-type diuretics, mannitol, intravenous immune globulin, desmopressin (dDAVP), ecstasy (methylenedioxymethamphetamine), and medications acting on the central nervous system including some antidepressants, antiepileptics, and antipsychotics. (See "Diuretic-induced hyponatremia" and "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)", section on 'Drugs'.)

●Very recent surgery. (See "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)", section on 'Surgery' and "Hyponatremia following transurethral resection, hysteroscopy, or other procedures involving electrolyte-free irrigation".)

●Signs of peripheral edema and/or ascites, which can be due to heart failure, cirrhosis, or kidney failure. (See "Clinical manifestations and evaluation of edema in adults" and "Heart failure: Clinical manifestations and diagnosis in adults" and "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis".)

●Symptoms and signs suggestive of adrenal insufficiency or hypothyroidism. (See "Determining the etiology of adrenal insufficiency in adults" and "Diagnosis of and screening for hypothyroidism in nonpregnant adults".)

●A history of prior episodes of hyponatremia.

In addition, it is important to evaluate the rapidity of the onset of hyponatremia (if possible) and the severity of symptoms due to hyponatremia. This information helps guide the approach to therapy. (See "Overview of the treatment of hyponatremia in adults", section on 'Pretreatment evaluation'.)

Although the history and physical examination often provide important clues to the cause of hyponatremia, identification of subtle degrees of volume depletion or edema may be difficult, and the history may not always disclose poor dietary protein intake or polydipsia [4,5]. As a result, laboratory testing is almost always required to establish the diagnosis [5].

Tests that are often initially available — Some laboratory tests are typically available at the time that hyponatremia is diagnosed, and these provide important initial information in the differential diagnosis [2]:

●Serum glucose

●Serum creatinine

●Serum potassium and bicarbonate

These tests are usually part of a basic metabolic panel that also includes the serum sodium, potassium, chloride, bicarbonate, and urea concentrations. If severe hypertriglyceridemia is present, the clinical laboratory may report that the serum is lipemic; this information suggests the possibility of isotonic hyponatremia. (See "Causes of hyponatremia without hypotonicity (including pseudohyponatremia)".)

When hyponatremia is first discovered, results of a complete blood count, liver function tests (alanine transaminase, aspartate aminotransferase, bilirubin, and albumin), and the serum calcium may already be known. Abnormalities in these values can occasionally indicate an underlying disease that is causing or contributing to hyponatremia.

When to measure the serum osmolality — The serum osmolality, which normally ranges from 275 to 290 mosmol/kg, is not a required part of the diagnostic approach in all patients with hyponatremia; rather, it is measured in specific clinical scenarios. (Related Pathway(s): Hyponatremia: Evaluation in adults.)

Serum tonicity, also called the effective serum osmolality, is the parameter sensed by osmoreceptors; serum tonicity determines the transcellular distribution of water. Water can freely cross almost all cell membranes through aquaporin channels and moves from an area of lower tonicity (higher water content) to an area of higher tonicity (lower water content). Tonicity is not readily measured but is deduced from other laboratory measurements. (See "Causes of hyponatremia without hypotonicity (including pseudohyponatremia)".)

The main difference between tonicity and osmolality is that tonicity reflects the concentration of solutes that do not easily cross cell membranes (mostly sodium salts with a small contribution from glucose) and therefore affect the movement of water between cells and the extracellular fluid. By contrast, osmolality also includes the osmotic contributions of urea and (if present) ethanol or other alcohols or glycols, which are considered "ineffective" osmoles since they can equilibrate across the cell membrane and therefore have little effect on water movement. (See 'Ineffective osmoles' below.)

Hyperglycemia is a common cause of hypertonic hyponatremia. In patients with normal serum glucose, or in those whose serum sodium remains low after correcting for hyperglycemia, the serum osmolality should be measured if other causes of isotonic or hypertonic hyponatremia are suspected. As noted, such patients include (see "Causes of hyponatremia without hypotonicity (including pseudohyponatremia)"):

●Patients who have had recent transurethral prostate surgery or recent hysteroscopy

●Patients who were recently prescribed mannitol, glycerol, or intravenous immune globulin

●Patients with lipemic serum

●Patients with obstructive jaundice

●Patients with a known or suspected plasma cell dyscrasia

Ineffective osmoles — The measured serum osmolality can sometimes be misleading, suggesting a diagnosis of hypertonic hyponatremia or isotonic hyponatremia in a patient who instead has hypotonic hyponatremia. This most commonly occurs with:

●Azotemia – Patients with advanced kidney disease may develop hyponatremia because their reduced kidney function impairs their ability to excrete excess water. Although the low serum sodium concentration will tend to lower the serum osmolality, this effect is counterbalanced to a variable degree by azotemia, which increases the osmolality. Thus, the measured osmolality may be normal or elevated. However, despite the fact that high urea concentrations raise the osmolality, they do not increase tonicity. In contrast to sodium and glucose, urea is an ineffective osmole since it can freely cross cell membranes and therefore does not obligate water movement out of cells. Thus, patients with hyponatremia and kidney failure have a low effective serum osmolality (ie, a low tonicity) that becomes apparent if the measured osmolality is corrected for the effect of urea:

Dividing the blood urea nitrogen (BUN) by 2.8 converts mg/dL of urea nitrogen into mmol/L of urea, which is required when calculating osmolality. If blood urea is measured in units of mmol/L, the formula is:

●Alcohol intoxication – True hyponatremia is common in patients with alcoholism. The reduction in the plasma osmolality resulting from the low serum sodium concentration can be offset in some patients by high circulating levels of ethanol. Ethanol, like urea, is an ineffective osmole since it can freely cross cell membranes and therefore does not obligate water movement out of cells. Thus, patients with hyponatremia and alcoholism may have a low serum sodium concentration and a low calculated serum osmolality, but a measured osmolality that is not low [6]. The reason for the gap between the calculated and measured serum osmolality becomes apparent when the blood alcohol level is measured. (See "Serum osmolal gap", section on 'Ethanol ingestion'.)

PATIENTS WITH POTENTIALLY NORMAL OR ELEVATED PLASMA TONICITY — The majority of hyponatremic patients have hypotonic hyponatremia. However, the history, physical exam, and laboratory studies that are available initially can indicate whether a patient with hyponatremia might have pseudohyponatremia or hypertonic or isotonic hyponatremia, rather than hypotonic hyponatremia. As examples, patients with lipemic serum, obstructive jaundice, or a history of monoclonal gammopathy may have pseudohyponatremia, whereas patients with severe hyperglycemia or a history of recent prostate or uterine surgery may have hypertonic or isotonic hyponatremia.

Patients who might have pseudohyponatremia — Hyperlipidemia or hyperproteinemia lowers the serum sodium concentration (and therefore the calculated serum osmolality) when it is measured with certain analyzers, without causing a major change in the sodium concentration in the water phase of serum or the measured serum osmolality [7]. This laboratory artifact, which is called pseudohyponatremia, is presented elsewhere. (See "Causes of hyponatremia without hypotonicity (including pseudohyponatremia)", section on 'Pseudohyponatremia'.) (Related Pathway(s): Hyponatremia: Evaluation in adults.)

Because point-of-care devices are not affected by this laboratory artifact, a discrepancy between the serum sodium concentration determined by a point-of-care device and the sodium value determined by a central laboratory should suggest the possibility of pseudohyponatremia.

Patients with lipemic serum — Hypertriglyceridemia that is severe enough to result in clinically significant pseudohyponatremia has been reported primarily in patients with pancreatitis and diabetic ketoacidosis. If an electrolyte analyzer is used that is susceptible to artifacts created by hyperlipidemia, a 10 mmol/L (886 mg/dL) increase in plasma triglycerides will reduce the serum sodium concentration by approximately 1 mEq/L [8].

Patients with obstructive jaundice — Pseudohyponatremia can occur in jaundiced patients with biliary obstruction or cholestasis who have extreme elevations of total serum cholesterol and high levels of lipoprotein-X. The lowest reported total serum cholesterol resulting in pseudohyponatremia was 977 mg/dL (the corresponding serum sodium was 129 mmol/L), and the highest was 4091 mg/dL (the corresponding serum sodium was 101 mmol/L) [9]. Lipoprotein-X is an insoluble compound that forms when there is reflux of unesterified cholesterol and phospholipids into the circulation. Lipoprotein-X does not accumulate in other diseases resulting in severely elevated total serum cholesterol, such as homozygous familial hypercholesterolemia, which is not associated with pseudohyponatremia. In contrast to hypertriglyceridemia, elevated lipoprotein-X levels do not cause the serum to appear lipemic.

Patients with a plasma cell dyscrasia — Pseudohyponatremia can occur in patients with myeloma who have severe hyperproteinemia (usually greater than 10 g/dL). A 1 g/dL increase in plasma protein concentration will decrease the serum sodium concentration by approximately 0.7 mEq/L [10]. In addition to the reduction in plasma water content caused by a high protein concentration, monoclonal proteins may artifactually lower the sodium concentration measured by volume-sensitive devices because of hyperviscosity and other factors that interfere with proper dilution of the plasma sample.

Patients who might have isotonic or hypertonic hyponatremia — Most patients with hyponatremia have hypotonic hyponatremia because serum tonicity is primarily determined by the sodium concentration and accompanying anions. However, some patients have isotonic or hypertonic hyponatremia. (Related Pathway(s): Hyponatremia: Evaluation in adults.)

Hyperglycemic patients — In patients with marked hyperglycemia, the increase in serum glucose raises the serum tonicity, which pulls water out of cells, expands the extracellular water space, and thereby lowers the serum sodium concentration. (See "Causes of hyponatremia without hypotonicity (including pseudohyponatremia)", section on 'Hypertonic hyponatremia caused by hyperglycemia' and "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis", section on 'Serum sodium'.)

Patients with recent prostate or uterine surgery — The absorption of nonconductive glycine, sorbitol, or mannitol irrigation solutions during transurethral resection of the prostate or bladder (called the transurethral resection syndrome) or during hysteroscopy or laparoscopic surgery can lower the serum sodium by increasing the extracellular fluid volume with these sodium-free solutions. These disorders are discussed in detail separately. (See "Causes of hyponatremia without hypotonicity (including pseudohyponatremia)", section on 'Hypertonic or isotonic hyponatremia caused by exogenous solutes' and "Hyponatremia following transurethral resection, hysteroscopy, or other procedures involving electrolyte-free irrigation", section on 'Pathogenesis of neurologic symptoms' and "Hysteroscopy: Managing fluid and gas distending media".)

Patients given mannitol or intravenous immune globulin — Parenteral formulations of immune globulin are usually suspended in hypertonic mannitol, maltose, or sucrose. The administration of these products to patients with impaired kidney function (which may be an adverse effect of the infused solutions) can generate hyponatremia. (See "Causes of hyponatremia without hypotonicity (including pseudohyponatremia)", section on 'Hypertonic or isotonic hyponatremia caused by exogenous solutes' and "Complications of mannitol therapy" and "Intravenous immune globulin: Adverse effects".)

PATIENTS WITH HYPOTONIC HYPONATREMIA — The serum creatinine concentration, which can be used to estimate glomerular filtration rate (GFR), and the patient's medication history are typically available at the time that hyponatremia is discovered. Both severely reduced GFR and thiazide (or thiazide-type) diuretics impair the ability to dilute the urine normally, and they are important causes of hypotonic hyponatremia. (See 'Patients with severely reduced GFR' below and 'Patients taking thiazides' below.)

Additional evaluation is needed in patients with hypotonic hyponatremia who do not have severely reduced GFR and are not taking thiazides, or whose initial history, examination, and laboratory studies suggest another possible cause of hyponatremia (eg, peripheral edema and/or ascites, history of lung cancer, history of vomiting and/or diarrhea, history of a psychotic disorder, etc). (See 'Other patients' below.) (Related Pathway(s): Hyponatremia: Evaluation in adults.)

Patients with severely reduced GFR — The ability to excrete free water is not significantly impaired in patients with mild to moderate kidney function impairment. Thus, normonatremia is usually maintained. By contrast, in advanced kidney function impairment (eg, <15 mL/min), the minimum urine osmolality rises to as high as 200 to 250 mosmol/kg despite the appropriate suppression of antidiuretic hormone (ADH). The osmotic diuresis induced by increased solute excretion per functioning nephron is thought to be responsible for the inability to dilute the urine. The impairment of free water excretion in advanced kidney failure can lead to the retention of ingested water and the development of hyponatremia. (See "Causes of hypotonic hyponatremia in adults", section on 'Unimpaired urine dilution'.)

Patients taking thiazides — Hyponatremia, which can be severe, is an occasional complication of therapy with thiazide diuretics. It typically begins soon after the onset of thiazide therapy, but hyponatremia can also occur in patients receiving long-term thiazide therapy who had previously had a normal serum sodium concentration if they develop an intercurrent illness. (See "Diuretic-induced hyponatremia".)

Patients with hyponatremia that is caused by thiazide diuretics can present with features similar to those in patients with the syndrome of ADH secretion (SIADH), including apparent euvolemia by physical examination as well as low serum uric acid and urea nitrogen concentrations. It is therefore often difficult to distinguish between SIADH and thiazide-induced hyponatremia. One small study of seven patients who had been treated with thiazides suggested that the fractional excretion of uric acid (FEUA) could distinguish between thiazide-induced hyponatremia and SIADH [11]. Specifically, the authors concluded that an FEUA >12 percent identified SIADH with 100 percent positive predictive value, while an FEUA <8 percent excluded SIADH with 100 percent negative predictive value. However, this finding was not confirmed in a subsequent, larger study; FEUA in 42 patients with hyponatremia due to SIADH (16.1±4.4 percent) did not differ significantly from FEUA in 24 patients with hyponatremia due to thiazides (14.6±6.6 percent) [12].

Thus, the diagnosis of thiazide-induced hyponatremia can only be confirmed (and distinguished from hyponatremia due to SIADH) if discontinuation of the drug results in correction of the serum sodium. Although there will be a marked improvement in the severity of hyponatremia when the diuretic is discontinued, such patients may remain mildly hyponatremic for a week or longer, and therefore, complete recovery should not be expected in the short term.

Other patients — Hyponatremia is most commonly caused by SIADH or by effective arterial blood volume depletion, both of which are associated with persistent ADH release. The term "effective arterial blood volume" (also called effective circulating volume) refers to the volume of arterial blood that is perfusing the tissues. Effective arterial blood volume depletion can occur by two mechanisms: true volume depletion; and edematous states in patients with heart failure or cirrhosis in whom tissue perfusion is reduced because of a low cardiac output or arterial vasodilation, respectively. Regardless of the mechanism, significantly decreased tissue perfusion is a potent stimulus to the secretion of ADH (figure 2).

In patients without severely reduced GFR and who are not taking a thiazide diuretic, or in patients suspected of having an additional cause of hyponatremia, the subsequent evaluation depends upon whether or not the patient has clinically apparent edema and/or ascites:

●Patients with hyponatremia due to heart failure or cirrhosis typically have advanced disease and present with clinically apparent peripheral edema and/or ascites along with a previous diagnosis of heart or liver failure. (See 'Patients with edema and/or ascites' below.)

●Nonedematous patients with hyponatremia are either euvolemic or hypovolemic. Most patients with hyponatremia due to true hypovolemia will have obvious signs of volume depletion; however, some hypovolemic patients have more subtle signs and are mistakenly judged to be euvolemic. As outlined below, the evaluation of hyponatremia in nonedematous patients includes measurement of the urine sodium concentration. Additional tests may sometimes be required. (See 'Nonedematous patients' below.)

Patients with edema and/or ascites — The major causes of hyponatremia in patients with peripheral edema, pulmonary edema, or ascites include:

●Heart failure (see "Hyponatremia in patients with heart failure")

●Cirrhosis (see "Hyponatremia in patients with cirrhosis")

Even though the plasma and extracellular volumes may be markedly increased in heart failure and cirrhosis, the pressure sensed at the carotid sinus baroreceptors is generally reduced due to the fall in cardiac output in heart failure and to arterial vasodilatation in cirrhosis. Both ADH release and the associated reduction in the serum sodium concentration parallel the severity of the heart failure or cirrhosis.

Detailed discussions of hyponatremia in heart failure and cirrhosis, including the management of such patients, are presented elsewhere. (See "Hyponatremia in patients with heart failure" and "Hyponatremia in patients with cirrhosis".)

Nonedematous patients — The diagnostic evaluation of nonedematous patients with hyponatremia and relatively preserved GFR depends in part upon whether or not clinical signs of hypovolemia are present or absent:

●Patients with true volume depletion may present with postural dizziness, decreased skin turgor, axillary dryness, dry mucous membranes, and orthostatic hypotension (see "Etiology, clinical manifestations, and diagnosis of volume depletion in adults"). However, none of these clinical findings are diagnostic of volume depletion. Measurement of the urine sodium and chloride concentrations in such patients can help to distinguish between hypovolemia produced by extrarenal losses (eg, gastrointestinal losses) and hypovolemia produced by renal losses (eg, primary adrenal insufficiency). (See 'Apparent hypovolemia' below.)

●Although patients who appear euvolemic may have a normal volume status, clinical signs of hypovolemia are insensitive, and some patients who appear to be euvolemic may in fact have hyponatremia due to hypovolemia. The urine sodium and chloride concentrations are helpful in the further evaluation of patients who appear euvolemic. (See 'Apparent euvolemia' below.)

Apparent hypovolemia — Hyponatremic patients who present with clinical symptoms and signs of hypovolemia may have extrarenal fluid losses or renal fluid losses. Measurement of the urine sodium and chloride concentrations can often distinguish between these two causes [5]:

●Low urine sodium (<25 mEq/L) – The urine sodium concentration is usually below 25 mEq/L in patients with hypovolemia caused by gastrointestinal fluid losses (eg, diarrhea), by movement of fluid into the "third space" (eg, pancreatitis), and by renal fluid losses due to diuretics if the measurement is performed after the effect of the diuretic has abated.

●High urine sodium (>40 mEq/L) with low urine chloride (<25 mEq/L) – In hypovolemic hyponatremic patients who have metabolic alkalosis caused by vomiting, the urine sodium concentration may intermittently be greater than 25 mEq/L, but the urine chloride concentration will be consistently low (less than 25 mEq/L). (See "Clinical manifestations and evaluation of metabolic alkalosis", section on 'Disorders associated with a low urine chloride concentration (less than 20 mEq/L)'.)

●High urine sodium and chloride (>40 mEq/L) – The sodium and chloride concentrations are usually above 40 mEq/L in hypovolemic hyponatremic patients with renal salt losses. This is most commonly seen with diuretic therapy if the urine electrolytes are measured while the effect of the diuretic is still present. Renal fluid loss with hyponatremia may also result from primary adrenal insufficiency (in which there is deficiency of both cortisol and aldosterone) and cerebral salt wasting (in which the mechanism of renal salt wasting is poorly understood). Diagnosis of primary adrenal insufficiency and cerebral salt wasting are discussed separately. (See "Determining the etiology of adrenal insufficiency in adults" and "Cerebral salt wasting".)

Apparent euvolemia — Most hyponatremic patients who appear to be euvolemic by physical examination have the SIADH. However, such patients may occasionally have hyponatremia due to true volume depletion, primary polydipsia, malnutrition, glucocorticoid deficiency, or severe hypothyroidism.

The urine sodium (and, occasionally, urine chloride) concentration is used to distinguish between hypovolemia and euvolemia. The diagnostic value of the urine sodium concentration was illustrated in a study of 58 hyponatremic patients without edema [5]. The mean urine sodium concentration was 18 mEq/L in patients who were judged to be hypovolemic (as determined by a significant rise in serum sodium following isotonic saline) compared with 72 mEq/L in those with SIADH (as determined by no increase in serum sodium following isotonic saline). In contrast to the utility of the urine sodium concentration, clinical assessment of volume status correctly identified only 48 percent of patients.

In addition to urine electrolytes, evaluation of the urine osmolality and urine urea and creatinine concentrations is helpful in patients who are suspected of having primary polydipsia or malnutrition as the cause of hyponatremia [13]. Evaluation of acid-base and potassium balance may also be helpful, particularly in selected hyponatremic patients in whom the diagnosis is not apparent. (See 'Low urine sodium and osmolality' below and 'Abnormal serum potassium and bicarbonate' below.)

We do not use the fractional excretion of sodium (FENa) to evaluate volume status in patients with hyponatremia. In patients with acute kidney injury, the FENa provides a more accurate assessment of volume status than the urine sodium concentration because it corrects for the effect that variations in urine volume have on the urine sodium. A FENa below 1 percent suggests effective volume depletion, while a value of approximately 2 percent suggests acute tubular necrosis. (See "Fractional excretion of sodium, urea, and other molecules in acute kidney injury".)

This observation has led some clinicians to use the FENa in any situation in which measurement of the urine sodium concentration might be helpful. Calculators for the FENa are available using either standard units (calculator 1) or SI units (calculator 2).

However, such an approach can lead to an erroneous diagnosis. The FENa is most useful in evaluating patients with oliguria to distinguish between prerenal azotemia and acute kidney injury; in this setting, a FENa below 1 percent is an indicator of effective volume depletion. A FENa below 1 percent is not an indicator of effective volume depletion in patients with normal or mild to moderate kidney dysfunction who have a much higher GFR and a much greater filtered sodium load.

As an example, patients with a normal GFR of 180 L/day (125 mL/min) have a filtered sodium load of approximately 27,000 mEq/day at a normal serum sodium concentration. The FENa that is diagnostic of effective volume depletion may be as low as 0.1 percent, which represents the excretion of 27 mEq of sodium per day. By contrast, patients with SIADH are euvolemic, and urinary sodium excretion is roughly equal to dietary sodium intake. Since sodium intake is usually less than 270 mEq/day, the FENa is typically less than 1 percent. These issues are discussed in detail elsewhere. (See "Fractional excretion of sodium, urea, and other molecules in acute kidney injury".)

Low urine sodium and osmolality — Some apparently euvolemic patients with hyponatremia have both a low urine sodium and a low urine osmolality. Occasionally, these findings herald an increase in urine volume to >100 mL/hour, a spontaneous increase in the serum sodium concentration in the absence of saline administration, or a more-rapid-than-predicted increase in the serum sodium concentration during saline therapy. In patients with chronic hyponatremia whose serum sodium is <120 mEq/L, and in patients with advanced liver disease or severe malnutrition, such a rapid increase in serum sodium concentration can result in the osmotic demyelination syndrome. (See "Osmotic demyelination syndrome (ODS) and overly rapid correction of hyponatremia".)

A low urine sodium (<25 mEq/L) with a low urine osmolality (<100 mosmol/kg) can be seen in the following settings:

●Primary polydipsia, which is most often seen in patients with psychiatric illnesses, can cause hyponatremia when water excretion is normal but intake is so high that it exceeds excretory capacity. Once water intake stops, the serum sodium concentration will increase spontaneously. With the exception of malnourished alcoholic patients, the risk of osmotic demyelination syndrome is usually low in this setting because of the short duration of hyponatremia. (See "Causes of hypotonic hyponatremia in adults", section on 'Primary polydipsia due to psychosis'.)

●A large fluid intake combined with protein malnutrition, described primarily in beer drinkers (called beer potomania or beer drinker's potomania) or in those on a low-protein, high-water diet (called tea and toast syndrome), in which dietary solute intake (sodium, potassium, protein), and therefore solute excretion, is so low that the rate of water excretion is markedly diminished even though urinary dilution is intact. A typical Western diet will yield at least 600 milliosmoles of solute per day, of which approximately one-half is comprised of urea, a metabolite of dietary protein. Urea excretion less than 150 milliosmoles per day suggests an extremely low dietary protein intake, which will markedly impair the ability to excrete electrolyte-free water, predisposing to hyponatremia.

Daily urea excretion can be estimated from urine chemistries by multiplying urine urea concentration in mmol/L by the urine volume [14]. If urine urea nitrogen is reported in mg/dL, the concentration is converted to mmol/L by dividing by 2.8. If it is not measured, the urine volume can be roughly estimated from the urine creatinine concentration (Ucreat) in mg/dL by assuming that urine creatinine excretion is 1 g per day:

A calculation based on urine creatinine concentration alone will overestimate urine volume in small older adults or frail patients with reduced muscle mass who excrete <1 g of creatinine daily, and it will underestimate volume in young, muscular patients who excrete >1 g of creatinine daily. A more accurate estimate of urine volume can be obtained if the estimated glomerular filtration rate (eGFR) is included. If we assume that eGFR equals creatinine clearance in mL/min (an assumption that is not precisely valid), urine volume can be estimated as follows:

Although eGFR is actually expressed in mL/min of glomerular filtration per 1.73 m² of body surface area (and not creatinine clearance in mL/min), a small study showed that estimated values based on this equation correlated reasonably well with measured urine volume [14].

If severe hyponatremia is caused or exacerbated by protein malnutrition, an increase in urine solute excretion, most commonly after the administration of saline, will cause the serum sodium concentration to increase spontaneously. The resulting rapid correction of hyponatremia can be dangerous in this setting because malnutrition increases the risk of osmotic demyelination syndrome. (See "Causes of hypotonic hyponatremia in adults", section on 'Low dietary solute intake'.)

●The urine may also be dilute if it is measured after the reason for ADH release has been corrected (eg, following volume expansion with isotonic saline in a patient with hypovolemia, following reversal of SIADH by cessation of an offending drug, following glucocorticoid replacement in adrenal insufficiency, or with the passage of time after surgical procedures). This is commonly seen in patients with hyponatremia due to hypovolemia who are treated (often in the emergency department) with isotonic saline before the urine sodium and osmolality are measured. In such patients, the low urine osmolality heralds the spontaneous and rapid correction of hyponatremia, which can result in the osmotic demyelination syndrome in patients whose initial serum sodium was <120 mEq/L. (See "Overview of the treatment of hyponatremia in adults".)

●Reset osmostat, in which a water load appropriately suppresses ADH release but at a lower serum osmolality than in normal individuals. As in patients with SIADH, the urine osmolality and urine sodium will be high in patients with reset osmostat if they are measured when water intake is restricted; the urine osmolality and urine sodium will be low if they are measured immediately after water is ingested. However, once the serum sodium concentration has increased to a level above the threshold that stimulates ADH release, the urine osmolality and urine sodium concentrations will again be high. The major clinical clue to the presence of this disorder, which presents with clinical features similar to the SIADH, is a moderately reduced plasma sodium concentration (usually between 125 and 135 mEq/L) that is stable on multiple measurements. As in patients with SIADH, urine sodium excretion matches sodium intake in patients with reset osmostat. (See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat", section on 'Reset osmostat'.)

●Surreptitious diuretic use, in which hyponatremia develops while the patient is taking diuretics and then corrects when diuretics are stopped. This syndrome should be suspected in patients whose serum sodium and urine electrolytes fluctuate from day to day, with episodic hypokalemia and metabolic alkalosis. Patients with surreptitious diuretic use may be malnourished because of associated eating disorders, which increases their risk of osmotic demyelination if a large increase in serum sodium occurs.

High urine sodium and osmolality — In apparently euvolemic patients with hyponatremia, a high urine sodium (>40 mEq/L) with a high urine osmolality (usually >300 mosmol/kg) can be seen in the following settings:

●SIADH, which is the most common cause of hyponatremia in euvolemic patients with a high urine osmolality, is diagnosed after other etiologies are excluded. The urine sodium concentration is usually above 40 mEq/L in patients with the SIADH who are normovolemic and whose rate of sodium excretion is determined by sodium intake, as it is in normal individuals [5,15,16].

SIADH is frequently associated with hypouricemia (serum uric acid concentration that is less than 4 mg/dL or 238 micromol/L) due to increased urinary uric acid clearance [15,17-19], and low blood urea nitrogen (BUN that is less than 5 mg/dL or 1.8 mmol/L) due to increased urea clearance [18,20]. Increased uric acid clearance can be identified in a spot urine sample by a high fractional excretion of uric acid (FEUA >10 to 12 percent); in two relatively small studies, an FEUA <8 percent excluded SIADH with 100 percent specificity [11,12].

It is presumed that increased clearance of uric acid and urea results from water retention and volume expansion in the SIADH. However, stimulation of the vasopressin V1a receptor (which primarily causes vasoconstriction) may also contribute via an uncertain mechanism. As an example, if hyponatremia is induced in normal volunteers with desmopressin (dDAVP), an agent that stimulates the V2 receptor (which primarily mediates the antidiuretic response) but not the V1a receptor, the serum uric acid concentration does not fall as much (29 versus 53 percent) as it does in patients with a similar degree of hyponatremia caused by the SIADH (in which the native hormone stimulates both the V1a and V2 receptors) [21]. However, not all patients with SIADH have hypouricemia and low BUN, and therefore, the absence of these findings does not exclude the diagnosis.

Calculation of the FEUA before and after correction of hyponatremia has been proposed as a way of distinguishing SIADH from cerebral salt wasting [22]. According to this theory, before correction of hyponatremia, FEUA is >11 percent in both SIADH and salt wasting. Conversely, after correction of hyponatremia, an FEUA that remains >11 percent is said to indicate salt wasting, caused by impaired proximal tubule sodium reabsorption, whereas an FEUA <11 percent identifies patients with SIADH. However, serial measurements of FEUA have not been validated with a consistent, rigorous, and convincing gold standard for identifying salt wasting [23-25]. For this reason, the diagnostic validity of these measurements is unproven.

The fractional excretion of urea (FEurea) might also be useful in evaluating patients with hyponatremia and suspected SIADH. In one study, for example, a FEurea <55 percent essentially excluded the diagnosis of SIADH (ie, 96 percent specificity) although the test was insensitive [26].

There are many potential causes of SIADH, including hereditary (nephrogenic) SIADH. The pathophysiology and etiology of SIADH are presented elsewhere in detail. (See "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)".)

●In reset osmostat, a water load can suppress ADH release but at a lower serum osmolality than in normal individuals. As discussed earlier, patients with a reset osmostat present with the same features that are seen in patients with SIADH, except after these patients ingest water, the urine osmolality and urine sodium transiently fall. The major clinical clue to the presence of this disorder is a moderately reduced plasma sodium concentration (usually between 125 and 135 mEq/L) that is stable on multiple measurements. (See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat", section on 'Reset osmostat'.)

●Severe hypothyroidism can cause hyponatremia via uncertain mechanisms, particularly in patients with primary hypothyroidism and myxedema. However, because hypothyroidism and hyponatremia are common findings in hospitalized patients, their coexistence may not necessarily be causal; other explanations for hyponatremia should still be sought unless hypothyroidism is severe. The evaluation of hypothyroidism is presented elsewhere. (See "Diagnosis of and screening for hypothyroidism in nonpregnant adults".)

●Cortisol deficiency can result in the hypersecretion of ADH due, in part, to reductions in systemic blood pressure and cardiac output (via an unknown mechanism) and the interruption of a negative feedback loop in which cortisol suppresses ADH release. Secondary adrenal insufficiency (hypopituitarism), in contrast to primary adrenal insufficiency (which also results in aldosterone deficiency), presents with euvolemic hyponatremia and biochemical features of SIADH. These issues, and the diagnosis of cortisol deficiency, are discussed in detail elsewhere. (See "Hyponatremia and hyperkalemia in adrenal insufficiency" and "Determining the etiology of adrenal insufficiency in adults".)

Low urine sodium with high urine osmolality — Some hyponatremic patients with apparent euvolemia have a low urine sodium and high urine osmolality. In such patients, serial measurement of the urine sodium and urine osmolality after infusion of isotonic saline (eg, one liter over one hour) can help to clarify the diagnosis. However, infusion of isotonic saline should be avoided or performed with extreme caution in patients with a very low serum sodium (eg, <120 mEq/L) and in hyponatremic patients with severe hypokalemia, alcoholism, liver disease, or malnutrition because of the increased risk of osmotic demyelination syndrome with these disorders. If the hyponatremia is due to hypovolemia, isotonic saline reverses the stimulus to ADH secretion, which increases water excretion and produces overly rapid correction of the serum sodium. If, by contrast, the hyponatremia is due to SIADH, isotonic saline may further lower the serum sodium and thereby induce or exacerbate neurologic symptoms; the reason why isotonic saline can lower the serum sodium in patients with SIADH is presented elsewhere. (See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat", section on 'Intravenous hypertonic saline'.)

Infusion of isotonic saline with frequent serial monitoring of the serum sodium, urine sodium, and urine osmolality can help to distinguish SIADH and hypovolemia:

●Patients with SIADH will have a low urine sodium concentration if they are also volume depleted or if their sodium intake is extremely low. In such patients, the diagnosis of SIADH is made by observing the response to a saline load: the urine sodium rises as the hypovolemia is corrected, but the urine osmolality remains high.

●If the patient is hypovolemic, isotonic saline should suppress the hypovolemic stimulus to ADH release, promoting the excretion of a dilute urine (urine osmolality is usually less than 100 mosmol/kg) and rapid correction of the hyponatremia.

In both disorders, the urine sodium concentration will increase with saline therapy, although the increase in hypovolemic patients will not be seen until the hypovolemia is mostly corrected.

Abnormal serum potassium and bicarbonate — Evaluation of acid-base and potassium balance may be helpful in selected hyponatremic patients in whom the diagnosis is not apparent. As examples, metabolic alkalosis and hypokalemia suggest diuretic use or vomiting, metabolic acidosis and hypokalemia suggest diarrhea or laxative abuse, and metabolic acidosis and hyperkalemia suggest primary adrenal insufficiency in patients without kidney failure [2]. (See "Hyponatremia and hyperkalemia in adrenal insufficiency".)

On the other hand, the serum bicarbonate and potassium concentrations are typically normal in the SIADH [15]. Although water retention tends to lower these values by dilution (as it does the plasma sodium and chloride concentrations), normal levels are restored by the factors that regulate acid-base and potassium balance. The release of potassium from cells in an attempt to minimize cell swelling induced by hypoosmolality is an additional factor that will raise the serum potassium concentration to normal [15], and increased acid excretion due to mild hyperaldosteronism induced by hyponatremia can raise the plasma bicarbonate concentration [15,27]. (See "Manifestations of hyponatremia and hypernatremia in adults".)

Patients with hypopituitarism develop hyponatremia with many features of the SIADH (including normal serum potassium as well as low BUN and serum uric acid) because they lack cortisol but not aldosterone. However, they tend to have slightly lower plasma bicarbonate concentrations than other patients with the SIADH, most likely because of lower plasma aldosterone levels [27].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hyponatremia" and "Society guideline links: Fluid and electrolyte disorders in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Hyponatremia (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Hyponatremia, defined as a serum sodium concentration below 135 mEq/L, is usually caused by a failure to excrete water normally. In healthy individuals, the ingestion of water does not lead to hyponatremia because suppressed release of antidiuretic hormone (ADH), also called vasopressin, allows excess water to be excreted in a dilute urine (figure 1). (See 'Introduction' above.)

●The initial diagnostic approach to the adult patient with hyponatremia consists of a directed history and physical examination as well as selected laboratory tests. When hyponatremia is first discovered, some elements of the history, key features of the physical exam, and the results of several helpful laboratory tests are usually already available, and these guide the subsequent diagnostic approach (algorithm 1) (see 'The initial evaluation' above and 'History and physical examination' above and 'Tests that are often initially available' above):

•If hyperglycemia is present, the serum sodium concentration should be corrected for the effect of glucose to exclude hypertonic hyponatremia. To calculate the "corrected" serum sodium, we recommend the use of the following ratio: the sodium concentration will fall by approximately 2 mEq/L for each 100 mg/100 mL (5.5 mmol/L) increase in glucose concentration. (See 'Hyperglycemic patients' above.)

•Patients with lipemic serum, severe obstructive jaundice, or a known plasma cell dyscrasia may have pseudohyponatremia. This laboratory artifact can occur if the sodium is measured with flame photometry or indirect potentiometry using ion-selective electrodes when the solid phase portion of serum or plasma is increased due to severe elevations of triglycerides, lipoprotein-X, or protein. The true concentration of sodium in plasma water can be measured using direct ion-selective electrodes, which are not susceptible to the artifact. Such direct ion-selective electrodes are utilized by most "point of care" bedside analyzers and devices used to measure blood gases. In addition, patients with pseudohyponatremia typically have a normal serum osmolality. (See 'Patients who might have pseudohyponatremia' above.)

•Patients who have had recent surgery utilizing large volumes of electrolyte-poor irrigation fluid (eg, prostate or intrauterine procedures) and those treated with mannitol, glycerol, or intravenous immune globulin may have isotonic or hypertonic hyponatremia. Measurement of the plasma osmolality is helpful in these settings. (See 'When to measure the serum osmolality' above.)

•Patients who do not have hyperglycemia or one of these other features associated with pseudohyponatremia, isotonic hyponatremia, or hypertonic hyponatremia are likely to have hypotonic hyponatremia. (See 'Patients with hypotonic hyponatremia' above.)

●The serum creatinine concentration, which can be used to estimate glomerular filtration rate (GFR), and the patient's medication history are typically available at the time that hyponatremia is discovered. Both severely reduced GFR and thiazide (or thiazide-type) diuretics are important causes of hypotonic hyponatremia. (See 'Patients with severely reduced GFR' above and 'Patients taking thiazides' above.)

●In patients with hypotonic hyponatremia who do not have severely reduced GFR and who are not taking a thiazide diuretic, or in patients suspected of having an additional cause of hyponatremia, the subsequent evaluation depends upon whether or not the patient has clinically apparent edema and/or ascites:

•Patients with hyponatremia due to heart failure or cirrhosis typically have advanced disease and present with clinically apparent peripheral edema and/or ascites along with a previous diagnosis of heart or liver failure. (See 'Patients with edema and/or ascites' above.)

•Nonedematous patients with hypotonic hyponatremia are either euvolemic or hypovolemic. Most patients with hyponatremia due to true hypovolemia will have obvious signs of volume depletion; however, some hypovolemic patients have more subtle signs and are mistakenly judged to be euvolemic. The evaluation of nonedematous patients usually requires further testing (see 'Nonedematous patients' above):

-Hyponatremic patients who present with clinical symptoms and signs of hypovolemia may have extrarenal fluid losses or renal fluid losses. Measurement of the urine sodium and chloride concentrations can often distinguish between these two causes. (See 'Apparent hypovolemia' above.)

-Most hyponatremic patients who appear to be euvolemic by physical examination have the syndrome of inappropriate ADH (SIADH). However, such patients may occasionally have hyponatremia due to true volume depletion, primary polydipsia, malnutrition, glucocorticoid deficiency, or severe hypothyroidism. The subsequent evaluation in such patients includes measurement of the urine sodium and urine osmolality as well as levels of cortisol and thyroid-stimulating hormone. (See 'Apparent euvolemia' above.)