Causes of hyponatremia in adultsAuthorRichard H Sterns, MDSection EditorMichael Emmett, MDDeputy EditorJohn P Forman, MD, MScDisclosures:Richard H Sterns, MDNothing to disclose.Michael Emmett, MDConsultant/Advisory Boards: ZS Pharma [treatment of hyperkalemia (potassium binder, zirconium silicate)].John P Forman, MD, MScNothing to disclose.Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.Conflict of interest policyAll topics are updated as new evidence becomes available and ourpeer review processis complete.Literature review current through:May 2015.|This topic last updated:Aug 12, 2014.INTRODUCTIONHyponatremia is commonly defined as a serum sodium concentration below 135meq/Lbut can vary to a small degree in different clinical laboratories [1,2]. The dilutional fall in serum sodium is in most patients associated with a proportional reduction in the serum osmolality (ie, to a level below 275mosmol/kg),but there are some exceptions. (See'Hyponatremia with a high or normal serum osmolality'below.)In virtually all patients, hyponatremia results from the intake (either oral or intravenous) and subsequent retention of water [3]. A water load will, in normal individuals, be rapidly excreted as the dilutional fall in serum osmolality suppresses the release of antidiuretic hormone (ADH, also called vasopressin) (figure 1), thereby allowing excretion of the excess water in a dilute urine. The maximum attainable urine volume in normal individuals on a regular diet is over 10L/day. This provides an enormous range of protection against the development of hyponatremia since the daily fluid intake in most healthy individuals is less than 2 to 2.5L/day.In contrast to the response in normal individuals, patients who develop hyponatremia typically have an impairment in renal water excretion, most often due to an inability to suppress ADH secretion. An uncommon exception occurs in patients with primary polydipsia who can become hyponatremic because they rapidly drink such large quantities of fluid that they overwhelm the excretory capacity of the kidney even though ADH release is appropriately suppressed.An overview of the causes of hyponatremia will be presented here (table 1). Most of the individual causes of hyponatremia are discussed in detail separately, as are issues related to the diagnosis and treatment of hyponatremia [3,4]. (See"Evaluation of adults with hyponatremia"and"Overview of the treatment of hyponatremia in adults".)DETERMINANTS OF THE SERUM SODIUM CONCENTRATIONUnderstanding the factors that determine the serum sodium concentration is required to appreciate the factors that promote the development of hyponatremia and what the composition of intravenous fluids must be to correct the hyponatremia.In the following discussion, the term "tonicity" (also called the effective plasma osmolality) refers to the osmotic activity of solutes that do not easily cross cell membranes and therefore determine the transcellular distribution of water.The extracellular and intracellular fluids are in osmotic equilibrium since water moves freely across most cell membranes. As a result, plasma tonicity is equal to the effective intracellular osmolality and to the effective osmolality of the total body water (TBW). These relationships can be summarized by the following equation:Plasma tonicity = (Extracellular solute + Intracellular solute) TBWExchangeable sodium salts (Nae) are the primary effective extracellular solute and exchangeable potassium (Ke) and its associated intracellular anions are the primary intracellular solutes; these solutes are the major determinants of the effective plasma osmolality. Glucose, the other major extracellular solute is, in the absence of marked hyperglycemia, present in a much lower molar concentration than sodium (eg, 5mmol/L[90mg/dL]versus 140mmol/L).Approximately 30 percent of total body sodium and a smaller fraction of total body potassium are bound in areas such as bone where they are "nonexchangeable" and therefore not osmotically active. In addition, urea is considered an ineffective osmole since it freely equilibrates across the cell membranes. When the plasma concentration of an ineffective osmole changes, the solute rapidly moves into or out of cells to equalize the concentrations. Thus, there is little or no water shift into or out of the cells as occurs with changes in the plasma sodium concentration.Thus, plasma tonicity (effective plasma osmolality) can be expressed as:Plasma tonicity (2 x Nae + 2 x Ke) TBWThe multiplier 2 accounts for the osmotic contributions of the anions accompanying sodium and potassium. In the absence of marked hyperglycemia or the administration ofmannitol, the above equation can be simplified to:2 x plasma Na (2 x Nae + 2 x Ke) TBWand then to:Plasma Na (Nae + Ke) TBWAs shown in the figure, this relationship applies over a wide range of plasma or serum sodium concentrations (figure 2) [5].Application to hyponatremiaThe importance of considering the effect of potassium on the plasma sodium concentration in patients with hyponatremia can be illustrated by the following examples:In patients with hyponatremia induced by thiazide diuretics, the sodium plus potassium concentration in the urine may exceed that in the plasma, which will directly lower the plasma sodium concentration independent of fluid intake. (See'Diuretic-induced hyponatremia'below.)In a patient who has both severe hyponatremia and severe hypokalemia (due, for example, to diuretic therapy or vomiting), treatment with large amounts of potassium in addition to isotonic or hypertonic saline may lead to overly rapid correction of the hyponatremia and possible brain injury due to osmotic demyelination syndrome. (See"Overview of the treatment of hyponatremia in adults", section on 'Risk of osmotic demyelination'.)CLASSIFICATIONAt least two classification systems have been used for the etiology of hyponatremia with a low serum osmolality (defined as a serum osmolality less than 275mosmol/kg):one stratifies patients according to whether circulating antidiuretic hormone (ADH) levels are inappropriately elevated or appropriately suppressed [3], and the other stratifies patients according to volume status (hypovolemia, normovolemia, or hypervolemia) [6,7]. In either case, the development of hyponatremia requires the intake of water that cannot be excreted.The individual causes of hyponatremia are described below in the appropriate sections.According to serum ADH levelsUrinary excretion of a water load requires the suppression of ADH release, which is mediated by the reduction in serum osmolality (figure 1). An inability to suppress ADH release is the most common cause of hyponatremia and can be seen in the following settings:True volume depletion, which can be due to gastrointestinal losses (eg, vomiting or diarrhea) or renal losses (most often thiazide rather than loop diuretics)Decreased tissue perfusion (also called effective arterial volume depletion) due to reduced cardiac output in heart failure or to systemic vasodilation in cirrhosisA primary (ie, not hypovolemic) increase in ADH release in the syndrome of inappropriate ADH secretion (SIADH), including an infrequent variant characterized by resetting of the osmostatThere are also disorders in which hyponatremia occurs despite appropriate suppression of ADH secretion. These include primary polydipsia, a low dietary solute intake, and advanced renal failure.According to volume statusThe causes of hyponatremia can also be stratified by volume status [6,7]:Hypovolemia due to gastrointestinal losses (eg, vomiting or diarrhea) or renal losses (most often thiazide rather than loop diuretics)Normovolemia, which is most often associated with the SIADH but can also be seen with primary polydipsia and a low dietary solute intakeHypervolemia due to heart failure or cirrhosisHyponatremia can also occur in patients with advanced renal failure. These patients may appear either euvolemic or, if they also retain salt and develop edema, hypervolemic.HYPONATREMIA WITH A LOW SERUM OSMOLALITYThe serum osmolality (Sosm) can be calculated by the concentration in millimoles per liter of the major serum solutes according to the following equation:Sosm(mmol/kg)= (2 x serum [Na]) + (serum[glucose]/18)+ (blood ureanitrogen/2.8)The serum sodium concentration is multiplied by two to account for the accompanying anions (mostly chloride and bicarbonate) that provide electroneutrality, and the corrections in the glucose concentration and blood urea nitrogen (BUN) are to convertmg/dLintommol/L. These corrections in glucose and BUN do not need to be made when standard units are used.The contributions of glucose and BUN to the serum osmolality are normally small, except in conditions such as diabetes mellitus and renal failure. Thus, the serum osmolality can be estimated in most patients by doubling the serum sodium concentration. (See"General principles of disorders of water balance (hyponatremia and hypernatremia) and sodium balance (hypovolemia and edema)", section on 'Plasma osmolality'.)The two most common causes of hyponatremia with a low serum osmolality are effective arterial blood volume depletion and the syndrome of inappropriate antidiuretic hormone (ADH) secretion, both of which are associated with persistent ADH release [6-8].Most patients with hyponatremia have a single cause but, in some patients, multiple factors contribute to the fall in serum sodium. Symptomatic infection with human immunodeficiency virus (HIV) is an example of this phenomenon, as volume depletion, the syndrome of inappropriate ADH secretion, and adrenal insufficiency all may be present. (See"Electrolyte disturbances with HIV infection".)Effective arterial blood volume depletionThe 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 patients with heart failure or cirrhosis in whom tissue perfusion is reduced because of a low cardiac output or arterial vasodilation, respectively. The reduction in tissue perfusion is sensed by baroreceptors at three sites: in the carotid sinus and aortic arch that regulate sympathetic activity and, with significant volume depletion, the release of antidiuretic hormone; in the glomerular afferent arterioles that regulate the activity of the renin-angiotensin system; and in the atria and ventricles that regulate the release of natriuretic peptides. (See"General principles of disorders of water balance (hyponatremia and hypernatremia) and sodium balance (hypovolemia and edema)", section on 'Effective arterial blood volume'.)Regardless of the mechanism, significantly decreased tissue perfusion is a potent stimulus to the secretion of ADH (figure 3). This response is mediated by baroreceptors in the carotid sinus, which sense a reduction in pressure or stretch, and can overcome the inhibitory effect of hyponatremia on ADH secretion. Thus, water retention and hyponatremia can develop in patients with any disorder causing effective arterial blood volume depletion.True volume depletionTrue volume depletion can be caused by the loss of sodium and water from the gastrointestinal tract (eg, vomiting or diarrhea), in the urine (most often due to diuretic therapy), or bleeding. Such patients may also have hypokalemia and, if enough fluid is lost, azotemia due to decreased renal perfusion.The replacement of severe diarrhea losses due to cholera (which is associated with a sodium concentration in stool of 120 to 140meq/L)with an oral rehydration solution with reduced osmolality (ie, more free water) may result in an increased incidence of hyponatremia as compared to replacement with standard oral rehydration therapy, which has a higher sodium concentration [9]. (See"Oral rehydration therapy".)Diuretic-induced hyponatremiaHyponatremia, which can be severe, is an occasional complication of therapy with thiazide diuretics. It typically begins soon after the onset of thiazide therapy. In contrast, hyponatremia is only rarely induced by loop diuretics since the inhibition of sodium chloride transport in the loop of Henle prevents the generation of the countercurrent gradient and therefore limits the ability of ADH to promote water retention.The following discussion will briefly review the mechanisms involved in thiazide-induced hyponatremia. A more complete discussion is presented elsewhere. (See"Diuretic-induced hyponatremia", section on 'Pathogenesis'.)Although hypovolemia can contribute to thiazide-induced hyponatremia, most patients appear clinically euvolemic and several other factors appear to play a role in the development of hyponatremia:An underlying tendency to increased water intake.A reduction in diluting ability and therefore impaired water excretion, which is a direct effect of reduced sodium chloride reabsorption without water in the distal tubule.The sodium plus potassium concentration in the urine may exceed that in the plasma, which will directly lower the plasma sodium concentration (see'Determinants of the serum sodium concentration'above). As an example, in a study of five patients with recent onset of severe thiazide-induced hyponatremia (mean serum sodium 105meq/L),the urine sodium plus potassium concentration was 156meq/L[10].Heart failure and cirrhosisEven 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 [3,11]. Thus, serum ADH levels tend to reflect the severity of the underlying disease, making the development of hyponatremia an important prognostic sign. A stable serum sodium below 130meq/Lis a marker of near end-stage liver or heart disease (figure 4). (See"Hyponatremia in patients with heart failure"and"Hyponatremia in patients with cirrhosis".)In contrast, hyponatremia is an uncommon finding in patients with the nephrotic syndrome in the absence of concurrent renal failure. Most such patients have relatively normal tissue perfusion and effective arterial volume and therefore do not have a clinically important stimulus to ADH secretion. (See"Pathophysiology and treatment of edema in patients with the nephrotic syndrome", section on 'Volume regulatory hormones'.)Syndrome of inappropriate ADH secretionPersistent ADH release and water retention can be seen in a variety of disorders that are not associated with hypovolemia, a condition called syndrome of inappropriate ADH secretion (SIADH). Major causes include central nervous system disease, malignancy, certain drugs, and recent surgery. (See"Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)", section on 'Etiology'.)Endocrine disordersThe original definition of SIADH excluded patients with glucocorticoid deficiency or hypothyroidism [12,13]. However, hyponatremia with features that are identical to those found in patients meeting the classical definition of SIADH (ie, euvolemia with a high urine osmolality and urine sodium) can also occur in patients with hypothyroidism or secondary adrenal insufficiency (not primary adrenal insufficiency, in which hyponatremia is associated with hypovolemia). Because these endocrine disorders are not always clinically apparent when patients first present with unexplained hyponatremia, some authors include endocrine disorders in the differential diagnosis of SIADH.HypothyroidismHyponatremia is sometimes associated with moderate to severe hypothyroidism, particularly in patients with primary hypothyroidism and myxedema [14-18]. Thus, thyroid function should be evaluated in any patient with an otherwise unexplained reduction in the plasma sodium concentration. 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 mechanism by which hypothyroidism induces hyponatremia is incompletely understood. Patients with hypothyroidism have a diminished ability to excrete free water and fail to achieve maximally dilute urine after a water load. Some but not all studies have reported elevated levels of ADH in patients who have hyponatremia associated with hypothyroidism [14-16]. This may be due in part to a reduced cardiac output, which can lead to the release of ADH via the carotid sinus baroreceptors [15,16,19]. However, some patients fulfill criteria for SIADH since the urine sodium is not low as would be expected if a reduced cardiac output were responsible [20].The glomerular filtration rate is also decreased in hypothyroidism. This can directly diminish free water excretion by diminishing water delivery to the diluting segments [17,18]. Decreased delivery may be particularly important in those cases in which hyponatremia develops despite appropriate suppression of ADH release [21,22]. Regardless of the mechanism, the net effect of the impairment in water excretion is the retention of ingested water and a reduction in the plasma sodium concentration by dilution.Some have questioned whether hypothyroidism deserves its traditional listing as a cause of hyponatremia [23]. As an example, a study that compared 999 ambulatory patients with newly diagnosed hypothyroidism with 4875 euthyroid controls found no difference in serum sodium concentrations [24]. In addition, none of the hypothyroid patients had a serum sodium concentration