Chapter 49.3: Hyponatremia

Disorders of serum Na⁺ concentration are caused by abnormalities in water homeostasis, leading to changes in the relative ratio of Na⁺ to body water. Water intake and circulating AVP constitute the two key effectors in the defense of serum osmolality; defects in one or both of these two defense mechanisms cause most cases of hyponatremia and hypernatremia. In contrast, abnormalities in sodium homeostasis per se lead to a deficit or surplus of whole-body Na⁺-Cl^– content, a key determinant of the ECFV and circulatory integrity. Notably, volume status also modulates the release of AVP by the posterior pituitary, such that hypovolemia is associated with higher circulating levels of the hormone at each level of serum osmolality. Similarly, in “hypervolemic” causes of arterial underfilling, e.g., heart failure and cirrhosis, the associated neurohumoral activation encompasses an increase in circulating AVP, leading to water retention and hyponatremia. Therefore, a key concept in sodium disorders is that the absolute plasma Na⁺ concentration tells one nothing about the volume status of a given patient, which furthermore must be taken into account in the diagnostic and therapeutic approach.

Hyponatremia, which is defined as a plasma Na⁺ concentration <135 mM, is a very common disorder, occurring in up to 22% of hospitalized patients. This disorder is almost always the result of an increase in circulating AVP and/or increased renal sensitivity to AVP, combined with an intake of free water; a notable exception is hyponatremia due to low solute intake (see below). The underlying pathophysiology for the exaggerated or “inappropriate” AVP response differs in patients with hyponatremia as a function of their ECFV. Hyponatremia is thus subdivided diagnostically into three groups, depending on clinical history and volume status, i.e., “hypovolemic,” “euvolemic,” and “hypervolemic” (Fig. 49-5).

Hypovolemic Hyponatremia

Hypovolemia causes a marked neurohumoral activation, increasing circulating levels of AVP. The increase in circulating AVP helps preserve blood pressure via vascular and baroreceptor V_1A receptors and increases water reabsorption via renal V₂ receptors; activation of V₂ receptors can lead to hyponatremia in the setting of increased free water intake. Nonrenal causes of hypovolemic hyponatremia include GI loss (e.g., vomiting, diarrhea, tube drainage) and insensible loss (sweating, burns) of Na⁺-Cl^– and water, in the absence of adequate oral replacement; urine Na⁺ concentration is typically <20 mM. Notably, these patients may be clinically classified as euvolemic, with only the reduced urinary Na⁺ concentration to indicate the cause of their hyponatremia. Indeed, a urine Na⁺ concentration <20 mM, in the absence of a cause of hypervolemic hyponatremia, predicts a rapid increase in plasma Na⁺ concentration in response to intravenous normal saline; saline therapy thus induces a water diuresis in this setting, as circulating AVP levels plummet.

The renal causes of hypovolemic hyponatremia share an inappropriate loss of Na⁺-Cl^– in the urine, leading to volume depletion and an increase in circulating AVP; urine Na⁺ concentration is typically >20 mM (Fig. 49-5). A deficiency in circulating aldosterone and/or its renal effects can lead to hyponatremia in primary adrenal insufficiency and other causes of hypoaldosteronism; hyperkalemia and hyponatremia in a hypotensive and/or hypovolemic patient with high urine Na⁺ concentration (much greater than 20 mM) should strongly suggest this diagnosis. Salt-losing nephropathies may lead to hyponatremia when sodium intake is reduced, due to impaired renal tubular function; typical causes include reflux nephropathy, interstitial nephropathies, postobstructive uropathy, medullary cystic disease, and the recovery phase of acute tubular necrosis. Thiazide diuretics cause hyponatremia via a number of mechanisms, including polydipsia and diuretic-induced volume depletion. Notably, thiazides do not inhibit the renal concentrating mechanism, such that circulating AVP retains a full effect on renal water retention. In contrast, loop diuretics, which are less frequently associated with hyponatremia, inhibit Na⁺-Cl^– and K⁺ absorption by the TALH, blunting the countercurrent mechanism and reducing the ability to concentrate the urine. Increased excretion of an osmotically active nonreabsorbable or poorly reabsorbable solute can also lead to volume depletion and hyponatremia; important causes include glycosuria, ketonuria (e.g., in starvation or in diabetic or alcoholic ketoacidosis), and bicarbonaturia (e.g., in renal tubular acidosis or metabolic alkalosis, where the associated bicarbonaturia leads to loss of Na⁺).

Finally, the syndrome of “cerebral salt wasting” is a rare cause of hypovolemic hyponatremia, encompassing hyponatremia with clinical hypovolemia and inappropriate natriuresis in association with intracranial disease; associated disorders include subarachnoid hemorrhage, traumatic brain injury, craniotomy, encephalitis, and meningitis. Distinction from the more common syndrome of inappropriate antidiuresis (SIAD) is critical because cerebral salt wasting will typically respond to aggressive Na⁺-Cl^– repletion.

Hypervolemic Hyponatremia

Patients with hypervolemic hyponatremia develop an increase in total-body Na⁺-Cl^– that is accompanied by a proportionately greater increase in total-body water, leading to a reduced plasma Na⁺ concentration. As in hypovolemic hyponatremia, the causative disorders can be separated by the effect on urine Na⁺ concentration, with acute or chronic renal failure uniquely associated with an increase in urine Na⁺ concentration (Fig. 49-5). The pathophysiology of hyponatremia in the sodium-avid edematous disorders (congestive heart failure [CHF], cirrhosis, and nephrotic syndrome) is similar to that in hypovolemic hyponatremia, except that arterial filling and circulatory integrity is decreased due to the specific etiologic factors (e.g., cardiac dysfunction in CHF, peripheral vasodilation in cirrhosis). Urine Na⁺ concentration is typically very low, i.e., <10 mM, even after hydration with normal saline; this Na⁺-avid state may be obscured by diuretic therapy. The degree of hyponatremia provides an indirect index of the associated neurohumoral activation and is an important prognostic indicator in hypervolemic hyponatremia.

Euvolemic Hyponatremia

Euvolemic hyponatremia can occur in moderate to severe hypothyroidism, with correction after achieving a euthyroid state. Severe hyponatremia can also be a consequence of secondary adrenal insufficiency due to pituitary disease; whereas the deficit in circulating aldosterone in primary adrenal insufficiency causes hypovolemic hyponatremia, the predominant glucocorticoid deficiency in secondary adrenal failure is associated with euvolemic hyponatremia. Glucocorticoids exert a negative feedback on AVP release by the posterior pituitary such that hydrocortisone replacement in these patients can rapidly normalize the AVP response to osmolality, reducing circulating AVP.

The SIAD is the most frequent cause of euvolemic hyponatremia (Table 49-1). The generation of hyponatremia in SIAD requires an intake of free water, with persistent intake at serum osmolalities that are lower than the usual threshold for thirst; as one would expect, the osmotic threshold and osmotic response curves for the sensation of thirst are shifted downward in patients with SIAD. Four distinct patterns of AVP secretion have been recognized in patients with SIAD, independent for the most part of the underlying cause. Unregulated, erratic AVP secretion is seen in about a third of patients, with no obvious correlation between serum osmolality and circulating AVP levels. Other patients fail to suppress AVP secretion at lower serum osmolalities, with a normal response curve to hyperosmolar conditions; others have a “reset osmostat,” with a lower threshold osmolality and a left-shifted osmotic response curve. Finally, the fourth subset of patients have essentially no detectable circulating AVP, suggesting either a gain in function in renal water reabsorption or a circulating antidiuretic substance that is distinct from AVP. Gain-in-function mutations of a single specific residue in the V₂ AVP receptor have been described in some of these patients, leading to constitutive activation of the receptor in the absence of AVP and “nephrogenic” SIAD.

Strictly speaking, patients with SIAD are not euvolemic but are subclinically volume-expanded, due to AVP-induced water and Na⁺-Cl^– retention; “AVP escape” mechanisms invoked by sustained increases in AVP serve to limit distal renal tubular transport, preserving a modestly hypervolemic steady state. Serum uric acid is often low (<4 mg/dL) in patients with SIAD, consistent with suppressed proximal tubular transport in the setting of increased distal tubular Na⁺-Cl^– and water transport; in contrast, patients with hypovolemic hyponatremia will often be hyperuricemic, due to a shared activation of proximal tubular Na⁺-Cl^– and urate transport.

Common causes of SIAD include pulmonary disease (e.g., pneumonia, tuberculosis, pleural effusion) and central nervous system (CNS) diseases (e.g., tumor, subarachnoid hemorrhage, meningitis). SIAD also occurs with malignancies, most commonly with small-cell lung carcinoma (75% of malignancy-associated SIAD); ~10% of patients with this tumor will have a plasma Na⁺ concentration of <130 mM at presentation. SIAD is also a frequent complication of certain drugs, most commonly the selective serotonin reuptake inhibitors (SSRIs). Other drugs can potentiate the renal effect of AVP, without exerting direct effects on circulating AVP levels (Table 49-1).

Low Solute Intake and Hyponatremia

Hyponatremia can occasionally occur in patients with a very low intake of dietary solutes. Classically, this occurs in alcoholics whose sole nutrient is beer, hence the diagnostic label of beer potomania; beer is very low in protein and salt content, containing only 1–2 mM of Na⁺. The syndrome has also been described in nonalcoholic patients with highly restricted solute intake due to nutrient-restricted diets, e.g., extreme vegetarian diets. Patients with hyponatremia due to low solute intake typically present with a very low urine osmolality (<100–200 mOsm/kg) with a urine Na⁺ concentration that is <10–20 mM. The fundamental abnormality is the inadequate dietary intake of solutes; the reduced urinary solute excretion limits water excretion such that hyponatremia ensues after relatively modest polydipsia. AVP levels have not been reported in patients with beer potomania but are expected to be suppressed or rapidly suppressible with saline hydration; this fits with the overly rapid correction in plasma Na⁺ concentration that can be seen with saline hydration. Resumption of a normal diet and/or saline hydration will also correct the causative deficit in urinary solute excretion, such that patients with beer potomania typically correct their plasma Na⁺ concentration promptly after admission to the hospital.

Hyponatremia induces generalized cellular swelling, a consequence of water movement down the osmotic gradient from the hypotonic ECF to the ICF. The symptoms of hyponatremia are primarily neurologic, reflecting the development of cerebral edema within a rigid skull. The initial CNS response to acute hyponatremia is an increase in interstitial pressure, leading to shunting of ECF and solutes from the interstitial space into the cerebrospinal fluid and then on into the systemic circulation. This is accompanied by an efflux of the major intracellular ions, Na⁺, K⁺, and Cl^–, from brain cells. Acute hyponatremic encephalopathy ensues when these volume regulatory mechanisms are overwhelmed by a rapid decrease in tonicity, resulting in acute cerebral edema. Early symptoms can include nausea, headache, and vomiting. However, severe complications can rapidly evolve, including seizure activity, brainstem herniation, coma, and death. A key complication of acute hyponatremia is normocapneic or hypercapneic respiratory failure; the associated hypoxia may amplify the neurologic injury. Normocapneic respiratory failure in this setting is typically due to noncardiogenic, “neurogenic” pulmonary edema, with a normal pulmonary capillary wedge pressure.

Acute symptomatic hyponatremia is a medical emergency, occurring in a number of specific settings (Table 49-2). Women, particularly before menopause, are much more likely than men to develop encephalopathy and severe neurologic sequelae. Acute hyponatremia often has an iatrogenic component, e.g., when hypotonic intravenous fluids are given to postoperative patients with an increase in circulating AVP. Exercise-associated hyponatremia, an important clinical issue at marathons and other endurance events, has similarly been linked to both a “nonosmotic” increase in circulating AVP and excessive free water intake. The recreational drugs Molly and ecstasy, which share an active ingredient (MDMA, 3,4-methylenedioxymethamphetamine), cause a rapid and potent induction of both thirst and AVP, leading to severe acute hyponatremia.

Persistent, chronic hyponatremia results in an efflux of organic osmolytes (creatine, betaine, glutamate, myoinositol, and taurine) from brain cells; this response reduces intracellular osmolality and the osmotic gradient favoring water entry. This reduction in intracellular osmolytes is largely complete within 48 h, the time period that clinically defines chronic hyponatremia; this temporal definition has considerable relevance for the treatment of hyponatremia (see below). The cellular response to chronic hyponatremia does not fully protect patients from symptoms, which can include vomiting, nausea, confusion, and seizures, usually at plasma Na⁺ concentration <125 mM. Even patients who are judged “asymptomatic” can manifest subtle gait and cognitive defects that reverse with correction of hyponatremia; notably, chronic “asymptomatic” hyponatremia increases the risk of falls. Chronic hyponatremia also increases the risk of bony fractures owing to the associated neurologic dysfunction and to a hyponatremia-associated reduction in bone density. Therefore, every attempt should be made to safely correct the plasma Na⁺ concentration in patients with chronic hyponatremia, even in the absence of overt symptoms (see the section on treatment of hyponatremia below).

The management of chronic hyponatremia is complicated significantly by the asymmetry of the cellular response to correction of plasma Na⁺ concentration. Specifically, the reaccumulation of organic osmolytes by brain cells is attenuated and delayed as osmolality increases after correction of hyponatremia, sometimes resulting in degenerative loss of oligodendrocytes and an osmotic demyelination syndrome (ODS). Overly rapid correction of hyponatremia (>8–10 mM in 24 h or 18 mM in 48 h) is also associated with a disruption in integrity of the blood-brain barrier, allowing the entry of immune mediators that may contribute to demyelination. The lesions of ODS classically affect the pons, a neuroanatomic structure wherein the delay in the reaccumulation of osmotic osmolytes is particularly pronounced; clinically, patients with central pontine myelinolysis can present 1 or more days after overcorrection of hyponatremia with paraparesis or quadriparesis, dysphagia, dysarthria, diplopia, a “locked-in syndrome,” and/or loss of consciousness. Other regions of the brain can also be involved in ODS, most commonly in association with lesions of the pons but occasionally in isolation; in order of frequency, the lesions of extrapontine myelinolysis can occur in the cerebellum, lateral geniculate body, thalamus, putamen, and cerebral cortex or subcortex. Clinical presentation of ODS can, therefore, vary as a function of the extent and localization of extrapontine myelinolysis, with the reported development of ataxia, mutism, parkinsonism, dystonia, and catatonia. Relowering of plasma Na⁺ concentration after overly rapid correction can prevent or attenuate ODS (see the section on treatment of hyponatremia below). However, even appropriately slow correction can be associated with ODS, particularly in patients with additional risk factors; these include alcoholism, malnutrition, hypokalemia, and liver transplantation.

Clinical assessment of hyponatremic patients should focus on the underlying cause; a detailed drug history is particularly crucial (Table 49-1). A careful clinical assessment of volume status is obligatory for the classical diagnostic approach to hyponatremia (Fig. 49-5). Hyponatremia is frequently multifactorial, particularly when severe; clinical evaluation should consider all the possible causes for excessive circulating AVP, including volume status, drugs, and the presence of nausea and/or pain. Radiologic imaging may also be appropriate to assess whether patients have a pulmonary or CNS cause for hyponatremia. A screening chest x-ray may fail to detect a small-cell carcinoma of the lung; computed tomography (CT) scanning of the thorax should be considered in patients at high risk for this tumor (e.g., patients with a smoking history).

Laboratory investigation should include a measurement of serum osmolality to exclude pseudohyponatremia, which is defined as the coexistence of hyponatremia with a normal or increased plasma tonicity. Most clinical laboratories measure plasma Na⁺ concentration by testing diluted samples with automated ion-sensitive electrodes, correcting for this dilution by assuming that plasma is 93% water. This correction factor can be inaccurate in patients with pseudohyponatremia due to extreme hyperlipidemia and/or hyperproteinemia, in whom serum lipid or protein makes up a greater percentage of plasma volume. The measured osmolality should also be converted to the effective osmolality (tonicity) by subtracting the measured concentration of urea (divided by 2.8, if in mg/dL); patients with hyponatremia have an effective osmolality of <275 mOsm/kg.

Elevated BUN and creatinine in routine chemistries can also indicate renal dysfunction as a potential cause of hyponatremia, whereas hyperkalemia may suggest adrenal insufficiency or hypoaldosteronism. Serum glucose should also be measured; plasma Na⁺ concentration falls by ~1.6–2.4 mM for every 100-mg/dL increase in glucose, due to glucose-induced water efflux from cells; this “true” hyponatremia resolves after correction of hyperglycemia. Measurement of serum uric acid should also be performed; whereas patients with SIAD-type physiology will typically be hypouricemic (serum uric acid <4 mg/dL), volume-depleted patients will often be hyperuricemic. In the appropriate clinical setting, thyroid, adrenal, and pituitary function should also be tested; hypothyroidism and secondary adrenal failure due to pituitary insufficiency are important causes of euvolemic hyponatremia, whereas primary adrenal failure causes hypovolemic hyponatremia. A cosyntropin stimulation test is necessary to assess for primary adrenal insufficiency.

Urine electrolytes and osmolality are crucial tests in the initial evaluation of hyponatremia. A urine Na⁺ concentration <20–30 mM is consistent with hypovolemic hyponatremia, in the clinical absence of a hypervolemic, Na⁺-avid syndrome such as CHF (Fig. 49-5). In contrast, patients with SIAD will typically excrete urine with an Na⁺ concentration that is >30 mM. However, there can be substantial overlap in urine Na⁺ concentration values in patients with SIAD and hypovolemic hyponatremia, particularly in the elderly; the ultimate “gold standard” for the diagnosis of hypovolemic hyponatremia is the demonstration that plasma Na⁺ concentration corrects after hydration with normal saline. Patients with thiazide-associated hyponatremia may also present with higher than expected urine Na⁺ concentration and other findings suggestive of SIAD; one should defer making a diagnosis of SIAD in these patients until 1–2 weeks after discontinuing the thiazide. A urine osmolality <100 mOsm/kg is suggestive of polydipsia; urine osmolality >400 mOsm/kg indicates that AVP excess is playing a more dominant role, whereas intermediate values are more consistent with multifactorial pathophysiology (e.g., AVP excess with a significant component of polydipsia). Patients with hyponatremia due to decreased solute intake (beer potomania) typically have urine Na⁺ concentration <20 mM and urine osmolality in the range of <100 to the low 200s. Finally, the measurement of urine K⁺ concentration is required to calculate the urine-to-plasma electrolyte ratio, which is useful to predict the response to fluid restriction (see the section on treatment of hyponatremia below).