What are the causes of hyponatremia, categorized by volume status?

Causes of Hyponatremia by Volume Status

Hyponatremia results from water retention exceeding sodium loss in most cases, and should be systematically classified by volume status—hypovolemic, euvolemic, or hypervolemic—to guide appropriate treatment. 1, 2

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Hypovolemic Hyponatremia (ECF Volume Depletion)

Characterized by decreased extracellular fluid volume with clinical signs of dehydration including orthostatic hypotension, dry mucous membranes, decreased skin turgor, and flat neck veins. 1, 3

Extrarenal Sodium Losses (Urine Sodium <30 mmol/L)

• Gastrointestinal losses from vomiting, diarrhea, or nasogastric suction cause sodium depletion with appropriate renal sodium conservation 4, 5
• Third-spacing in conditions such as severe burns, pancreatitis, or peritonitis leads to effective volume depletion 4, 5
• Excessive sweating from prolonged exercise or heat exposure can produce significant sodium and water losses 5

Renal Sodium Losses (Urine Sodium >20 mmol/L)

• Diuretic use (particularly thiazides and loop diuretics) causes excessive renal sodium wasting 1, 4
• Cerebral salt wasting (CSW) occurs in neurosurgical patients with CNS injury, producing hypovolemia with inappropriately elevated urinary sodium (>20 mmol/L) despite volume depletion 1, 6
• Adrenal insufficiency impairs sodium retention due to mineralocorticoid deficiency 6, 4
• Salt-losing nephropathy from chronic kidney disease or tubulointerstitial disease prevents adequate sodium reabsorption 6

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Euvolemic Hyponatremia (Normal ECF Volume)

Characterized by absence of clinical signs of hypovolemia or hypervolemia—no edema, no orthostatic hypotension, normal skin turgor, and moist mucous membranes. 1, 6

Syndrome of Inappropriate Antidiuretic Hormone (SIADH)

• Diagnostic criteria include: hypotonic hyponatremia (serum sodium <134 mEq/L), plasma osmolality <275 mOsm/kg, inappropriately elevated urine osmolality (>500 mOsm/kg), urine sodium >20-40 mEq/L, and euvolemia with normal thyroid, adrenal, and renal function 6, 3
• Malignancies (especially small cell lung cancer) produce ectopic ADH secretion 6, 4
• CNS disorders including meningitis, encephalitis, stroke, and head trauma stimulate nonosmotic ADH release 6, 4
• Pulmonary diseases such as pneumonia and tuberculosis trigger ADH secretion 6, 4
• Medications including SSRIs, carbamazepine, cyclophosphamide, NSAIDs, and opioids cause drug-induced SIADH 6, 2
• Postoperative state with pain, nausea, and stress provides nonosmotic stimuli for ADH release 6

Other Euvolemic Causes

• Hypothyroidism impairs free water excretion through reduced cardiac output and GFR 4, 3
• Glucocorticoid deficiency (isolated cortisol deficiency without mineralocorticoid loss) prevents adequate water excretion 4
• Polydipsia from excessive water intake overwhelms renal excretory capacity 3
• Reset osmostat syndrome where ADH secretion occurs at a lower osmotic threshold 4

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Hypervolemic Hyponatremia (ECF Volume Expansion)

Characterized by total body sodium and water excess with clinical signs of volume overload including peripheral edema, ascites, jugular venous distention, and pulmonary congestion. 1, 3

Congestive Heart Failure

• Reduced effective arterial blood volume activates the renin-angiotensin-aldosterone system and stimulates nonosmotic ADH release despite total body fluid excess 4, 5
• Urinary sodium typically 50-70 mEq/L reflecting persistent renal sodium avidity 1

Liver Cirrhosis with Ascites

• Portal hypertension and systemic vasodilation create perceived arterial underfilling, triggering ADH secretion and sodium retention 1, 5
• Urinary sodium typically <10 mEq/L (unless on diuretics) due to maximal renal sodium conservation 1
• Affects approximately 21.6% of cirrhotic patients with sodium ≤130 mmol/L 1

Advanced Renal Failure

• Impaired free water excretion from reduced GFR prevents adequate water elimination 6, 4
• Urinary sodium may be elevated (>20 mEq/L) despite volume overload due to kidney dysfunction 6

Nephrotic Syndrome

• Severe hypoalbuminemia reduces oncotic pressure, causing fluid shifts and effective volume depletion despite total body fluid excess 4

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Special Diagnostic Considerations

Volume Status Assessment

• Physical examination alone has poor accuracy (sensitivity 41.1%, specificity 80%) for determining volume status 1, 6
• Urinary sodium <30 mmol/L has 71-100% positive predictive value for response to isotonic saline in hypovolemic hyponatremia 1
• Serum uric acid <4 mg/dL has 73-100% positive predictive value for SIADH (though may also occur in CSW) 1, 6

Critical Distinction: SIADH vs. Cerebral Salt Wasting

• SIADH: euvolemic with normal to slightly elevated CVP (6-10 cm H₂O), treated with fluid restriction 1, 6
• CSW: hypovolemic with CVP <6 cm H₂O, treated with volume and sodium replacement—fluid restriction worsens outcomes 1, 6

Pseudohyponatremia

• Hyperglycemia causes hypertonic hyponatremia (add 1.6 mEq/L to sodium for each 100 mg/dL glucose >100 mg/dL) 3
• Severe hyperlipidemia or hyperproteinemia produces isotonic pseudohyponatremia from laboratory artifact 4, 3

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Common Diagnostic Pitfalls

• Misdiagnosing volume status leads to inappropriate therapy—fluid restriction in CSW can precipitate cerebral ischemia 1, 6
• Obtaining ADH and natriuretic peptide levels is not supported by evidence and delays diagnosis 1
• Ignoring mild hyponatremia (130-135 mmol/L) despite associations with increased falls (23.8% vs 16.4%), fractures, cognitive impairment, and mortality 2
• Failing to identify medication causes (diuretics, SSRIs, carbamazepine, NSAIDs) before pursuing extensive workup 6, 2