Etiology of Hyponatremia Based on Osmolality

Classification Framework by Plasma Osmolality

Hyponatremia must first be classified by plasma osmolality to determine the underlying mechanism and guide appropriate management. 1, 2 The calculated plasma osmolality uses the formula: 2 × Na (mEq/L) + BUN (mg/dL)/2.8 + glucose (mg/dL)/18, with normal values ranging from 275-295 mOsm/kg. 3

Hypertonic Hyponatremia (Plasma Osmolality >295 mOsm/kg)

Pathophysiology and Causes

Hypertonic hyponatremia occurs when osmotically active solutes draw water from the intracellular to extracellular space, diluting serum sodium despite elevated total body osmolality. 4, 5

Hyperglycemia is the most common cause, with serum sodium decreasing by approximately 1.6 mEq/L for every 100 mg/dL increase in glucose above 100 mg/dL 5, 2
Mannitol administration creates an osmotic gradient that pulls water into the vascular space 4
This represents pseudohyponatremia in the sense that total body sodium is not truly depleted—the measured sodium is artificially low due to osmotic water shifts 4, 5

Isotonic Hyponatremia (Plasma Osmolality 275-295 mOsm/kg)

Pseudohyponatremia

Isotonic hyponatremia typically indicates pseudohyponatremia, where laboratory artifact creates falsely low sodium measurements without true hypotonicity. 4, 5

Severe hyperlipidemia (triglycerides >1500 mg/dL) or hyperproteinemia (total protein >10 g/dL) reduce the aqueous fraction of plasma, leading to falsely low sodium measurements by flame photometry or indirect ion-selective electrodes 6, 5
Post-transurethral resection of prostate (TURP) syndrome occurs when large volumes of glycine or sorbitol irrigation solutions are absorbed, creating isotonic hyponatremia 5
Modern direct ion-selective electrode methods have largely eliminated pseudohyponatremia from hyperlipidemia and hyperproteinemia 4

Hypotonic Hyponatremia (Plasma Osmolality <275 mOsm/kg)

Hypotonic hyponatremia represents true hyponatremia with decreased plasma osmolality and requires further classification by volume status and urine studies. 1, 4, 2 This is the most clinically significant category, affecting 15-30% of hospitalized patients. 3, 6

Classification by Volume Status

After confirming hypotonic hyponatremia, the next critical step is assessing extracellular fluid (ECF) volume status through physical examination, though this has limited accuracy (sensitivity 41.1%, specificity 80%). 1

A. Hypovolemic Hypotonic Hyponatremia (ECF Volume Depletion)

Hypovolemic hyponatremia results from combined sodium and water losses, with proportionally greater sodium loss, triggering non-osmotic ADH release to preserve intravascular volume. 1, 7

Renal Losses (Urine Sodium >20-30 mEq/L)

Diuretic use (especially thiazides) causes excessive renal sodium wasting while impairing free water excretion 1, 5, 2
Salt-wasting nephropathies including chronic kidney disease, medullary cystic disease, and polycystic kidney disease 5
Cerebral salt wasting (CSW) in neurosurgical patients, produced by excessive natriuretic peptide secretion causing hyponatremia through excessive natriuresis and volume contraction 1
Mineralocorticoid deficiency (Addison's disease, adrenal insufficiency) impairs sodium reabsorption 5, 2
Osmotic diuresis from hyperglycemia or mannitol 2

Extrarenal Losses (Urine Sodium <20-30 mEq/L)

Gastrointestinal losses from vomiting, diarrhea, nasogastric suction, or fistulas 5, 7, 2
Third-spacing in pancreatitis, peritonitis, or burns 6, 5
Excessive sweating or other dermal losses 2

The urine sodium concentration is critical for differentiating renal from extrarenal causes: urine sodium <30 mmol/L has a 71-100% positive predictive value for response to saline infusion. 1

B. Euvolemic Hypotonic Hyponatremia (Normal ECF Volume)

Euvolemic hyponatremia occurs when water retention exceeds sodium retention without clinically apparent volume expansion, most commonly due to inappropriate ADH activity. 1, 4

Syndrome of Inappropriate Antidiuretic Hormone (SIADH)

SIADH is the most important cause of euvolemic hyponatremia, characterized by inappropriate ADH secretion despite low plasma osmolality and normal volume status. 8, 6, 5

Diagnostic criteria for SIADH include: 8

Hypotonic hyponatremia (serum sodium <135 mEq/L, plasma osmolality <275 mOsm/kg)
Inappropriately concentrated urine (urine osmolality >100 mOsm/kg, typically >500 mOsm/kg)
Elevated urine sodium (>20-40 mEq/L) despite euvolemia
Normal renal, thyroid, and adrenal function
Absence of diuretic use, hypovolemia, or hypervolemia

Common causes of SIADH: 8, 6

Malignancies: Small cell lung cancer (most common), pancreatic cancer, lymphomas 8
CNS disorders: Meningitis, encephalitis, subarachnoid hemorrhage, traumatic brain injury, stroke 3, 8
Pulmonary diseases: Pneumonia, tuberculosis, positive pressure ventilation 3, 8
Medications: SSRIs, carbamazepine, cyclophosphamide, vincristine, NSAIDs, opioids 8
Postoperative state, pain, nausea, stress trigger non-osmotic ADH release 3

A serum uric acid <4 mg/dL has a 73-100% positive predictive value for SIADH. 1

Other Euvolemic Causes

Hypothyroidism causes reduced cardiac output and glomerular filtration rate, leading to water retention 5, 2
Glucocorticoid deficiency (secondary adrenal insufficiency) impairs free water excretion without mineralocorticoid deficiency 5, 2
Primary polydipsia (psychogenic or reset osmostat) with water intake exceeding renal excretory capacity 6, 5
Beer potomania involves poor solute intake limiting free water excretion capacity 1

C. Hypervolemic Hypotonic Hyponatremia (ECF Volume Expansion)

Hypervolemic hyponatremia results from total body sodium and water excess, with proportionally greater water retention due to non-osmotic ADH release and impaired renal water excretion. 1, 2

Pathophysiology

In hypervolemic states, decreased effective arterial blood volume triggers non-osmotic ADH release and activation of the renin-angiotensin-aldosterone system (RAAS), causing enhanced proximal nephron sodium reabsorption and impaired free water clearance. 1 This occurs despite total body sodium and water overload. 1

Major Causes

Congestive heart failure with reduced cardiac output and effective circulating volume 1, 5, 2
Cirrhosis with ascites due to portal hypertension, systemic vasodilation, and decreased systemic vascular resistance 1
- Hyponatremia affects ~60% of cirrhotic patients and increases risk of spontaneous bacterial peritonitis (OR 3.40), hepatorenal syndrome (OR 3.45), and hepatic encephalopathy (OR 2.36) 1
Nephrotic syndrome with severe hypoalbuminemia reducing oncotic pressure 5, 2
Advanced chronic kidney disease with impaired diluting capacity 5, 2

Clinical signs of hypervolemia include: peripheral edema, ascites, pulmonary congestion, and jugular venous distention. 1

Diagnostic Algorithm Summary

Step 1: Measure plasma osmolality 1, 2

High (>295 mOsm/kg) → Check glucose, consider mannitol
Normal (275-295 mOsm/kg) → Consider pseudohyponatremia (lipids, proteins)
Low (<275 mOsm/kg) → Proceed to Step 2

Step 2: Assess volume status (hypovolemic, euvolemic, hypervolemic) 1, 2

Step 3: Measure urine osmolality and urine sodium 1, 2

Urine osmolality <100 mOsm/kg suggests appropriate ADH suppression (primary polydipsia)
Urine osmolality >100 mOsm/kg indicates impaired water excretion
Urine sodium <30 mEq/L suggests extrarenal losses or decreased effective circulating volume
Urine sodium >20-40 mEq/L suggests renal losses, SIADH, or adrenal insufficiency

Step 4: Consider additional tests based on clinical context 1

Thyroid function (TSH) to exclude hypothyroidism
Cortisol/ACTH to exclude adrenal insufficiency
Serum uric acid (<4 mg/dL suggests SIADH)

Critical Clinical Pearls

Hospital-acquired hyponatremia from hypotonic IV fluids in the setting of elevated ADH is entirely preventable by using isotonic maintenance fluids, yet affects 15-30% of hospitalized patients 3
Distinguishing SIADH from cerebral salt wasting in neurosurgical patients is critical: SIADH requires fluid restriction while CSW requires volume and sodium replacement 1, 8
Osmotic demyelination syndrome risk necessitates limiting sodium correction to ≤8 mmol/L in 24 hours, with even slower rates (4-6 mmol/L/day) in high-risk patients with cirrhosis, alcoholism, or malnutrition 1, 8
Even mild hyponatremia (130-135 mmol/L) increases fall risk (21% vs 5%) and mortality (60-fold increase with sodium <130 mmol/L) 1

What is the etiology of hyponatremia based on plasma osmolality?

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