What are the causes of hyponatremia (low serum sodium level)?

Causes of Hyponatremia

Classification by Volume Status

Hyponatremia results from three primary mechanisms based on extracellular fluid volume status: hypovolemic, euvolemic, and hypervolemic hyponatremia. 1

Hypovolemic Hyponatremia (Volume Depletion)

Hypovolemic hyponatremia occurs when both sodium and water are lost, but sodium loss exceeds water loss 1:

• Renal losses (urine sodium >20 mmol/L): Excessive diuretic use (particularly thiazides), salt-wasting nephropathy, cerebral salt wasting, mineralocorticoid deficiency 1, 2
• Extrarenal losses (urine sodium <20 mmol/L): Gastrointestinal losses from vomiting, diarrhea, or third-space sequestration; burns; excessive sweating 1, 2
• Blood loss: Significant hemorrhage leading to volume depletion 2

Clinical signs include orthostatic hypotension, dry mucous membranes, decreased skin turgor, and flat neck veins 1.

Euvolemic Hyponatremia (Normal Volume Status)

Euvolemic hyponatremia represents water retention without significant changes in total body sodium 1:

• Syndrome of Inappropriate Antidiuretic Hormone (SIADH): The most common cause, characterized by inappropriate ADH secretion despite low plasma osmolality 1, 3

  • Malignancies (especially small cell lung cancer) 1
  • CNS disorders (meningitis, encephalitis, head trauma, stroke, subarachnoid hemorrhage) 1, 3
  • Pulmonary diseases (pneumonia, tuberculosis, positive pressure ventilation) 1, 3
  • Medications: SSRIs, carbamazepine, cyclophosphamide, antipsychotics, NSAIDs 1, 4
  • Postoperative states, pain, nausea, and stress 1, 3

• Endocrine disorders: Hypothyroidism, adrenal insufficiency 1, 4

• Primary polydipsia: Excessive water intake overwhelming renal excretion capacity 1

• Beer potomania: Poor solute intake combined with excessive beer consumption 1

Diagnostic criteria for SIADH include hypotonic hyponatremia, inappropriately concentrated urine (>100 mOsm/kg), elevated urine sodium (>20-40 mmol/L), and normal renal, thyroid, and adrenal function in a euvolemic patient 1.

Hypervolemic Hyponatremia (Volume Overload)

Hypervolemic hyponatremia occurs when total body water increases more than total body sodium, despite both being elevated 1:

• Congestive heart failure: Non-osmotic vasopressin release due to decreased effective arterial blood volume 1, 3
• Liver cirrhosis with ascites: Portal hypertension causes systemic vasodilation, decreased effective plasma volume, and activation of the renin-angiotensin-aldosterone system, leading to excessive sodium and water reabsorption 1, 2
• Nephrotic syndrome: Severe proteinuria leading to decreased oncotic pressure and fluid retention 1, 2
• Advanced renal failure: Impaired free water excretion 1, 2

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

Special Clinical Scenarios

Cerebral Salt Wasting (CSW)

CSW occurs primarily in neurosurgical patients and is caused by excessive secretion of natriuretic peptides 1:

• More common in patients with poor clinical grade, ruptured anterior communicating artery aneurysms, and hydrocephalus 1
• Distinguished from SIADH by evidence of true hypovolemia: hypotension, tachycardia, low central venous pressure (<6 cm H₂O), and dry mucous membranes 1
• High urine sodium (>20 mmol/L) despite volume depletion 1

Medication-Induced Hyponatremia

Multiple medications can cause hyponatremia through various mechanisms 1, 4:

• Thiazide diuretics: Most common cause of drug-induced hyponatremia, particularly in elderly patients 1
• Antidepressants (SSRIs, trazodone): Increase ADH release or enhance renal sensitivity to ADH 1
• Antiepileptics (carbamazepine, oxcarbazepine): Stimulate ADH release 1
• Chemotherapy agents (cyclophosphamide, vincristine): Direct ADH-like effects 1

Hospital-Acquired Hyponatremia

Hospital-acquired hyponatremia from hypotonic IV fluids in the setting of elevated ADH affects 15-30% of hospitalized patients and is entirely preventable by using isotonic maintenance fluids 1.

Pathophysiologic Mechanisms

The fundamental mechanism underlying most hyponatremia is elevated arginine vasopressin (AVP) levels in the presence of continued water intake 3:

• Osmotic stimuli: Hyperosmolality normally triggers AVP release 3
• Non-osmotic stimuli: Volume depletion, pain, nausea, stress, and certain medications can trigger AVP release even when plasma osmolality is low 1, 3
• Impaired free water excretion: Results from inability to suppress ADH appropriately or impaired renal response 1

Clinical Significance by Severity

• Mild hyponatremia (130-135 mmol/L): Associated with cognitive impairment, gait disturbances, increased fall risk (21% vs 5% in normonatremic patients), and fractures 1, 5
• Moderate hyponatremia (120-129 mmol/L): Increased risk of complications, particularly in cirrhotic patients (spontaneous bacterial peritonitis OR 3.40, hepatorenal syndrome OR 3.45, hepatic encephalopathy OR 2.36) 1
• Severe hyponatremia (<120 mmol/L): Associated with 60-fold increase in hospital mortality (11.2% vs 0.19%) and life-threatening neurological symptoms 1, 5

Common Pitfalls in Diagnosis

• Pseudohyponatremia: Occurs with severe hyperglycemia (add 1.6 mEq/L to sodium for each 100 mg/dL glucose >100 mg/dL), hyperlipidemia, or hyperproteinemia 1
• Failing to assess volume status accurately: Physical examination alone has poor sensitivity (41.1%) and specificity (80%) 1
• Confusing SIADH with cerebral salt wasting in neurosurgical patients, as they require opposite treatments 1