Causes of Hyponatremia
Classification by Volume Status
Hyponatremia develops through three primary mechanisms based on extracellular fluid volume status: hypovolemic, euvolemic, and hypervolemic—each requiring distinct diagnostic and therapeutic approaches. 1, 2
Hypovolemic Hyponatremia (True Sodium and Water Depletion)
Renal Sodium Losses
- Excessive diuretic use, particularly thiazides and loop diuretics, is a leading cause of hypovolemic hyponatremia 1, 2
- Mineralocorticoid deficiency (adrenal insufficiency) 3
- Salt-wasting nephropathies 3
- Cerebral salt wasting syndrome in neurosurgical patients, characterized by excessive natriuretic peptide secretion causing hyponatremia through excessive natriuresis and volume contraction 1, 2
Extrarenal Sodium Losses
- Gastrointestinal losses: severe or recurrent diarrhea, vomiting, nasogastric suction 3, 4
- Third-spacing: burns, pancreatitis, peritonitis 3
- Significant blood loss 4
- Excessive sweating 5
Diagnostic clue: Urinary sodium <30 mmol/L suggests extrarenal losses with 71-100% positive predictive value for response to saline infusion 1, 2
Euvolemic Hyponatremia (Normal Total Body Sodium, Excess Water)
Syndrome of Inappropriate Antidiuretic Hormone (SIADH)
SIADH is the most common cause of euvolemic hyponatremia, characterized by inappropriate ADH secretion despite low plasma osmolality and normal volume status 1, 3, 5
Malignancies
Central Nervous System Disorders
Pulmonary Diseases
Medications (High-Risk)
- Selective serotonin reuptake inhibitors (SSRIs) and trazodone 1, 2
- Anticonvulsants: carbamazepine, oxcarbazepine 1, 2
- Chemotherapy agents: vincristine, cyclophosphamide, platinum-based agents 1, 2
- Desmopressin 1, 2
- Opioid analgesics (adjusted OR 4.46 for hyponatremia) 2
- NSAIDs, particularly indomethacin (adjusted OR 3.61) 2
- Tramadol 2
Endocrine Disorders
Other Euvolemic Causes
Diagnostic clues: Urinary sodium >20-40 mmol/L with high urine osmolality (>300-500 mOsm/kg) suggests SIADH; serum uric acid <4 mg/dL has 73-100% positive predictive value for SIADH 1, 2
Hypervolemic Hyponatremia (Excess Total Body Sodium and Water)
Cardiac Causes
- Congestive heart failure with reduced cardiac output triggering neurohormonal activation and increased ADH release 1, 3
Hepatic Causes
- Cirrhosis with portal hypertension, occurring in approximately 60% of cirrhotic patients 1, 3
- Non-osmotic hypersecretion of vasopressin due to systemic vasodilation and perceived arterial underfilling 1
Renal Causes
- Advanced chronic kidney disease with impaired free water excretion 2, 3
- Nephrotic syndrome 2, 3
- Acute kidney injury 3
Diagnostic clue: Urinary sodium typically >20 mmol/L due to compensatory natriuresis despite total body sodium excess 3
Pseudohyponatremia (Artifactual)
- Hyperglycemia (add 1.6 mEq/L to measured sodium for each 100 mg/dL glucose >100 mg/dL) 3, 5
- Severe hyperlipidemia 6, 3
- Hyperproteinemia 6, 3
- Post-transurethral prostatic resection syndrome 3
High-Risk Populations Requiring Vigilance
- Malnourished older adults taking RAAS inhibitors, diuretics, opioids, or antidepressants 2
- Pediatric patients receiving perioperative medications (desmopressin, antiepileptics, chemotherapy) 2
- Patients with congenital or acquired heart disease, liver disease, renal dysfunction, or adrenal insufficiency 2
- Neurosurgical patients (high risk for cerebral salt wasting) 1, 2
Essential Diagnostic Workup
Initial assessment must include: 1, 2
- Serum and urine osmolality
- Urine sodium concentration
- Serum uric acid
- Clinical assessment of extracellular fluid volume status (orthostatic vital signs, skin turgor, mucous membranes, jugular venous distention, edema)
Volume status assessment is the critical first step to differentiate hypovolemic, euvolemic, and hypervolemic causes, as each requires fundamentally different treatment approaches 1, 3, 5