Causes of Hyponatremia
Classification by Volume Status
Hyponatremia develops through three primary mechanisms based on volume status: hypovolemic (volume depletion), euvolemic (normal volume), and hypervolemic (volume overload), each with distinct underlying causes. 1
Hypovolemic Hyponatremia (Volume Depletion)
Renal Causes (Urinary Sodium >20-30 mmol/L):
- Excessive diuretic use, particularly thiazides and loop diuretics 1, 2
- Salt-wasting nephropathies and renal tubular disorders 2
- Mineralocorticoid deficiency (adrenal insufficiency) 2
- Cerebral salt wasting syndrome in neurosurgical patients 1
Extrarenal Causes (Urinary Sodium <20-30 mmol/L):
- Gastrointestinal losses: vomiting, diarrhea, nasogastric suction 2, 3
- Third-space fluid sequestration: burns, pancreatitis, peritonitis 2
- Excessive sweating or other skin losses 2
Euvolemic Hyponatremia (Normal Volume Status)
Primary Mechanism: Syndrome of Inappropriate Antidiuretic Hormone (SIADH) 1, 2
Common SIADH Causes:
- Malignancies: Small cell lung cancer (affects 1-5% of lung cancer patients), pancreatic cancer, lymphomas 1, 2
- Central nervous system disorders: Meningitis, encephalitis, head trauma, subarachnoid hemorrhage, brain tumors 2, 3
- Pulmonary diseases: Pneumonia, tuberculosis, positive pressure ventilation 2
- Medications: Carbamazepine, oxcarbazepine, selective serotonin reuptake inhibitors (SSRIs), vincristine, cyclophosphamide, desmopressin 4, 2
Other Euvolemic Causes:
- Hypothyroidism (uncontrolled) 5, 2
- Glucocorticoid deficiency (uncontrolled adrenal insufficiency) 5, 2
- Primary polydipsia (excessive water intake) 5, 2
- Reset osmostat syndrome 2
Hypervolemic Hyponatremia (Volume Overload)
Edematous States with Impaired Water Excretion:
- Cirrhosis with portal hypertension: Systemic vasodilation leads to decreased effective plasma volume, activation of renin-angiotensin-aldosterone system, and non-osmotic vasopressin release; occurs in approximately 60% of cirrhotic patients 1, 6
- Congestive heart failure: Reduced cardiac output triggers neurohormonal activation with increased ADH release 4, 2, 3
- Nephrotic syndrome and advanced renal disease: Impaired sodium and water excretion 4, 2
Pathophysiologic Mechanisms
The fundamental mechanisms underlying hyponatremia are either defective water excretion (most common, usually from elevated vasopressin) or excessive fluid intake relative to excretion capacity. 7
Key Pathophysiologic Factors:
- Non-osmotic vasopressin (ADH) release despite low serum osmolality 6, 7
- Enhanced proximal tubular sodium and water reabsorption 1
- Impaired free water clearance by the kidneys 6, 7
- Continued fluid intake in the setting of impaired excretion 7, 3
Special High-Risk Populations
Pediatric patients receiving certain perioperative medications are at particularly high risk:
- Desmopressin for Von Willebrand disease 4
- Antiepileptic medications (carbamazepine) 4
- Chemotherapeutic agents (IV cyclophosphamide, vincristine) 4
Patients with congenital or acquired heart disease, liver disease, renal dysfunction, or adrenal insufficiency require isotonic fluids and close monitoring when receiving intravenous maintenance fluids. 4
Diagnostic Approach to Determine Cause
Initial assessment should include serum and urine osmolality, urine sodium concentration, urine electrolytes, serum uric acid, and clinical assessment of extracellular fluid volume status. 1
Key Diagnostic Indicators:
- Urinary sodium <30 mmol/L: Suggests hypovolemic hyponatremia with 71-100% positive predictive value for response to saline 1
- Urinary sodium >20-40 mmol/L with high urine osmolality (>300-500 mOsm/kg): Suggests SIADH or renal salt wasting 1, 2
- Serum uric acid <4 mg/dL: Has 73-100% positive predictive value for SIADH (though may include cerebral salt wasting) 1