Causes of Hyponatremia
Classification by Volume Status
Hyponatremia develops through three primary mechanisms based on extracellular fluid volume status: hypovolemic, euvolemic, and hypervolemic—each with distinct underlying causes that guide both diagnosis and treatment. 1
Hypovolemic Hyponatremia (True Volume Depletion)
Extrarenal Sodium Losses (Urinary Sodium <30 mmol/L)
Gastrointestinal fluid losses from vomiting, diarrhea, or nasogastric suction cause hypovolemic hyponatremia with urinary sodium typically <30 mmol/L, reflecting appropriate renal sodium conservation 2, 3
Third-spacing of fluids in conditions such as severe burns, pancreatitis, or peritonitis leads to effective volume depletion despite total body fluid accumulation 2
Excessive sweating from prolonged exercise or heat exposure can produce hypovolemic hyponatremia when fluid losses are replaced with hypotonic fluids 4
Renal Sodium Losses (Urinary Sodium >20 mmol/L)
Thiazide diuretics are among the most common causes of hyponatremia, producing hypovolemic hyponatremia through excessive renal sodium and water loss, and should be discontinued when sodium falls below 125 mmol/L 2, 1, 5
Loop diuretics (furosemide, bumetanide) cause renal sodium wasting, particularly in patients with cirrhosis or heart failure 1
Cerebral salt wasting syndrome occurs in neurosurgical patients (especially after subarachnoid hemorrhage) and is characterized by excessive renal sodium loss with urinary sodium >20 mmol/L despite clinical hypovolemia 2, 1
Adrenal insufficiency produces hypovolemic hyponatremia through aldosterone deficiency, leading to renal sodium wasting and impaired free water excretion 6, 3
Salt-losing nephropathy from chronic kidney disease or tubulointerstitial disease causes inappropriate renal sodium losses 6
Euvolemic Hyponatremia (Normal Extracellular Volume)
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, with urinary sodium >20-40 mmol/L and urine osmolality >300-500 mOsm/kg 6, 1, 7
Malignancies are a leading cause of SIADH, particularly small cell lung cancer (most common), pancreatic cancer, lymphomas, and other neuroendocrine tumors 1, 4
Central nervous system disorders including meningitis, encephalitis, brain tumors, subarachnoid hemorrhage, and traumatic brain injury trigger non-osmotic ADH release 6, 7
Pulmonary diseases such as pneumonia, tuberculosis, and acute respiratory failure stimulate ADH secretion through inflammatory mediators 4
Medications causing SIADH include selective serotonin reuptake inhibitors (SSRIs), carbamazepine, oxcarbazepine, vincristine, cyclophosphamide, desmopressin, and trazodone 1, 4
Postoperative states commonly produce SIADH through pain, nausea, and stress-induced non-osmotic ADH release 7, 4
Endocrine Disorders
Hypothyroidism causes euvolemic hyponatremia through reduced cardiac output and glomerular filtration rate, impairing free water excretion 6, 3
Adrenal insufficiency (when mild) can present as euvolemic hyponatremia before progressing to hypovolemia 6
Other Causes
Psychogenic polydipsia produces hyponatremia when water intake exceeds renal excretory capacity, typically >10-15 liters per day 3
Beer potomania occurs in chronic alcoholics with poor nutritional intake, where low solute intake limits free water excretion 2
Exercise-induced hyponatremia develops during prolonged endurance activities when hypotonic fluid intake exceeds sweat losses 8, 4
Hypervolemic Hyponatremia (Increased Total Body Sodium and Water)
Cardiac Causes
- Congestive heart failure produces hypervolemic hyponatremia through reduced cardiac output, which triggers neurohormonal activation with increased ADH release despite total body fluid overload 1, 3, 4
Hepatic Causes
- Cirrhosis with portal hypertension is a major cause of hypervolemic hyponatremia, occurring in approximately 60% of cirrhotic patients through systemic vasodilation, reduced effective arterial blood volume, and non-osmotic ADH secretion 2, 1, 4
Renal Causes
- Advanced chronic kidney disease and nephrotic syndrome cause hypervolemic hyponatremia through impaired free water excretion and sodium retention 6, 3, 8
High-Risk Medications
Antidepressants including SSRIs and trazodone carry particularly high risk for hyponatremia in older adults and require regular serum sodium monitoring 1
Chemotherapeutic agents such as vincristine and cyclophosphamide commonly induce SIADH 1
Antiepileptic drugs including carbamazepine and oxcarbazepine are well-established causes of SIADH 1, 4
Desmopressin directly induces SIADH and places patients at exceptionally high risk 6, 1
Opioid analgesics have an adjusted odds ratio of 4.46 for hyponatremia through non-osmotic ADH stimulation 1
NSAIDs (particularly indomethacin) increase hyponatremia risk with an adjusted odds ratio of 3.61 1
Diagnostic Approach to Determine Etiology
Initial assessment should include serum and urine osmolality, urine sodium concentration, serum uric acid, and clinical assessment of extracellular fluid volume status to differentiate between hypovolemic, euvolemic, and hypervolemic causes 2, 1
Urinary sodium <30 mmol/L suggests hypovolemic hyponatremia with 71-100% positive predictive value for response to isotonic saline, indicating extrarenal losses 2, 1
Urinary sodium >20-40 mmol/L with high urine osmolality (>300-500 mOsm/kg) suggests SIADH or renal salt wasting in the appropriate clinical context 6, 1
Serum uric acid <4 mg/dL has 73-100% positive predictive value for SIADH, though it may also be seen in cerebral salt wasting 2, 6
Physical examination alone has poor accuracy (sensitivity 41.1%, specificity 80%) for determining volume status, and should be supplemented with laboratory parameters 2, 6
Special Populations at Increased Risk
Pediatric patients receiving perioperative medications such as desmopressin, antiepileptic drugs, and chemotherapeutic agents are at exceptionally high risk for developing hyponatremia 1
Malnourished older adults are particularly vulnerable when taking renin-angiotensin-aldosterone system inhibitors, diuretics, opioids, and antidepressants 1
Patients with congenital or acquired heart disease, liver disease, renal dysfunction, or adrenal insufficiency require isotonic fluids and close sodium monitoring when receiving intravenous maintenance fluids 1
Common Diagnostic Pitfalls
Failing to assess volume status accurately is a common error, as misdiagnosis leads to inappropriate therapy—fluid restriction worsens hypovolemic states while isotonic saline worsens hypervolemic conditions 2
Not reviewing medication lists for SIADH-inducing drugs (SSRIs, carbamazepine, NSAIDs, opioids, chemotherapy) may miss a readily reversible cause 1
Ordering ADH levels adds no clinical value and delays diagnosis, as this test is not supported by evidence and does not alter management 2, 6