Differential Diagnosis for Hyponatremia
Classification by Volume Status
The differential diagnosis of hyponatremia is best organized by assessing the patient's extracellular fluid (ECF) volume status (hypovolemic, euvolemic, or hypervolemic), combined with serum osmolality and urinary sodium measurements. 1
Initial Diagnostic Approach
Step 1: Confirm True Hyponatremia
- Measure serum osmolality to exclude pseudohyponatremia 1, 2
- Normal serum osmolality (275-290 mOsm/kg) suggests pseudohyponatremia from hyperglycemia, hypertriglyceridemia, or hyperproteinemia 1, 3
- Low serum osmolality (<275 mOsm/kg) confirms true hypotonic hyponatremia 1, 4
Step 2: Assess Volume Status
- Physical examination alone has poor accuracy (sensitivity 41.1%, specificity 80%) and should be supplemented with laboratory findings 1, 2
- Measure urine osmolality and urine sodium concentration to guide differential diagnosis 1, 3
Hypovolemic Hyponatremia (ECF Depletion)
Clinical Features
Urine Sodium <30 mmol/L (Extrarenal Losses)
- Gastrointestinal losses: vomiting, diarrhea, nasogastric suction 1, 3
- Third-space losses: burns, pancreatitis, peritonitis 3
- Excessive sweating 3
Urine Sodium >20 mmol/L (Renal Losses)
- Diuretic use (especially thiazides) 1, 4
- Cerebral salt wasting (particularly in neurosurgical patients) 1, 2, 5
- Salt-losing nephropathy 2
- Adrenal insufficiency 2, 6
- Mineralocorticoid deficiency 3
Euvolemic Hyponatremia (Normal ECF)
Clinical Features
- No edema, no orthostatic hypotension, normal skin turgor, moist mucous membranes 1
Urine Sodium >20-40 mmol/L with Urine Osmolality >300 mOsm/kg
Syndrome of Inappropriate Antidiuretic Hormone (SIADH) 1, 2, 4
- Malignancies: small cell lung cancer, pancreatic cancer, lymphoma 2, 6
- CNS disorders: meningitis, encephalitis, stroke, subarachnoid hemorrhage, head trauma 2, 6
- Pulmonary diseases: pneumonia, tuberculosis, positive pressure ventilation 2, 6
- Medications: SSRIs, carbamazepine, oxcarbazepine, cyclophosphamide, vincristine, NSAIDs 1, 6, 7
- Postoperative state 6
Diagnostic criteria for SIADH 2, 4:
- Hypotonic hyponatremia (serum Na <134 mEq/L, plasma osmolality <275 mOsm/kg)
- Inappropriately elevated urine osmolality (>500 mOsm/kg)
- Elevated urinary sodium (>20-40 mEq/L)
- Euvolemia (absence of hypovolemia or hypervolemia)
- Normal renal, adrenal, and thyroid function
Serum uric acid <4 mg/dL has a positive predictive value of 73-100% for SIADH 1, 2, 5
Other Euvolemic Causes
- Hypothyroidism 1, 6, 7
- Adrenal insufficiency (glucocorticoid deficiency) 2, 6
- Psychogenic polydipsia (primary polydipsia) 1, 6
- Reset osmostat syndrome 3, 6
- Exercise-induced hyponatremia 6, 7
- Beer potomania 1
Hypervolemic Hyponatremia (ECF Expansion)
Clinical Features
Urine Sodium Variable
- Congestive heart failure (urine Na typically <30 mmol/L)
- Liver cirrhosis with ascites (urine Na typically <30 mmol/L)
- Nephrotic syndrome (urine Na typically <30 mmol/L)
- Advanced renal failure (urine Na >20 mmol/L) 2
Pathophysiology: Non-osmotic hypersecretion of vasopressin, enhanced proximal nephron sodium reabsorption, and impaired free water clearance 1, 4
Special Diagnostic Considerations
Neurosurgical Patients
Distinguishing SIADH from Cerebral Salt Wasting (CSW) is critical as treatment approaches differ fundamentally 1, 2, 5:
- Euvolemia (CVP 6-10 cm H₂O)
- Urine sodium >20-40 mmol/L
- Urine osmolality >500 mOsm/kg
- Treatment: fluid restriction
Cerebral Salt Wasting characteristics 1, 2, 5:
- Hypovolemia (CVP <6 cm H₂O)
- Urine sodium >20 mmol/L despite volume depletion
- Clinical signs of volume depletion
- More common in poor clinical grade, ruptured anterior communicating artery aneurysms, hydrocephalus 1
- Treatment: volume and sodium replacement (NOT fluid restriction)
Urinary Sodium Interpretation
- Urine sodium <30 mmol/L has a positive predictive value of 71-100% for response to 0.9% saline infusion, indicating hypovolemic hyponatremia 1, 2, 5
- Urine sodium >20-40 mmol/L with euvolemia suggests SIADH 1, 2
- Urine sodium >20 mmol/L with hypovolemia suggests renal salt wasting (diuretics, CSW, adrenal insufficiency) 1, 2
Common Diagnostic Pitfalls
- Relying solely on physical examination to determine volume status is not recommended due to poor sensitivity 1, 2, 5
- Misdiagnosing CSW as SIADH leads to inappropriate fluid restriction, which worsens outcomes 1, 5
- Ignoring mild hyponatremia (130-135 mmol/L) as clinically insignificant, when it increases fall risk and mortality 1
- Failing to recognize drug-induced hyponatremia, particularly with antidepressants, diuretics, and antiepileptics 1, 6, 7
- Obtaining ADH and natriuretic peptide levels is not supported by evidence and should not delay treatment 1