Causes of Hyponatremia
Hyponatremia results from an excess of free water relative to total body sodium and can be systematically categorized by extracellular fluid (ECF) volume status, which is the key distinguishing feature for determining the underlying cause 1.
Primary Classification by Volume Status
The most clinically useful approach to identifying causes of hyponatremia is to categorize patients by their ECF volume status (hypovolemic, euvolemic, or hypervolemic) combined with urine sodium and osmolality measurements 1, 2.
Hypovolemic Hyponatremia (Sodium and Water Depletion)
Extrarenal sodium loss:
- Vomiting or diarrhea (one of the most frequent causes in hospitalized patients) 3
- Third-spacing from burns, pancreatitis, or peritonitis 3
- Characterized by urine sodium <30 mmol/L 1
Renal sodium loss:
- Thiazide diuretics (the number one culprit in drug-induced hyponatremia, with highest risk in the first weeks after initiation) 4
- Loop diuretics (though these may actually decrease hyponatremia risk) 4
- Salt-wasting nephropathy 3
- Cerebral salt wasting (CSW) in neurosurgical patients, distinguished by CVP <6 cm H₂O 1
- Characterized by urine sodium >30 mmol/L 1
Euvolemic Hyponatremia (Water Excess)
Syndrome of Inappropriate Antidiuresis (SIAD):
- The most common cause of euvolemic hyponatremia 5, 2
- Characterized by high urine osmolality and high urine sodium concentration (>30 mmol/L) 2
- Serum uric acid <4 mg/dL has a positive predictive value of 73-100% for SIAD 1
- In neurosurgical patients, distinguished by CVP 6-10 cm H₂O 1
Drug-induced SIAD:
- Selective serotonin reuptake inhibitors (SSRIs) 6, 4
- Antipsychotics 4
- Antiepileptic drugs 6, 4
- Proton pump inhibitors 4
- Typically occurs shortly after treatment initiation and is often asymptomatic 6, 4
Endocrine disorders:
- Hypothyroidism (requires high index of suspicion as clinical signs can be subtle) 7
- Secondary adrenocortical insufficiency from hypopituitarism 7
- Hypophysitis and adrenalitis from immune checkpoint inhibitors 4
Primary adrenal insufficiency (Addison's disease):
- May present with pigmentation, salt craving, hypotension, and concomitant hyperkalemia 7
- Critical diagnosis not to miss due to grave consequences 7
Hypervolemic Hyponatremia (Sodium and Water Excess, with Relatively More Water)
Additional Causes and Risk Factors
Pseudohyponatremia and translocational hyponatremia:
- Must be excluded by measuring plasma osmolality 2
- Hyperglycemia or hypertriglyceridemia can cause laboratory artifact 1
Patient-specific risk factors:
Critical Diagnostic Pitfall
Physical examination alone for determining ECF status has been shown to have poor sensitivity (41.1%) despite reasonable specificity (80%) 1. Clinical determination using mucosal hydration, skin turgor, jugular vein distention, and orthostatic vital signs is inadequate and must be supplemented with biochemical parameters including urine sodium, urine osmolality, and serum uric acid 1.
A urinary sodium <30 mmol/L has a positive predictive value of 71-100% for saline responsiveness, helping distinguish true hypovolemia from other causes 1.