Causes of Hyponatremia
Hyponatremia can be classified into three main categories based on volume status: hypovolemic, euvolemic, and hypervolemic, with each having distinct underlying causes that require different management approaches. 1
Classification by Volume Status
1. Hypovolemic Hyponatremia
Characterized by decreased extracellular fluid volume:
- Diuretic-induced losses: Particularly thiazide diuretics (most common cause of diuretic-induced hyponatremia) 2, 3
- Gastrointestinal losses: Vomiting, diarrhea, severe burns
- Renal losses: Salt-wasting nephropathies, cerebral salt wasting syndrome
- Third-space losses: Severe burns, pancreatitis
- Adrenal insufficiency: Cortisol deficiency leading to impaired free water excretion
2. Euvolemic Hyponatremia
Normal extracellular fluid volume:
- Syndrome of Inappropriate Antidiuretic Hormone (SIADH):
- Malignancies (lung, pancreas)
- CNS disorders (stroke, hemorrhage, trauma, infection)
- Pulmonary diseases (pneumonia, tuberculosis, COPD)
- Medications (antidepressants, antipsychotics, anticonvulsants)
- Endocrine disorders:
- Hypothyroidism
- Hypopituitarism
- Reset osmostat syndrome: Abnormal setting of the osmotic threshold
- Psychogenic polydipsia: Excessive water intake
- Post-operative state: Especially after pituitary surgery
3. Hypervolemic Hyponatremia
Increased extracellular fluid volume:
- Liver cirrhosis: Systemic vasodilation causes decreased effective plasma volume, activating the renin-angiotensin-aldosterone system and increasing ADH secretion 4
- Heart failure: Decreased cardiac output leads to increased ADH secretion
- Nephrotic syndrome: Hypoalbuminemia leads to decreased oncotic pressure
- Advanced kidney disease: Impaired free water excretion
Other Important Causes
Medication-Induced Hyponatremia
- Diuretics: Especially thiazides 2, 3
- Antidepressants: SSRIs, TCAs
- Antipsychotics: Haloperidol, phenothiazines
- Anticonvulsants: Carbamazepine, oxcarbazepine
- Antineoplastic agents: Cyclophosphamide, vincristine
- Others: NSAIDs, opioids, amiodarone
Pseudohyponatremia
- Hyperlipidemia: Elevated lipids decrease the water fraction of plasma
- Hyperproteinemia: Multiple myeloma, macroglobulinemia
Translocational Hyponatremia
- Hyperglycemia: Each 100 mg/dL increase in glucose above normal decreases serum sodium by approximately 1.6-2.4 mEq/L
- Mannitol administration
- Post-transurethral prostatic resection syndrome: Absorption of hypotonic irrigation fluid
Diagnostic Approach
The diagnostic approach to hyponatremia should include:
- Assessment of volume status: Physical examination findings have limited accuracy (sensitivity 41.1%, specificity 80%) 1
- Measurement of serum osmolality:
- High osmolality (>300 mOsm/kg): Translocational hyponatremia
- Normal osmolality: Pseudohyponatremia
- Low osmolality (<280 mOsm/kg): True hyponatremia
- Urine sodium and osmolality assessment:
- Urine osmolality >500 mOsm/kg with urine sodium >20-40 mEq/L suggests SIADH
- Urine sodium <20 mEq/L with elevated osmolality suggests hypervolemic hyponatremia 1
Special Considerations
Cirrhosis-Related Hyponatremia
In liver cirrhosis, hyponatremia is primarily dilutional, caused by:
- Systemic vasodilation due to portal hypertension
- Decreased effective plasma volume
- Hyperdynamic circulation
- Excessive activation of the renin-angiotensin-aldosterone system
- Inadequate regulation of antidiuretic hormone 4
Diuretic-Induced Hyponatremia
- Thiazides are more commonly implicated than loop diuretics
- Can develop rapidly in susceptible patients (elderly, females, low body weight)
- Mechanism involves impaired urinary diluting ability and stimulation of vasopressin release 3
Clinical Implications
Hyponatremia in cirrhosis with serum sodium <130 mmol/L significantly increases the risk of:
- Spontaneous bacterial peritonitis (OR 3.40)
- Hepatorenal syndrome (OR 3.45)
- Hepatic encephalopathy (OR 2.36) 4
Understanding the specific cause of hyponatremia is essential for appropriate management and prevention of complications such as cerebral edema and osmotic demyelination syndrome.