What are the causes of hyponatremia?

Causes of Hyponatremia

Hyponatremia results from an imbalance between total body water and exchangeable sodium stores, with most cases caused by impaired renal water excretion in the presence of continued water intake. 1, 2

Classification by Volume Status

The underlying causes of hyponatremia are best understood by assessing the patient's extracellular fluid volume status, which guides both diagnosis and treatment 1, 2:

Hypovolemic Hyponatremia (True Sodium and Water Depletion)

Renal Losses:

• Diuretic use (especially thiazides) – the most common iatrogenic cause, producing both sodium loss and impaired diluting capacity 3, 4
• Salt-wasting nephropathy and renal tubular disorders 2
• Cerebral salt wasting (CSW) – occurs in neurosurgical patients with CNS injury, characterized by excessive natriuretic peptide secretion causing renal sodium wasting and true volume depletion 1
• Mineralocorticoid deficiency (adrenal insufficiency) 2, 5

Extrarenal Losses:

• Gastrointestinal losses – vomiting, diarrhea, nasogastric suction 2, 4
• Third-spacing – burns, pancreatitis, peritonitis 2
• Blood loss and hemorrhage 4
• Excessive sweating without adequate sodium replacement 2

In hypovolemic states, urine sodium is typically <30 mmol/L for extrarenal losses** and **>20 mmol/L for renal losses 1

Euvolemic Hyponatremia (Normal Total Body Sodium, Excess Water)

Syndrome of Inappropriate Antidiuretic Hormone (SIADH):

• Malignancies – particularly small cell lung cancer (affects 1-5% of lung cancer patients) 1
• CNS disorders – meningitis, encephalitis, head trauma, subarachnoid hemorrhage, brain tumors 1, 4
• Pulmonary diseases – pneumonia, tuberculosis, positive-pressure ventilation 1
• Medications – SSRIs, carbamazepine, cyclophosphamide, vincristine, NSAIDs, opioids 1, 4
• Postoperative state – pain, nausea, and stress stimulate nonosmotic ADH release 1, 6

SIADH is characterized by urine sodium >20-40 mmol/L, urine osmolality >300 mOsm/kg, and serum uric acid <4 mg/dL (73-100% positive predictive value) 1

Other Euvolemic Causes:

• Hypothyroidism – impaired free water excretion 6, 5
• Adrenal insufficiency (glucocorticoid deficiency) 6, 5
• Primary polydipsia – excessive water intake overwhelming renal excretory capacity 2
• Beer potomania – poor solute intake combined with high fluid consumption 1

Hypervolemic Hyponatremia (Excess Total Body Sodium and Water, with Relatively More Water)

Edematous States with Impaired Water Excretion:

• Congestive heart failure – reduced cardiac output triggers nonosmotic ADH release and RAAS activation 1, 2, 5
• Cirrhosis with ascites – systemic vasodilation and portal hypertension cause perceived arterial underfilling, leading to ADH hypersecretion and enhanced proximal sodium reabsorption (affects ~60% of cirrhotic patients) 1
• Nephrotic syndrome – hypoalbuminemia reduces effective circulating volume 2, 4
• Advanced renal failure – impaired GFR prevents adequate free water excretion 2, 6, 5

In hypervolemic hyponatremia, urine sodium is typically >20 mmol/L due to compensatory natriuresis despite total body sodium excess 1

Mechanism-Based Classification

Impaired Renal Water Excretion (Most Common Pathway)

For the kidney to excrete free water and prevent hyponatremia, four conditions must be met 6:

1. Adequate glomerular filtration rate – renal failure impairs this 6
2. Adequate delivery of filtrate to diluting segments – reduced by increased proximal reabsorption in volume-depleted and edematous states 6
3. Intact tubular diluting mechanisms – impaired by thiazide diuretics 3, 6
4. Appropriate suppression of ADH – fails in SIADH, postoperative states, and edematous disorders 6, 5

Exercise-Associated Hyponatremia (EAH)

Dilutional hyponatremia from excessive fluid intake relative to sodium losses during prolonged exercise (>4 hours) 3

Risk factors include:

• Excessive fluid consumption beyond sweat losses 3
• Female sex and low body mass index 3
• Longer race times (typically >4 hours) 3
• Altered renal function during exercise 3

Incidence ranges from 3-22% in marathon runners, with six deaths reported in the USA and UK 3

Iatrogenic Hyponatremia

Hospital-acquired hyponatremia from hypotonic IV fluids in the setting of elevated ADH is entirely preventable by using isotonic maintenance fluids, yet affects 15-30% of hospitalized patients 1, 5

Pseudohyponatremia (Artifactual)

• Hyperglycemia – each 100 mg/dL glucose >100 mg/dL lowers measured sodium by 1.6 mEq/L 1
• Hyperlipidemia and hyperproteinemia – interfere with laboratory measurement 2, 4

Clinical Significance

Even mild hyponatremia (130-135 mmol/L) carries significant morbidity, including a 21% fall risk (vs. 5% in normonatremic patients) and increased mortality 1. Sodium levels <130 mmol/L are associated with a 60-fold increase in hospital mortality (11.2% vs. 0.19%) 1.

In cirrhotic patients, hyponatremia increases risk of spontaneous bacterial peritonitis (OR 3.40), hepatorenal syndrome (OR 3.45), and hepatic encephalopathy (OR 2.36) 1.