What are the causes of hyponatremia?

Causes of Hyponatremia

Hyponatremia is primarily classified into three major categories based on volume status: hypovolemic, euvolemic, and hypervolemic hyponatremia, each with distinct pathophysiological mechanisms and clinical presentations. 1

Classification by Volume Status

1. Hypovolemic Hyponatremia

Caused by sodium and water loss with relatively greater sodium loss:

• Renal Losses:

  • Diuretic excess (especially thiazides)
  • Salt-losing nephropathies
  • Mineralocorticoid deficiency (Addison's disease)
  • Cerebral salt wasting

• Extra-Renal Losses:

  • Gastrointestinal losses (vomiting, diarrhea)
  • Excessive sweating
  • Third-space losses (burns, pancreatitis)
  • Blood loss

2. Euvolemic Hyponatremia

Characterized by normal total body sodium with excess water:

• Syndrome of Inappropriate ADH Secretion (SIADH)

  • Malignancies (especially small cell lung cancer)
  • CNS disorders (stroke, hemorrhage, trauma, infection)
  • Pulmonary diseases (pneumonia, tuberculosis)
  • Pain, nausea, stress
  • Post-operative state

• Medications:

  • Antidepressants (SSRIs, TCAs)
  • Antipsychotics
  • Antiepileptics (carbamazepine)
  • Chemotherapeutic agents
  • Opioids

• Other Causes:

  • Hypothyroidism
  • Glucocorticoid deficiency
  • Reset osmostat syndrome
  • Primary polydipsia
  • Low solute intake (beer potomania, tea and toast diet)

3. Hypervolemic Hyponatremia

Characterized by increased total body sodium with proportionally greater increase in total body water:

• Congestive heart failure
• Liver cirrhosis
• Nephrotic syndrome
• Advanced kidney disease

Pathophysiological Mechanisms

Cirrhosis-Related Hyponatremia

In liver cirrhosis, hyponatremia results from:

• Systemic vasodilation due to portal hypertension
• Decreased effective plasma volume
• Decreased systemic vascular resistance
• Hyperdynamic circulation
• Accumulation of vasodilators (nitric oxide, glucagon, vasoactive intestinal peptide)
• Activation of renin-angiotensin-aldosterone system
• Impaired regulation of antidiuretic hormone (ADH)
• Increased arterial natriuretic peptide
• Decreased prostaglandin E2
• Decreased ADH degradation 2

Laboratory Evaluation

Key Diagnostic Parameters:

• Serum sodium <135 mmol/L
• Serum osmolality:
  • Low (<280 mOsm/kg): True hypotonic hyponatremia
  • Normal (280-295 mOsm/kg): Pseudohyponatremia
  • High (>295 mOsm/kg): Hypertonic hyponatremia (e.g., hyperglycemia)

Urine Studies:

• Urine sodium and osmolality help differentiate causes:
  • Urine sodium >20-40 mEq/L with high osmolality (>500 mOsm/kg): Suggests SIADH
  • Urine sodium <20 mEq/L with elevated osmolality: Suggests hypervolemic hyponatremia
  • Normal urine osmolality with variable sodium: May indicate reset osmostat syndrome 1

Special Considerations

Medication-Induced Hyponatremia

Always review medications as many can cause hyponatremia:

• Diuretics (especially thiazides)
• Antidepressants
• Antipsychotics
• Antiepileptics
• Chemotherapeutic agents 1

Pitfalls in Diagnosis

• Pseudohyponatremia: Normal plasma osmolality with low measured sodium due to hyperlipidemia or hyperproteinemia
• Translocational hyponatremia: High plasma osmolality with low sodium due to osmotically active substances like glucose or mannitol
• Post-TURP syndrome: Absorption of hypotonic irrigation fluid during transurethral resection of prostate
• Reset osmostat syndrome: A variant of SIADH where the threshold for ADH release is reset at a lower serum osmolality 3

Clinical Pearls

• Hyponatremia is associated with increased mortality and morbidity in patients with liver cirrhosis, particularly when serum sodium is <130 mmol/L 2
• Complications of hyponatremia in cirrhosis include increased risk of spontaneous bacterial peritonitis, hepatorenal syndrome, and hepatic encephalopathy 2
• The rate of correction of hyponatremia should not exceed 8-9 mmol/L in 24 hours to avoid osmotic demyelination syndrome 1
• Women appear to be more susceptible to hyponatremic brain injury than men 4

By understanding the diverse causes and mechanisms of hyponatremia, clinicians can develop a systematic approach to diagnosis and management, ultimately improving patient outcomes and reducing complications.