What diseases can cause hyponatremia in patients with varying demographics and medical histories, such as heart failure, Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH), liver cirrhosis, nephrotic syndrome, and cancer?

Diseases That Cause Hyponatremia

Hyponatremia develops primarily through excessive arginine vasopressin (AVP) activity, which occurs across multiple disease states including heart failure, SIADH, liver cirrhosis, nephrotic syndrome, and various malignancies—all sharing the common mechanism of non-osmotic AVP release leading to water retention and sodium dilution. 1, 2, 3

Primary Disease Categories and Mechanisms

Heart Failure (Hypervolemic Hyponatremia)

• Low cardiac output triggers compensatory neurohormonal activation, including the renin-angiotensin-aldosterone system and non-osmotic AVP release, despite total body sodium and water excess 4, 3
• The perceived arterial underfilling from reduced cardiac output stimulates AVP secretion, causing free-water reabsorption in renal collecting ducts and dilutional hyponatremia 4
• Hyponatremia occurs in heart failure patients despite volume overload, with clinical signs including jugular venous distention, orthopnea, dyspnea, and peripheral edema 5
• This represents dilutional hyponatremia—the most common form—caused by excess water retention relative to sodium 4

Liver Cirrhosis (Hypervolemic Hyponatremia)

• Portal hypertension causes systemic vasodilation and decreased effective plasma volume, triggering non-osmotic hypersecretion of vasopressin despite total body sodium excess 5
• Activation of renin-angiotensin-aldosterone system causes excessive sodium and water reabsorption in the proximal nephron 5
• Hyponatremia affects approximately 60% of cirrhotic patients and is mostly dilutional, defined at serum sodium <130 mmol/L 5, 6
• Cirrhotic patients with sodium <130 mmol/L face dramatically increased complications: spontaneous bacterial peritonitis (OR 3.40), hepatorenal syndrome (OR 3.45), and hepatic encephalopathy (OR 2.36) 5

Syndrome of Inappropriate Antidiuretic Hormone (SIADH) - Euvolemic Hyponatremia

• SIADH results from inappropriate AVP activity despite low plasma osmolality and normal volume status, leading to water retention and subsequent physiologic natriuresis 5, 3

• Common causes include:

  • Malignancies: particularly small cell lung cancer (affects 1-5% of lung cancer patients) and other paraneoplastic syndromes 5
  • CNS disorders: meningitis, stroke, subarachnoid hemorrhage, brain tumors 5, 3
  • Pulmonary diseases: pneumonia, tuberculosis, other infections 3
  • Medications: SSRIs, carbamazepine, cyclophosphamide, and other drugs that stimulate AVP release 5, 3
  • Postoperative states: pain, nausea, and stress trigger non-osmotic AVP release 5, 6

• Diagnostic criteria include hypotonic hyponatremia, inappropriately concentrated urine (>300 mOsm/kg), elevated urine sodium (>20-40 mmol/L), and normal renal, thyroid, and adrenal function 5

• Serum uric acid <4 mg/dL has 73-100% positive predictive value for SIADH 5

Nephrotic Syndrome (Hypervolemic Hyponatremia)

• Massive proteinuria leads to hypoalbuminemia and decreased oncotic pressure 5
• This causes fluid shift from intravascular to interstitial space, triggering perceived hypovolemia 5
• The body responds with AVP release and sodium/water retention despite total body fluid excess 5

Cancer-Related Hyponatremia

• Malignancies cause hyponatremia through multiple mechanisms: paraneoplastic SIADH (especially small cell lung cancer), ectopic AVP production, and tumor-related metabolic derangements 5, 2
• Whether hyponatremia in cancer is merely a marker of poor prognosis or directly alters quality of life requires further investigation 2

Additional Contributing Factors

Medications

• Diuretics (particularly thiazides and loop diuretics) cause hyponatremia through excessive sodium and water loss 5, 6, 4
• Antidepressants place patients at particularly high risk for developing hyponatremia through enhanced AVP activity 5
• Multiple medications can stimulate AVP release or enhance its action, especially problematic in elderly patients with polypharmacy 2, 3

Endocrine Disorders

• Hypothyroidism and adrenal insufficiency both cause hyponatremia through impaired free water excretion and must be ruled out in the diagnostic workup 5, 6
• These represent reversible causes requiring specific hormone replacement therapy 5

Acute Illness States

• Sepsis and underlying infections trigger non-osmotic AVP release through inflammatory mediators 6
• Acute pancreatitis is a well-established non-osmotic stimulus for AVP release through pain, nausea, and stress 5
• Trauma and postoperative states cause hyponatremia through pain-mediated AVP secretion 1, 3

Neurosurgical Conditions

• Cerebral salt wasting (CSW) occurs more commonly than SIADH in neurosurgical patients, particularly with subarachnoid hemorrhage, poor clinical grade, and hydrocephalus 5
• CSW is produced by excessive secretion of natriuretic peptides causing hyponatremia through excessive natriuresis and volume contraction 5
• Critical distinction: CSW requires volume and sodium replacement, while SIADH requires fluid restriction—opposite treatments 5

Common Clinical Pitfalls

• Failing to recognize the underlying cause leads to inappropriate treatment—distinguishing between hypovolemic, euvolemic, and hypervolemic states is essential 5
• Hospital-acquired hyponatremia from hypotonic IV fluids in the setting of elevated AVP affects 15-30% of hospitalized patients and is entirely preventable by using isotonic maintenance fluids 5
• Ignoring mild hyponatremia (130-135 mmol/L) is dangerous—even mild hyponatremia increases fall risk (21% vs 5%), mortality (60-fold increase when <130 mmol/L), and cognitive impairment 5, 2
• Misdiagnosing volume status in heart failure patients can lead to inappropriate fluid restriction when diuresis is actually needed 5

Key Diagnostic Approach

• Initial workup should include serum and urine osmolality, urine electrolytes, uric acid, and assessment of extracellular fluid volume status 5
• Physical examination alone has poor accuracy (sensitivity 41.1%, specificity 80%) for volume assessment 5
• Urine sodium <30 mmol/L suggests hypovolemic hyponatremia with 71-100% positive predictive value for saline responsiveness 5
• The vast majority of hyponatremia cases result from non-osmotic AVP release, regardless of the underlying disease 2, 3