Syndrome of inappropriate antidiuretic hormone secretion

Epidemiology

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Etiology

• Ectopic ADH Production: Small cell lung cancer (most common paraneoplastic cause).
• CNS Disorders: Stroke, hemorrhage, infection, trauma, surgery.
• Pulmonary Disease: Pneumonia (esp. bacterial), TB, positive pressure ventilation, PCP c.
• Drugs: Carbamazepine, Cyclophosphamide, SSRIs, TCAs.

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Pathophysiology

• ↑ ADH secretion → receptor-mediated signaling cascade in the distal convoluted tubules and the collecting ducts of the kidneys → build-up of additional water canals (aquaporin-2) in the luminal cell membrane
• Water is drawn out of the urine and into the hyperosmolar kidney tissue → concentration of urine and ↑ Urine osmolality (becomes higher than serum osmolality)
• Water retention → ↓ serum osmolality with transient volume expansion → ↑ ANP, ↑ BNP, and ↓ aldosterone → ↑ urinary sodium and water excretion → normal extracellular fluid volume and low plasma osmolality (euvolemic hyponatremia)
• Osmotic fluid shifts → cerebral edema and ↑ intracranial pressure (may occur in patients with extremely low Na⁺ levels)

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Clinical features

Symptoms of hyponatremia

• Mild
  • Anorexia
  • Nausea, vomiting
  • Headache
  • Muscle cramps
• Moderate
  • Muscle weakness
  • Lethargy
  • Confusion
• Severe
  • Seizures
  • Altered consciousness

Tip

Both SIADH and Primary hyperaldosteronism have no edema. A hyponatremic patient with edema should raise suspicion for other conditions (e.g. congestive heart failure).

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Diagnostics

• SIADH is a diagnosis of exclusion. Must verify normal renal, adrenal, and thyroid function.
• Initial: BMP to confirm hyponatremia (Na < 135 mEq/L).
• Key Labs (Must meet ALL for diagnosis):
  1. Hypotonicity: Serum Osmolality < 275 mOsm/kg.
  2. Inappropriate Urine Concentration: Urine Osmolality > 100 mOsm/kg.
  3. High Urine Na: Urine Na > 40 mEq/L (euvolemia triggers ANP/BNP release, causing natriuresis).
  4. Normal BUN/Cr and uric acid (frequently low uric acid < 4 mg/dL due to dilution/excretion).
• Further Workup: TSH, morning cortisol. CXR/CT Chest (if suspecting pulmonary etiology/SCLC). CT Head (if altered/suspected CNS lesion).

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Treatment

• Always treat the underlying cause (stop offending meds, treat infection/tumor).
• Mild / Asymptomatic: Fluid restriction (< 800 mL/day). c
• Moderate: Fluid restriction + oral salt tablets +/- Loop diuretics (furosemide to increase free water excretion).
• Severe / Symptomatic (e.g., seizures, coma, profound confusion): 3% Hypertonic Saline immediately.
• Chronic / Refractory: Demeclocycline (induces nephrogenic DI) or Vaptans (e.g., Tolvaptan - vasopressin V2 receptor antagonists).
• Complication of Treatment: Rapid correction of chronic hyponatremia (>8-10 mEq/L in 24h) can cause Osmotic Demyelination Syndrome (ODS), previously known as Central Pontine Myelinolysis. Remember: “From low to high, your pons will die.”

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