Syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is an endocrine disorder caused by increased ADH secretion in the pituitary gland (e.g., due to infection, drugs), ectopic production of ADH (e.g., small cell lung carcinoma), or enhanced stimulation of ADH in the kidneys as a result of a gene mutation. Hyponatremia develops as a result of increased water retention in the kidneys (not due to sodium deficiency) and systemic fluid overload. SIADH is usually asymptomatic and hyponatremia is often an incidental finding in laboratory results. In mild cases, symptoms include loss of appetite and nausea; in severe cases, seizures and altered consciousness can occur. Treatment depends on the severity of the disease and includes fluid restriction (asymptomatic patients) to hypertonic saline administration (severe cases).

• Increased pituitary ADH secretion
  • Diseases of the central nervous system (e.g., stroke, bleeding, infection, trauma)
  • Pulmonary disease (pneumonia, COPD)
  • Drugs (e.g., chlorpropamide, carbamazepine, cyclophosphamide, selective serotonin reuptake inhibitors)
  • Endocrine disorders (glucocorticoid deficiency)
  • Neurosurgery; (especially: transsphenoidal pituitary surgery)
• Ectopic source of ADH secretion: paraneoplastic (particularly: small cell lung carcinoma)
• Enhanced stimulation of ADH receptors in the kidney: hereditary (mutation of vasopressin-2 receptor gene)

References:^[1][2]

For more information regarding ADH secretion and regulation, see antidiuretic hormone.

• ↑ 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; → concentrates the urine and ↑ urine osmolality
• Water retention → ↓ serum osmolality → Euvolemic hyponatremia
• Osmotic fluid shifts → Cerebral edema and ↑ intracranial pressure

References:^[1][3][4]

• Symptoms of hyponatremia (see: “Sodium imbalance”)
  • Mild: anorexia, nausea, vomiting, headache, muscle cramps
  • Moderate: muscle weakness, lethargy, confusion
  • Severe: seizures, altered consciousness
• Normotensive
• Symptoms of the underlying condition

References:^[4]

• Blood
  • ↓ serum osmolality (< 280 mOsm/kg H₂O) and ↓ sodium (< 135 mmol/L)
  • Normal renal function (based on creatinine)
  • Normal adrenal function (based on ACTH stimulation test)
  • Normal thyroid function (based on thyroid hormones: TSH, T₄, T₃)
  • Plasma ADH normal to elevated
  • Frequently ↓ uric acid values
• Urine
  • Urine osmolality > 100 mOsm/kg H₂O
  • Urinary sodium excretion > 20 mmol/L

SIADH patients are usually euvolemic, normotensive, and have no edema. An hyponatremic patient with edema should raise suspicion of other conditions (e.g. congestive heart failure).
References:^[4]

See hyponatremia.

The differential diagnoses listed here are not exhaustive.

• Treatment of the underlying condition
• Asymptomatic patients
  • Fluid restriction!
  • Increased salt intake
• Symptomatic patients
  • Hypertonic saline administration ; with ICU monitoring to impede central pontine myelinolysis
  • If severe: consider adding a loop diuretic (e.g., furosemide) to hypertonic saline
    • Most effective if urine osmolality is > 2x the serum osmolality (typically urine osmolality > 500 mOsmol/kg)
  • If initial measures fail, consider ADH receptor antagonist (demeclocycline) or vasopressin antagonists (vaptans): IV conivaptan and PO tolvaptan

The sodium serum levels may increase by a maximum of 10 mmol/L within 24 hours or 0.5 mmol/L per hour. A rapid increase in serum sodium can lead to central pontine myelinolysis!

References:^[1][3][4]