Syndrome of inappropriate antidiuretic hormone secretion

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most common cause of euvolemic hypotonic hyponatremia. SIADH is an endocrine disorder caused by increased antidiuretic hormone (ADH) secretion in the pituitary gland (e.g., due to infection, drugs), ectopic production of ADH (e.g., in small cell lung carcinoma), or enhanced ADH receptor activation in the kidneys as a result of a genetic mutation (i.e., nephrogenic SIADH). Patients with SIADH present with hyponatremia caused by increased renal water retention. Diagnosis requires confirmation of serum hyponatremia and hypoosmolality, increased urine salt excretion and urine osmolality, clinical euvolemia, and exclusion of other causes of euvolemic hypotonic hyponatremia (e.g., hypothyroidism, adrenal insufficiency, diuretic use). Treatment involves managing symptoms of acute hyponatremia with hypertonic saline, addressing underlying causes (e.g., infection, cancer, medications), reducing free water intake with fluid restriction, and, if needed, increasing free water excretion with pharmacological treatments.

For detailed information on hyponatremia management, see “Treatment of hyponatremia.”

Increased pituitary ADH secretion ^[1]

CNS conditions

• Stroke
• Trauma, bleeding
• Infection
• Following neurosurgery (e.g., transsphenoidal pituitary surgery)
• Psychosis

Chronic disease

• Pulmonary
  • Pneumonia
  • COPD
• HIV
• Acute intermittent porphyria ^[2]

Drugs

• Anticonvulsants (e.g., carbamazepine, valproate)
• Antidepressants
  • SSRIs (e.g., sertraline)
  • MAO inhibitors
  • TCAs (e.g., amitriptyline)
• Antineoplastic agents
  • Mitotic inhibitors (e.g., vincristine)
  • Alkylating agents (e.g., cyclophosphamide, cisplatin)
• Antipsychotics (e.g., haloperidol)
• Analgesics (e.g., NSAIDS, opioids)
• Illicit substances (e.g., MDMA) ^[3]

Paraneoplastic ectopic ADH production ^[1]

• Small cell lung carcinoma
• Head and neck cancer
• Extrapulmonary small cell carcinoma
• Olfactory neuroblastoma

Nephrogenic SIADH ^[4]

• Mutation of vasopressin-2 receptor gene

• ↑ 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 → euvolemic hyponatremia
• Osmotic fluid shifts → cerebral edema and ↑ intracranial pressure (may occur in patients with extremely low Na⁺ levels)
• For more information regarding ADH secretion and regulation, see “Antidiuretic hormone.”

Symptoms of hyponatremia

Chronic hyponatremia may be asymptomatic and CNS symptoms are less common.

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

Other clinical features

• Normotension
• Symptoms of the underlying condition

SIADH patients are usually euvolemic, normotensive, and have no edema. A hyponatremic patient with edema should raise suspicion for other conditions (e.g. congestive heart failure).

Approach ^[5]

• Follow the diagnostic approach to hyponatremia to confirm euvolemic hypotonic hyponatremia.
  • Order initial blood studies (e.g., CMP, serum osmolality) and urine studies (e.g., sodium, creatinine, osmolality).
  • Order additional studies to exclude other causes of euvolemic hypotonic hyponatremia (e.g., TFTs, morning cortisol levels).
• Confirm the patient meets the diagnostic criteria for SIADH.
• Consider additional tests for possible underlying causes of SIADH, e.g.:
  • X-ray and/or CT chest
  • CT or MRI head

SIADH is a diagnosis of exclusion. Rule out other causes of euvolemic hypotonic hyponatremia before making a diagnosis of SIADH.

Diagnostic criteria ^[5][6][7][8]

Hyponatremia caused by hypothyroidism is usually accompanied by signs of myxedema coma and/or TSH > 50 mU/mL. Mild hypothyroidism should still prompt evaluation for another cause of hyponatremia. ^[5][10]

Additional findings ^[5][6][7][8]

These findings are not required to make a diagnosis, but may further support SIADH as the cause of euvolemic hypotonic hyponatremia.

• Blood studies
  • Plasma ADH (inappropriately) normal to elevated
  • BUN < 10 mg/dL
  • Serum uric acid < 4 mg/dL ^[8]
• Fractional excretion values
  • FEUA > 12%
  • FEUrea > 55%
  • FENa > 1%
• Response to initial therapeutic measures, e.g.: ^[5][8]
  • ↑ Serum sodium and ↓ urine sodium excretion after fluid restriction
  • ↓ Serum sodium (or no change) after a trial of volume expansion

FEUA and FEUrea values are not affected by diuretic use. ^[9][11]

See “Hyponatremia.”

The differential diagnoses listed here are not exhaustive.

For patients with acute hyponatremia and/or who are severely symptomatic; , initiate immediate 3% hypertonic saline administration; and start ICU monitoring; a loop diuretic (e.g., furosemide) may be added in severe cases. See also “Treatment of hyponatremia” for detailed information and dosages. ^[5]

In patients with acute and severely symptomatic hyponatremia, immediate use of hypertonic saline can treat and/or prevent serious neurologic complications (e.g., cerebral edema, brain herniation, seizures, altered mental status). ^[5]

Approach ^[5][8]

The following management applies to patients with nonacute, nonsevere hyponatremia associated with SIADH and after the initial stabilization of patients with acute and/or severely symptomatic hyponatremia.

• Management
  • Restrict all fluids; do not limit salt or protein intake.
  • If initial measures fail, consider pharmacotherapy.
  • Manage the underlying cause (e.g., nausea, infection, cancer, offending medications).
• Monitoring
  • Measure serum sodium frequently.
  • Follow the recommended sodium correction rates for chronic hyponatremia to prevent sodium overcorrection.
  • If recommended limits are exceeded, provide management of sodium overcorrection.

For patients with chronic hyponatremia, the maximum limit (not goal) for serum sodium level increase is 10–12 mEq/L per 24 hours. Use a lower maximum limit of 8 mEq/L per 24 hours for patients with high-risk factors for osmotic demyelination syndrome. ^[7]

In patients with chronic hyponatremia, sodium overcorrection can lead to osmotic demyelination syndrome. ^[5][7]

Fluid restriction ^[5][8]

Restriction of all fluids (e.g., PO intake, IV fluids, medications, IV flushes) is the first-line treatment for SIADH.

• Recommend < 1000 mL/day for most patients. ^[7][8]
• Adjust based on the patient's response (i.e., serum sodium levels and urine output).

Ideally, daily fluid intake should be 500 mL less than daily urine output. ^[5]

Pharmacotherapy ^[5][6][7][8]

These agents are used to increase free water excretion. Medications should be ordered in consultation with a specialist.

• Indications
  • Fluid restriction fails to increase serum sodium. ^[5][7]
  • Consider early pharmacotherapy if: ^[7]
    • Urine osmolality is ≥ 500 mOsm/kg
    • Urinary sodium is ≥ 130 mEq/L
• Important considerations
  • The optimal pharmacotherapy for SIADH is controversial; recommendations vary among guidelines and experts.
  • Vaptans, urea, and demeclocycline should not be used in combination.
  • If vaptans are used, avoid fluid restriction during the first 24–48 hours of treatment. ^[5]
• Agents ^[5][7]
  • Vaptans, e.g.:
    • Conivaptan
    • Tolvaptan
  • Urea (off-label) ^[6]
  • Demeclocycline (off-label)
  • Low-dose loop diuretics (e.g., furosemide) combined with oral salt tablets (off-label) ^[6][7]