Syndrome of inappropriate antidiuretic hormone secretion

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 by 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 ranges from fluid restriction (asymptomatic patients) to hypertonic saline administration (severe cases).

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

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)

Paraneoplastic ectopic ADH production ^[1]

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

Nephrogenic SIADH ^[2]

• 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→ ↓ aldosterone, ↑ ANP, and ↑ BNP→ ↑ 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

• 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).

Laboratory studies

Blood

• ↓ Serum osmolality (< 280 mOsm/kg H₂O) and ↓ sodium (< 135 mmol/L)
• Plasma ADH normal to elevated
• Normal renal function (indicated by normal creatinine)
• Normal adrenal function (judged by ACTH stimulation test)
• Normal thyroid function
• Frequently ↓ uric acid values

Urine ^[3]

• Urine osmolality > 100 mOsm/kg H₂O
• Urinary sodium excretion > 30 mEq/L

See “Hyponatremia.”

The differential diagnoses listed here are not exhaustive.

Approach

• In general: treatment of the underlying condition
• Specific measures depend on whether the patient is symptomatic or not.

Asymptomatic patients

• Fluid restriction
• Increased salt intake

Symptomatic patients

• Hypertonic saline administration with ICU monitoring to prevent osmotic demyelination syndrome
• A loop diuretic (e.g., furosemide) can be added in severe cases, which is most effective if urine osmolality is > 2x the serum osmolality.
• If initial measures fail: pharmacotherapy with vaptans or demeclocycline

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 osmotic demyelination syndrome!

Vasopressin (ADH) antagonists (vaptans)

• Agents
  • Tolvaptan
  • Conivaptan
• Mechanism of action: antagonism at vasopressin receptors in renal collecting ducts → ↑ aquaresis (i.e., free water excretion)
  • Tolvaptan: selective V₂-receptor antagonism
  • Conivaptan: dual V_1A and V₂ receptor antagonism
• Indications
  • SIADH
  • ADPKD ^[4]
  • Congestive heart failure
  • Liver cirrhosis
• Side effects
  • Nausea, vomiting, stomach pain
  • Increase in thirst, hunger, urination
  • Weight loss
• Contraindications
  • Dehydration
  • Liver disease, alcoholism
  • Hypernatremia

Demeclocycline

• Mechanism of action ^[5]
  • Not completely understood
  • Demeclocycline seems to disrupt the intracellular second messenger cascade that follows after the binding of vasopressin to the V₂ receptor in renal collecting ducts → ↓ ADH effect.
• Indications
  • Bacterial infections (primarily an antibiotic)
  • SIADH, using one of its side effects
• Side effects
  • Skin reactions
  • Nausea, vomiting, diarrhea
  • Nephrogenic diabetes insipidus
• Interactions
  • Birth control (↓ effectiveness)
  • ↓ Absorption of cations such as calcium, iron, magnesium
• Contraindications
  • Pregnancy (teratogenic)
  • Breastfeeding
  • Children under the age of 8