What is SIADH (Syndrome of Inappropriate Antidiuretic Hormone secretion)?

What is SIADH (Syndrome of Inappropriate Antidiuretic Hormone Secretion)?

SIADH is a disorder of sodium and water balance characterized by hypotonic hyponatremia (serum sodium < 134 mEq/L) with inappropriately concentrated urine (>500 mosm/kg), elevated urinary sodium (>20 mEq/L), and clinical euvolemia in the absence of hypothyroidism, adrenal insufficiency, or volume depletion. 1

Pathophysiology

• SIADH develops due to persistent or elevated plasma arginine vasopressin (AVP) despite hyponatremia and low plasma osmolality, leading to water retention and a physiologic natriuresis where fluid balance is maintained at the expense of plasma sodium 1
• The inappropriate increase in ADH release interferes with urinary dilution, preventing the excretion of ingested water, which produces the characteristic dilutional hyponatremia 2
• The concentrated urine with high sodium content results from the kidney's inability to properly excrete free water due to excessive ADH action on V2 receptors in the distal renal tubules 1, 3

Diagnostic Criteria

The diagnosis requires five cardinal criteria to be met 1, 4:

• Hypotonic hyponatremia: Serum sodium < 134 mEq/L with plasma osmolality < 275 mosm/kg 1
• Inappropriately high urine osmolality: > 500 mosm/kg (or at minimum >100 mOsm/kg) relative to low plasma osmolality 1, 4
• Elevated urinary sodium: > 20 mEq/L, indicating natriuresis 1
• Clinical euvolemia: Absence of edema, orthostatic hypotension, normal skin turgor, and moist mucous membranes 5, 4
• Normal renal, adrenal, and thyroid function: Excluding other causes of hyponatremia 1, 4

Clinical Presentation

• Symptoms are principally neuromuscular and gastrointestinal, with severity related to both the absolute serum sodium concentration and its rate of fall, particularly if greater than 0.5 mmol/L/hour 6, 4
• Mild symptoms include headache, nausea, vomiting, and confusion 6
• Severe symptoms (typically when sodium ≤ 125 mEq/L) include lethargy, seizures, coma, and death 6, 7
• Even mild hyponatremia may be associated with neurocognitive problems, including falls and attention deficits 5

Common Causes

The major groups of causes include 1, 4:

• Malignancy: Small cell lung cancer is the most common, affecting 1-5% of lung cancer patients, with SCLC cells commonly producing vasopressin 1
• CNS disorders: Infections, tumors, malformations (such as corpus callosum agenesis), subarachnoid hemorrhage, and other neurological diseases 1, 3
• Pulmonary diseases: Pneumonia and other lung pathology 1, 4
• Medications: Chemotherapeutic agents (cisplatin, vinca alkaloids), antidepressants (SSRIs), antiepileptic drugs (carbamazepine), NSAIDs, opioids, and chlorpropamide 1, 7
• Postoperative state: Inappropriate infusion of hypotonic fluids with pain, nausea, and stress as nonosmotic stimuli for AVP release 1, 4

Distinguishing SIADH from Cerebral Salt Wasting

Extracellular fluid (ECF) status assessment is critical to differentiate SIADH from cerebral salt wasting (CSW), as they require opposite management approaches 1, 6:

• SIADH: Euvolemic with CVP 6-10 cm H₂O, treated with fluid restriction 1, 6
• CSW: Hypovolemic with CVP <6 cm H₂O, evidence of volume depletion (hypotension, tachycardia, dry mucous membranes), and unquenchable thirst, treated with volume and sodium replacement 1, 6
• A serum uric acid level < 4 mg/dL has a 73-100% positive predictive value for SIADH 1, 6

Treatment Principles

• For mild/asymptomatic cases: Fluid restriction to 1 L/day is the cornerstone of treatment 1, 5
• For severe symptomatic hyponatremia: Transfer to ICU, administer 3% hypertonic saline with goal to correct 6 mmol/L over 6 hours or until severe symptoms resolve 1
• Critical safety rule: Total correction must not exceed 8 mmol/L in 24 hours to prevent osmotic demyelination syndrome 1, 5
• Second-line pharmacological options: Demeclocycline, urea, or vasopressin receptor antagonists (tolvaptan) for chronic SIADH when fluid restriction is ineffective 1, 3
• Treat underlying cause: Effective treatment of the underlying malignancy or discontinuation of offending medications often resolves paraneoplastic SIADH 1