What is SIADH?
SIADH (Syndrome of Inappropriate Antidiuretic Hormone Secretion) is a disorder characterized by excessive water retention due to inappropriate release of antidiuretic hormone (ADH/vasopressin), resulting in hyponatremia, hypoosmolality, and inappropriately concentrated urine despite low serum sodium levels. 1
Defining Diagnostic Criteria
SIADH is diagnosed when all five cardinal criteria are met 1, 2:
- Hypotonic hyponatremia (serum sodium < 134 mEq/L) with plasma osmolality < 275 mosm/kg 1
- Inappropriately high urine osmolality (> 500 mosm/kg) relative to low plasma osmolality 1
- Inappropriately high urinary sodium concentration (> 20 mEq/L) indicating continued sodium loss 1
- Euvolemic state - absence of clinical signs of volume depletion (no orthostatic hypotension, normal skin turgor, moist mucous membranes) or hypervolemia (no edema, ascites, or jugular venous distention) 3
- Normal renal, adrenal, and thyroid function - hypothyroidism and adrenal insufficiency must be excluded 1, 2
Pathophysiology
The core mechanism involves persistent, detectable, or elevated plasma AVP concentrations despite low serum osmolality, which would normally suppress ADH release 2, 4. This leads to 2:
- Water retention from continued antidiuretic effect on renal collecting ducts
- Dilutional hyponatremia as retained water dilutes serum sodium
- Secondary natriuresis as the body attempts to maintain volume homeostasis by excreting sodium, paradoxically worsening hyponatremia
- Impaired osmoregulated inhibition of thirst, allowing continued fluid intake that perpetuates the problem 2, 4
Types of Osmoregulatory Defects
Recent classification identifies five distinct patterns of AVP dysregulation in SIADH 4:
- Type A-E patterns showing different relationships between AVP release and serum osmolality
- 12% of patients demonstrate AVP-independent mechanisms of inappropriate antidiuresis 4
- 20% show reverse relation between hormone release and osmolality, possibly from interrupted nonosmotic inhibitory pathways 4
Common Causes
The major etiologic categories include 1, 2:
- Malignancy - particularly small cell lung cancer (most common), but also head and neck cancers 1, 5
- Neurological diseases - meningitis, encephalitis, subarachnoid hemorrhage, brain tumors 6, 2
- Pulmonary diseases - pneumonia, tuberculosis, positive pressure ventilation 2
- Medications - chlorpropamide, carbamazepine, SSRIs, cyclophosphamide, vincristine, cisplatin 1, 7
- Postoperative state - particularly with inappropriate hypotonic fluid administration 2
Clinical Presentation
Symptoms are primarily neuromuscular and gastrointestinal, with severity related to both the absolute sodium level and rate of decline 3, 2:
- Mild symptoms (sodium 125-134 mEq/L): headache, nausea, vomiting 3
- Moderate symptoms (sodium 120-125 mEq/L): confusion, lethargy 3
- Severe symptoms (sodium < 120 mEq/L): seizures, coma, death 3, 7
- Rapid decline (> 0.5 mmol/L/hour) produces more severe symptoms regardless of absolute level 2
Critical Diagnostic Distinctions
Cerebral salt wasting (CSW) must be distinguished from SIADH, as treatment approaches are fundamentally opposite 3:
- CSW shows hypovolemia (CVP < 6 cm H₂O) with unquenchable thirst, requiring volume and sodium replacement 3
- SIADH shows euvolemia (CVP 6-10 cm H₂O) without excessive thirst, requiring fluid restriction 3
- Serum uric acid < 4 mg/dL has 73-100% positive predictive value for SIADH 1
Treatment Principles
Management depends on symptom severity 1, 7, 6:
- Severe symptomatic hyponatremia: 3% hypertonic saline with goal to correct 6 mmol/L over 6 hours or until symptoms resolve, never exceeding 8 mmol/L in 24 hours to prevent osmotic demyelination syndrome 1
- Mild/asymptomatic chronic SIADH: fluid restriction to 1 L/day as first-line therapy 1, 7, 6
- Refractory cases: demeclocycline, vasopressin receptor antagonists (tolvaptan, conivaptan), or urea 1, 7
- Address underlying cause whenever possible, as SIADH is often transient 5