What is Syndrome of Inappropriate Antidiuretic Hormone (SIADH)?

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

Definition and Core Pathophysiology

SIADH is a disorder of sodium and water balance characterized by hypotonic hyponatremia (serum sodium < 134 mEq/L) and impaired water excretion due to persistent or elevated plasma arginine vasopressin (ADH) despite low plasma osmolality and normal volume status. 1, 2 The syndrome develops when inappropriate ADH activity leads to water retention via V2 receptors in the distal renal tubules, followed by a physiologic natriuresis where fluid balance is maintained at the expense of plasma sodium. 1, 3

The fundamental problem is that ADH continues to be secreted even when it should be suppressed—specifically when plasma osmolality falls below the normal threshold of 275 mosm/kg. 1, 4 This prevents the kidneys from excreting ingested water appropriately, leading to dilutional hyponatremia. 2, 4

Essential Diagnostic Criteria

SIADH remains a diagnosis of exclusion that requires meeting five cardinal criteria simultaneously: 1, 2, 4

• Hypotonic hyponatremia with serum sodium < 134 mEq/L and 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, 2
• Elevated urinary sodium concentration > 20 mEq/L (usually > 40 mEq/L) 1, 2
• Clinical euvolemia—absence of edema, orthostatic hypotension, normal skin turgor, moist mucous membranes, and no signs of volume depletion or overload 1, 5, 4
• Normal renal, adrenal, and thyroid function—specifically excluding hypothyroidism and adrenal insufficiency 1, 2, 4

A serum uric acid level < 4 mg/dL has a positive predictive value of 73-100% for SIADH, though this may include some patients with cerebral salt wasting. 1, 6

Clinical Presentation

The clinical features are principally neuromuscular and gastrointestinal, with severity related to both the absolute serum sodium concentration and its rate of fall (particularly if > 0.5 mmol/L/hour). 5, 4 Symptoms include headache, nausea, vomiting, confusion, lethargy, seizures, and in severe cases, coma. 5, 4

Critically, SIADH patients are euvolemic—they do not have unquenchable thirst, edema, or signs of dehydration. 5 The presence of hypovolemia (CVP < 6 cm H₂O, orthostatic hypotension, dry mucous membranes) suggests cerebral salt wasting instead, which requires opposite treatment. 1, 5

Common Causes

The major groups of causes include: 4, 7

• Malignancy: Small cell lung cancer (most common), head and neck cancers (rare but reported) 1, 7
• CNS disorders: Meningitis, encephalitis, brain tumors, subarachnoid hemorrhage, trauma 1, 4
• Pulmonary diseases: Pneumonia, tuberculosis, positive pressure ventilation 4
• Medications: Chemotherapy (cisplatin, vincristine, cyclophosphamide), SSRIs, carbamazepine, NSAIDs, opioids 1, 6
• Postoperative state: Particularly after neck dissection or neurosurgery, often due to pain, nausea, and stress stimulating nonosmotic ADH release 1, 8, 7

Inappropriate infusion of hypotonic fluids in hospitalized patients with elevated ADH remains a common and entirely preventable cause, affecting 15-30% of hospitalized patients. 6

Patterns of ADH Secretion

Four categories of osmoregulated AVP secretion have been described in SIADH: 4

1. Erratic AVP release (most common)
2. Reset osmostat (ADH secretion occurs but at a lower osmotic threshold)
3. Persistent AVP release at low plasma osmolality
4. Normal osmoregulated AVP secretion (suggesting enhanced renal sensitivity)

Treatment Principles

For chronic SIADH with mild to moderate symptoms, fluid restriction to 1 L/day (or < 800 mL/day for severe cases) is the cornerstone of therapy. 1, 5, 4 If fluid restriction fails, oral sodium chloride supplementation (100 mEq three times daily) can be added. 1, 6

For severe symptomatic hyponatremia with neurological symptoms (seizures, altered mental status), 3% hypertonic saline is administered with a target correction of 6 mmol/L over 6 hours or until symptoms resolve, but total correction must never exceed 8 mmol/L in 24 hours to prevent osmotic demyelination syndrome. 1, 6

Second-line pharmacological options include demeclocycline (induces nephrogenic diabetes insipidus) and V2-receptor antagonists like tolvaptan (15 mg once daily, FDA-approved for euvolemic hyponatremia). 1, 6, 3

Critical Distinction: SIADH vs Cerebral Salt Wasting

The most important clinical pitfall is confusing SIADH with cerebral salt wasting (CSW), as they require opposite treatments. 1, 5 SIADH is euvolemic (CVP 6-10 cm H₂O) and requires fluid restriction, while CSW is hypovolemic (CVP < 6 cm H₂O) and requires aggressive volume and sodium replacement. 1, 5 Using fluid restriction in CSW worsens outcomes and can be life-threatening. 1, 6