How is the diagnosis of Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) made in a patient presenting with hyponatremia?

Diagnosing SIADH in a Patient with Hyponatremia

The diagnosis of SIADH requires demonstrating hypotonic hyponatremia (serum sodium <135 mmol/L, plasma osmolality <275 mOsm/kg) with inappropriately concentrated urine (urine osmolality >100 mOsm/kg, typically >500 mOsm/kg), elevated urinary sodium (>20-40 mEq/L), and confirmation of euvolemia in the absence of hypothyroidism, adrenal insufficiency, or diuretic use. 1, 2, 3

Essential Diagnostic Criteria

The five cardinal criteria must be fulfilled to diagnose SIADH 4:

• Hypotonic hyponatremia: Serum sodium <135 mmol/L with plasma osmolality <275 mOsm/kg 2, 3
• Inappropriately concentrated urine: Urine osmolality >100 mOsm/kg (typically >500 mOsm/kg) despite low plasma osmolality 2, 3, 4
• Elevated urinary sodium: Urine sodium concentration >20-40 mEq/L, indicating physiologic natriuresis 2, 3
• Euvolemic state: Absence of clinical signs of hypovolemia (orthostatic hypotension, dry mucous membranes, decreased skin turgor) or hypervolemia (peripheral edema, ascites, jugular venous distention) 1, 2
• Normal renal, thyroid, and adrenal function: TSH within normal limits, normal cortisol response, and serum creatinine indicating adequate renal function 1, 2, 4

Initial Laboratory Workup

When serum sodium drops below 131 mmol/L, obtain the following tests 1, 2:

• Serum studies: Sodium, osmolality (calculated: 2 × Na + BUN/2.8 + glucose/18), creatinine, glucose, TSH, and morning cortisol 1, 2
• Urine studies: Osmolality, sodium concentration, and assess for concurrent measurement with serum values 1, 2
• Serum uric acid: A level <4 mg/dL has a 73-100% positive predictive value for SIADH, though it may also occur in cerebral salt wasting 1, 2

Critical pitfall: Physical examination alone has poor accuracy for determining volume status (sensitivity 41.1%, specificity 80%), so laboratory confirmation is essential 1, 2. Do not rely solely on clinical assessment of euvolemia.

Volume Status Assessment

Accurate determination of euvolemia is the most critical step in distinguishing SIADH from other causes of hyponatremia 1, 2:

• Euvolemic findings (SIADH): No edema, no orthostatic hypotension, normal skin turgor, moist mucous membranes, and central venous pressure 6-10 cm H₂O if measured 1, 2
• Hypovolemic findings (cerebral salt wasting, diuretic use): Orthostatic hypotension, dry mucous membranes, decreased skin turgor, flat neck veins, and CVP <6 cm H₂O 1, 2
• Hypervolemic findings (heart failure, cirrhosis): Peripheral edema, ascites, jugular venous distention, pulmonary congestion 1, 2

In neurosurgical patients with CNS pathology, distinguishing SIADH from cerebral salt wasting is critical because they require opposite treatments—SIADH requires fluid restriction while CSW requires volume and sodium replacement 1, 2, 3.

Excluding Alternative Diagnoses

Before confirming SIADH, systematically exclude 1, 2, 3:

• Hypothyroidism: Check TSH; hypothyroidism can cause hyponatremia independent of SIADH 1, 2
• Adrenal insufficiency: Morning cortisol or ACTH stimulation test; hypocortisolism mimics SIADH 1, 2
• Diuretic use: Thiazides cause hyponatremia within 2 weeks of initiation and must be discontinued before diagnosing SIADH 1, 3
• Medications: Review SSRIs, carbamazepine, oxcarbazepine, NSAIDs, opioids, and chemotherapy agents (cisplatin, vinca alkaloids) that induce SIADH 1, 3
• Pseudohyponatremia: Serum osmolality >275 mOsm/kg suggests hyperglycemia or hypertriglyceridemia causing laboratory artifact 1, 2

Identifying the Underlying Cause

Once SIADH is confirmed, investigate the etiology 1, 3, 4:

• Malignancy: Small cell lung cancer is the classic cause; consider chest imaging and paraneoplastic workup 1, 3
• CNS disorders: Meningitis, encephalitis, subarachnoid hemorrhage, traumatic brain injury, brain tumors 1, 3, 4
• Pulmonary diseases: Pneumonia, tuberculosis, positive pressure ventilation 1, 3, 4
• Postoperative state: Inappropriate hypotonic fluid administration with pain and nausea stimulating ADH release 1, 4
• Medications: As listed above, with SSRIs and carbamazepine being most common 1, 3

Patterns of AVP Secretion in SIADH

Four distinct patterns of osmoregulated AVP secretion can help characterize SIADH 4:

• Type A (erratic AVP release): Random, unpredictable AVP secretion independent of osmolality (37% of cases) 4
• Type B (reset osmostat): Normal osmoregulation but at a lower threshold, typically mild hyponatremia (33% of cases) 4
• Type C (persistent AVP release): Continuous AVP secretion despite low plasma osmolality (33% of cases) 4
• Type D (normal osmoregulation): Increased renal sensitivity to AVP or other mechanisms (rare) 4

Common Diagnostic Pitfalls

Avoid these errors when diagnosing SIADH 1, 2, 3:

• Obtaining ADH levels: Plasma ADH measurement is not supported by evidence and delays diagnosis; do not order it 1, 2
• Ignoring mild hyponatremia: Even sodium 130-135 mmol/L increases fall risk (21% vs 5%) and mortality (60-fold increase with sodium <130 mmol/L) 1
• Misdiagnosing volume status: Relying on physical examination alone leads to inappropriate treatment; use laboratory confirmation 1, 2
• Missing medication causes: Failure to review all medications, particularly SSRIs, carbamazepine, and thiazides, is a common oversight 1, 3
• Confusing SIADH with cerebral salt wasting: In neurosurgical patients, CSW presents with true hypovolemia (CVP <6 cm H₂O) and requires volume replacement, not fluid restriction 1, 2

When to Pursue Full Diagnostic Workup

Initiate comprehensive evaluation when 1, 2:

• Serum sodium drops below 131 mmol/L, even if asymptomatic 1
• Any symptomatic hyponatremia regardless of sodium level (nausea, confusion, headache, seizures) 1, 3
• Sodium 130-135 mmol/L in high-risk populations (elderly, cirrhosis, heart failure, neurosurgical patients) 1

The diagnosis of SIADH is one of exclusion—only after confirming euvolemia and ruling out hypothyroidism, adrenal insufficiency, and medication causes can you definitively diagnose SIADH. 1, 2, 4 Once diagnosed, treatment focuses on fluid restriction (1 L/day) for mild cases, with hypertonic saline reserved for severe symptomatic hyponatremia, always limiting correction to <8 mmol/L in 24 hours to prevent osmotic demyelination syndrome. 1, 3, 5