Diagnostic Criteria and Mechanisms of Hyponatremia in Specific Conditions
14. Diagnostic Criteria for SIADH
SIADH is diagnosed when a patient presents with euvolemic hypoosmolar hyponatremia (serum sodium <134 mEq/L, plasma osmolality <275 mosm/kg) with inappropriately concentrated urine (>500 mosm/kg) and elevated urinary sodium (>20 mEq/L), after excluding hypothyroidism, adrenal insufficiency, heart failure, cirrhosis, and diuretic use. 1
Essential Diagnostic Criteria
The five cardinal features that must be present include: 2
- Hypotonic hyponatremia with serum sodium <134 mEq/L 1
- Plasma hypoosmolality <275 mosm/kg 1
- Inappropriately concentrated urine with osmolality >500 mosm/kg relative to low serum osmolality 1
- Elevated urinary sodium concentration >20 mEq/L (typically >40 mEq/L) 1, 3
- Clinical euvolemia - absence of edema, orthostatic hypotension, normal skin turgor, and moist mucous membranes 1, 4
Additional Diagnostic Tools
- Serum uric acid <4 mg/dL has a positive predictive value of 73-100% for SIADH 1, 4
- Fractional excretion of uric acid (FE-UA) >12% improves diagnostic accuracy to approximately 95%, particularly valuable in patients on diuretics where urinary sodium becomes unreliable 1, 5
- Normal renal, adrenal, and thyroid function must be documented 1, 2
Critical Exclusions
SIADH remains a diagnosis of exclusion after ruling out: 1, 3
- Hypothyroidism (check TSH)
- Adrenal insufficiency (check cortisol)
- Volume depletion (clinical assessment)
- Hypervolemic states (heart failure, cirrhosis, nephrotic syndrome)
- Diuretic use
Volume Status Assessment
Distinguishing euvolemia from hypovolemia is critical. Central venous pressure (CVP) can differentiate SIADH (CVP 6-10 cm H₂O) from cerebral salt wasting (CVP <6 cm H₂O). 1, 4 In SIADH, patients have no edema, normal blood pressure, and normal skin turgor, contrasting with the hypovolemia of cerebral salt wasting or the hypervolemia of heart failure/cirrhosis. 1, 6
15. How Adrenal Insufficiency Leads to Hyponatremia
Adrenal insufficiency causes hyponatremia through cortisol deficiency, which leads to inappropriate ADH secretion and impaired free water excretion, mimicking SIADH but occurring in the context of glucocorticoid deficiency. 1
Mechanisms
- Cortisol deficiency removes the normal inhibition of ADH secretion, resulting in non-osmotic ADH release despite low plasma osmolality 1
- Impaired free water excretion occurs because cortisol is required for normal renal water handling 1
- Reduced cardiac output and decreased renal perfusion stimulate baroreceptor-mediated ADH release 1
- Aldosterone deficiency (in primary adrenal insufficiency) causes renal sodium wasting, though this is less prominent in secondary adrenal insufficiency 1
Clinical Distinction
Adrenal insufficiency must be excluded before diagnosing SIADH, as both present with euvolemic hyponatremia and elevated urinary sodium. 1, 2 Check morning cortisol and perform ACTH stimulation testing if adrenal insufficiency is suspected. 1
16. Mechanisms of Hyponatremia in Heart Failure, Cirrhosis, and Nephrotic Syndrome
These conditions cause hypervolemic hyponatremia through non-osmotic ADH secretion triggered by decreased effective arterial blood volume, despite total body sodium and water excess. 7, 6
Shared Pathophysiology
All three conditions involve: 7, 6
- Decreased effective arterial blood volume sensed by baroreceptors
- Non-osmotic ADH release despite hypo-osmolality
- Activation of renin-angiotensin-aldosterone system (RAAS) causing sodium and water retention
- Enhanced proximal tubular sodium reabsorption reducing distal delivery
- Impaired free water clearance despite total body water excess
Heart Failure Specific Mechanisms
- Reduced cardiac output decreases effective circulating volume 7
- Baroreceptor activation stimulates ADH release despite low plasma osmolality 7
- Increased venous pressure causes jugular venous distention, orthopnea, and peripheral edema 7
- Hyponatremia occurs in ~60% of advanced heart failure patients 7
Cirrhosis Specific Mechanisms
- Portal hypertension causes splanchnic vasodilation 7
- Systemic vasodilation reduces effective plasma volume and systemic vascular resistance 7
- RAAS activation causes excessive sodium and water reabsorption 7
- Non-osmotic vasopressin hypersecretion impairs free water excretion 7
- Hyponatremia is mostly dilutional and occurs in ~60% of cirrhotic patients with ascites 7
Nephrotic Syndrome Mechanisms
- Severe hypoalbuminemia reduces oncotic pressure 7
- Decreased effective arterial blood volume despite total body sodium excess 7
- Baroreceptor-mediated ADH release impairs water excretion 7
Clinical Distinction from SIADH
Unlike SIADH's euvolemia, these conditions present with: 6
- Clinical signs of volume overload (edema, ascites, elevated jugular venous pressure)
- Low blood pressure (in cirrhosis and advanced heart failure)
- Elevated plasma creatinine, urea, and urate (opposite of SIADH's low values) 6
17. Why Thiazide Diuretics Cause More Hyponatremia Than Loop Diuretics
Thiazide diuretics cause hyponatremia more frequently than loop diuretics because they impair urinary dilution in the distal tubule while preserving the medullary concentration gradient, preventing free water excretion even when ADH levels are appropriately suppressed. 7
Mechanism of Thiazide-Induced Hyponatremia
- Thiazides block the Na-Cl cotransporter in the distal convoluted tubule, the primary site for urinary dilution 7
- Impaired free water generation occurs because the distal tubule cannot dilute urine below plasma osmolality 7
- Preserved medullary concentration gradient allows continued water reabsorption in the collecting duct if any ADH is present 7
- Increased proximal tubular sodium reabsorption (compensatory) reduces distal delivery, further impairing dilution 7
Why Loop Diuretics Are Less Problematic
- Loop diuretics block the Na-K-2Cl cotransporter in the thick ascending limb, disrupting the medullary concentration gradient 7
- Destruction of the medullary gradient prevents maximal urinary concentration even with high ADH levels 7
- Preserved distal diluting capacity allows free water excretion when ADH is suppressed 7
- Patients can still excrete dilute urine and correct hyponatremia more easily 7
Clinical Implications
- Thiazide-induced hyponatremia typically develops within 2 weeks of initiation, particularly in elderly women 7
- Risk factors include low body weight, advanced age, and concurrent use of other medications affecting water balance 7
- Management requires discontinuing the thiazide and providing isotonic saline for volume repletion if sodium <125 mmol/L 7
- Monitoring serum sodium closely when initiating thiazides, especially in high-risk patients 7
Common Pitfall
Do not assume all diuretic-induced hyponatremia is the same—thiazides require discontinuation while loop diuretics can often be continued with appropriate monitoring. 7