What is the pathophysiology of hyponatremia, including its hypovolemic, euvolemic (SIADH), and hypervolemic forms?

Pathophysiology of Hyponatremia

Overview of Hyponatremia Mechanisms

Hyponatremia represents a disturbance in water metabolism rather than sodium metabolism, occurring when the normal ratio of solutes to body water is altered. 1 The condition is defined as serum sodium <135 mmol/L and reflects dysregulated antidiuretic hormone (ADH/vasopressin) secretion, fluid intake, and renal water excretion. 2

Classification by Volume Status

Hyponatremia is classified into three distinct pathophysiologic categories based on extracellular fluid volume status: hypovolemic, euvolemic, and hypervolemic. 3 Each type has fundamentally different underlying mechanisms. 4

Hypovolemic Hyponatremia

Hypovolemic hyponatremia results from combined loss of both sodium and water, with proportionally greater sodium loss. 5

Pathophysiologic Mechanism:

• True volume depletion triggers baroreceptor-mediated non-osmotic vasopressin release despite low plasma osmolality 2
• Sodium and fluid losses occur through gastrointestinal routes (vomiting, diarrhea), renal losses (diuretics, particularly thiazides), or third-spacing 3, 5
• The body prioritizes volume preservation over osmolality regulation, leading to continued water retention via ADH despite hyponatremia 2
• Enhanced proximal tubular sodium and water reabsorption reduces delivery to diluting segments, impairing free water excretion 3

Laboratory Characteristics:

• Urine sodium typically <30 mmol/L in extrarenal losses (indicating appropriate renal sodium conservation) 3
• Urine sodium >20 mmol/L suggests renal sodium wasting from diuretics or salt-wasting nephropathy 5
• Elevated blood urea nitrogen and creatinine reflect volume depletion 3

Euvolemic Hyponatremia (SIADH)

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most common cause of euvolemic hyponatremia and results from non-osmotic vasopressin release in the absence of volume depletion. 4

Pathophysiologic Mechanism:

• Inappropriate ADH secretion occurs despite low plasma osmolality and normal volume status 4
• Excessive free water reabsorption in renal collecting ducts increases blood volume while diluting plasma sodium 1
• Initial volume expansion triggers physiologic natriuresis (increased urinary sodium excretion) to maintain fluid balance, but this occurs at the expense of plasma sodium concentration 3
• The patient reaches a new steady state where they are euvolemic but hyponatremic 2

Distinguishing Features:

• Normal blood pressure without edema 2
• Strikingly lower plasma concentrations of urate (<4 mg/dL has 73-100% positive predictive value for SIADH), creatinine, and urea compared to hypervolemic causes 3, 2
• Urine sodium >20-40 mmol/L despite euvolemia (due to compensatory natriuresis) 3
• Urine osmolality inappropriately elevated (>300 mOsm/kg) relative to low serum osmolality 3

Common Etiologies:

• Malignancies (particularly small cell lung cancer, affecting 1-5% of lung cancer patients) 3
• CNS disorders (meningitis, encephalitis, subarachnoid hemorrhage) 4
• Pulmonary diseases (pneumonia, tuberculosis) 2
• Medications including SSRIs, carbamazepine, cyclophosphamide, NSAIDs, and opioids 3
• Postoperative states, pain, nausea, and stress (all non-osmotic stimuli for ADH release) 3

Hypervolemic Hyponatremia

Hypervolemic hyponatremia is dilutional, caused by excess water retention that exceeds the already elevated total body sodium, occurring in edematous states. 1, 5

Pathophysiologic Mechanism in Heart Failure:

• Low cardiac output and decreased blood pressure trigger compensatory neurohormonal activation 1
• Baroreceptor-mediated non-osmotic vasopressin release occurs in response to perceived arterial underfilling despite total body volume overload 1, 2
• Activation of renin-angiotensin-aldosterone system causes excessive sodium and water reabsorption 3
• The body perceives "effective" arterial volume depletion despite obvious total body fluid excess 2

Pathophysiologic Mechanism in Cirrhosis:

• Portal hypertension causes systemic vasodilation and decreased systemic vascular resistance 3
• Decreased effective plasma volume triggers the same compensatory mechanisms as heart failure 3
• Non-osmotic hypersecretion of vasopressin combined with enhanced proximal nephron sodium reabsorption leads to impaired free water clearance 3
• This affects approximately 60% of cirrhotic patients, with 21.6% having sodium ≤130 mmol/L 3

Clinical Presentation:

• Evident signs of volume overload: peripheral edema, ascites, jugular venous distention, pulmonary congestion 3, 2
• Low blood pressure despite fluid overload 2
• Slightly elevated plasma creatinine and urea (unlike SIADH) 2
• Urine sodium typically >20 mmol/L due to compensatory natriuresis attempting to offload excess sodium 3

Common Pathophysiologic Pitfall: Diuretic-Induced Hyponatremia

Thiazide diuretics represent a unique mechanism that can cause either hypovolemic or euvolemic hyponatremia. 5

• Thiazides impair urinary dilution by blocking sodium-chloride cotransporter in the distal tubule 3
• This prevents free water generation even when ADH is appropriately suppressed 5
• Volume depletion from diuresis triggers non-osmotic ADH release, compounding the problem 1
• Elderly patients and those on low-salt diets are particularly vulnerable 6

Clinical Significance of Pathophysiologic Understanding

Understanding the underlying mechanism is critical because treatment approaches differ fundamentally: hypovolemic hyponatremia requires volume repletion with isotonic saline, euvolemic hyponatremia (SIADH) requires fluid restriction, and hypervolemic hyponatremia requires treating the underlying condition plus fluid restriction. 3, 6 Misidentifying the volume status leads to inappropriate treatment that can worsen outcomes—for example, giving saline to a patient with SIADH will worsen hyponatremia, while fluid restriction in hypovolemic states is dangerous. 3