What are the causes of hyponatremia and how should it be worked up?

Causes and Workup of Hyponatremia

Hyponatremia (serum sodium <135 mmol/L) should be evaluated systematically based on volume status and serum osmolality, with initial workup including serum and urine osmolality, urine sodium, and assessment of extracellular fluid volume status. 1

Classification by Volume Status

The fundamental approach to hyponatremia requires categorizing patients into three volume states, as this determines both etiology and treatment 2:

Hypovolemic Hyponatremia (True Volume Depletion)

Causes:

• Extrarenal losses: Gastrointestinal losses (vomiting, diarrhea), third-spacing (burns, pancreatitis), excessive sweating—characterized by urine sodium <20 mmol/L 1
• Renal losses: Diuretic use (especially thiazides), salt-wasting nephropathy, cerebral salt wasting, adrenal insufficiency—characterized by urine sodium >20 mmol/L 1, 3

Clinical signs: Orthostatic hypotension, tachycardia, dry mucous membranes, decreased skin turgor, flat neck veins 1, 4

Euvolemic Hyponatremia (Normal Volume Status)

Primary cause: Syndrome of Inappropriate Antidiuretic Hormone (SIADH)

Common etiologies of SIADH: 1, 2

• Malignancies: Small cell lung cancer, pancreatic cancer, lymphomas
• CNS disorders: Meningitis, encephalitis, subarachnoid hemorrhage, traumatic brain injury, stroke
• Pulmonary diseases: Pneumonia, tuberculosis, positive-pressure ventilation
• Medications: SSRIs, carbamazepine, cyclophosphamide, NSAIDs, opioids, vincristine 1
• Postoperative states: Pain, nausea, stress-induced AVP release 1

Other euvolemic causes:

• Hypothyroidism
• Adrenal insufficiency (must be excluded before diagnosing SIADH) 1
• Psychogenic polydipsia (primary polydipsia)
• Beer potomania (poor solute intake with excessive fluid) 1

Clinical signs: No edema, no orthostatic hypotension, normal blood pressure, moist mucous membranes 4

Hypervolemic Hyponatremia (Volume Overload with Effective Hypovolemia)

Causes:

• Cirrhosis with ascites: Non-osmotic vasopressin hypersecretion due to portal hypertension and systemic vasodilation; occurs in ~60% of cirrhotic patients 1
• Heart failure: Reduced cardiac output triggers neurohormonal activation 1, 3
• Nephrotic syndrome: Severe hypoalbuminemia reduces effective arterial blood volume 3
• Advanced chronic kidney disease: Impaired free water excretion 3

Clinical signs: Peripheral edema, ascites, jugular venous distention, pulmonary congestion 1, 4

Essential Diagnostic Workup

Initial Laboratory Tests 1, 4, 2

Serum studies:

• Serum sodium, osmolality (normal 275-295 mOsm/kg)
• Serum glucose (exclude hyperglycemia-induced pseudohyponatremia: add 1.6 mEq/L to sodium for each 100 mg/dL glucose >100 mg/dL) 1
• BUN, creatinine (assess renal function and BUN:creatinine ratio)
• Serum uric acid (<4 mg/dL has 73-100% positive predictive value for SIADH) 1
• TSH (exclude hypothyroidism) 1
• Morning cortisol (exclude adrenal insufficiency) 1

Urine studies:

• Urine osmolality (<100 mOsm/kg suggests appropriate ADH suppression; >100 mOsm/kg indicates impaired water excretion) 1
• Urine sodium concentration:
  • <30 mmol/L: suggests hypovolemic hyponatremia with 71-100% positive predictive value for saline responsiveness 1

  • 20-40 mmol/L with high urine osmolality (>300 mOsm/kg): suggests SIADH 1

Diagnostic Algorithm Based on Serum Osmolality 3, 5

Step 1: Measure serum osmolality

• Low (<275 mOsm/kg): True hypotonic hyponatremia—proceed to volume assessment
• Normal (275-295 mOsm/kg): Pseudohyponatremia from hyperlipidemia or hyperproteinemia
• High (>295 mOsm/kg): Hypertonic hyponatremia from hyperglycemia or mannitol

Step 2: Assess volume status (see classifications above)

Step 3: Measure urine osmolality and sodium

• Urine osmolality <100 mOsm/kg: Primary polydipsia or beer potomania
• Urine osmolality >100 mOsm/kg: Proceed based on volume status and urine sodium

SIADH Diagnostic Criteria 1, 5

SIADH requires all of the following:

• Hypotonic hyponatremia (serum osmolality <275 mOsm/kg)
• Inappropriately concentrated urine (urine osmolality >100 mOsm/kg, typically >300 mOsm/kg)
• Urine sodium >20-40 mmol/L
• Clinical euvolemia (no edema, no orthostatic hypotension)
• Normal thyroid, adrenal, and renal function
• No recent diuretic use

Special Diagnostic Considerations

Cerebral Salt Wasting vs. SIADH in Neurosurgical Patients 1, 4

This distinction is critical because treatments are opposite:

Cerebral Salt Wasting (CSW):

• True hypovolemia with CVP <6 cm H₂O
• Urine sodium >20 mmol/L despite volume depletion
• Clinical signs: orthostatic hypotension, tachycardia, dry mucous membranes
• More common in subarachnoid hemorrhage, poor clinical grade, anterior communicating artery aneurysms 1
• Treatment: Volume and sodium replacement, NOT fluid restriction 1

SIADH:

• Euvolemia with normal to slightly elevated CVP
• Urine sodium >20-40 mmol/L
• No clinical signs of volume depletion
• Treatment: Fluid restriction 1

Severity Classification 3, 2

• Mild: 130-135 mmol/L (often asymptomatic but increases fall risk and mortality) 1, 4
• Moderate: 125-129 mmol/L (nausea, vomiting, confusion, headache)
• Severe: <125 mmol/L (seizures, coma, cardiorespiratory distress)

Symptom Assessment by Acuity 2, 6

Acute hyponatremia (<48 hours): More severe symptoms at any given sodium level due to rapid brain cell swelling 1

Chronic hyponatremia (>48 hours): Often minimally symptomatic even at low sodium levels due to cerebral adaptation, but associated with cognitive impairment, gait disturbances, falls (23.8% vs 16.4% in normonatremic patients), and fractures 2

Common Diagnostic Pitfalls

• Ignoring mild hyponatremia (130-135 mmol/L): Even mild chronic hyponatremia increases mortality, fall risk (21% vs 5%), and fracture risk 1, 2
• Relying on physical examination alone for volume assessment: Sensitivity only 41.1%, specificity 80% 1, 4
• Obtaining ADH or natriuretic peptide levels: Not supported by evidence and delays treatment 1, 4
• Failing to distinguish CSW from SIADH in neurosurgical patients: Leads to opposite and potentially harmful treatments 1, 4
• Missing medication causes: Always review SSRIs, carbamazepine, NSAIDs, diuretics, opioids, chemotherapy agents 1
• Not checking thyroid and adrenal function: Must exclude hypothyroidism and adrenal insufficiency before diagnosing SIADH 1

When to Pursue Full Workup

Hyponatremia warrants complete evaluation when serum sodium falls below 131 mmol/L, though even levels of 130-135 mmol/L require attention due to associated morbidity and mortality. 1, 4