What are the key steps in evaluating hyponatremia, including the role of serum osmolality, urine osmolality, and urine sodium in differentiating between various causes?

Diagnostic Approach to Hyponatremia

Initial Laboratory Assessment

The evaluation of hyponatremia follows a systematic three-step approach: first measure serum osmolality to confirm true hyponatremia, then assess urine osmolality to determine if ADH is appropriately suppressed, and finally use urine sodium to differentiate the underlying cause based on volume status. 1

Step 1: Serum Osmolality (Rule Out Pseudohyponatremia)

• Measure serum osmolality first to distinguish true hypotonic hyponatremia from pseudohyponatremia or hypertonic hyponatremia 1, 2
• Normal serum osmolality (275-290 mOsm/kg) suggests pseudohyponatremia from laboratory error, severe hyperlipidemia, or hyperproteinemia 1
• Elevated serum osmolality indicates hypertonic hyponatremia from hyperglycemia or mannitol administration 1
• Low serum osmolality (<275 mOsm/kg) confirms true hypotonic hyponatremia and warrants further evaluation 2, 3

Step 2: Urine Osmolality (Assess ADH Activity)

• Urine osmolality <100 mOsm/kg indicates appropriate ADH suppression, suggesting primary polydipsia, beer potomania, or reset osmostat 1, 2
• Urine osmolality >100 mOsm/kg (especially >300-500 mOsm/kg) indicates inappropriate ADH activity, pointing toward SIADH, volume depletion, or hypervolemic states 2, 4
• This step is critical because it determines whether the kidneys are appropriately trying to excrete free water 5

Step 3: Urine Sodium (Differentiate Etiology by Volume Status)

Urine sodium interpretation must be combined with clinical volume assessment to accurately categorize hyponatremia 1, 2:

Hypovolemic Hyponatremia

• Urine sodium <30 mmol/L suggests extrarenal losses (vomiting, diarrhea, third-spacing, burns) with appropriate renal sodium retention 1, 2
• Urine sodium >20 mmol/L suggests renal losses (diuretics, cerebral salt wasting, adrenal insufficiency, salt-losing nephropathy) 2, 6
• A urinary sodium <30 mmol/L has a positive predictive value of 71-100% for response to isotonic saline 1, 6

Euvolemic Hyponatremia

• Urine sodium >20-40 mmol/L with urine osmolality >300 mOsm/kg strongly suggests SIADH 2, 4
• Must rule out hypothyroidism (check TSH) and adrenal insufficiency (check cortisol) before diagnosing SIADH 1, 2
• Serum uric acid <4 mg/dL has a positive predictive value of 73-100% for SIADH, though this may also occur in cerebral salt wasting 1, 2, 6

Hypervolemic Hyponatremia

• Urine sodium <20 mmol/L suggests heart failure, cirrhosis, or nephrotic syndrome with avid sodium retention 2
• Urine sodium >20 mmol/L suggests advanced renal failure 2

Typical Laboratory Findings by Etiology

SIADH

• Serum osmolality <275 mOsm/kg 2, 3
• Urine osmolality >500 mOsm/kg (inappropriately concentrated) 2, 4
• Urine sodium >20-40 mEq/L 2, 4
• Serum uric acid <4 mg/dL (73-100% positive predictive value) 1, 2
• Euvolemic on clinical examination (no edema, no orthostatic hypotension, normal skin turgor, moist mucous membranes) 1
• BUN typically low or low-normal due to volume expansion 1

Adrenal Insufficiency

• Serum osmolality <275 mOsm/kg 1
• Urine osmolality >100 mOsm/kg 1
• Urine sodium >20 mmol/L (renal salt wasting) 2
• Hyperkalemia and metabolic acidosis often present 1
• Low cortisol level confirms diagnosis 1
• May present with hypotension and signs of volume depletion 1

Hypothyroidism

• Serum osmolality <275 mOsm/kg 1
• Urine osmolality >100 mOsm/kg 1
• Urine sodium variable 1
• Elevated TSH and low free T4 confirm diagnosis 1
• Hyponatremia typically mild and develops slowly 1

Cerebral Salt Wasting (CSW)

• Serum osmolality <275 mOsm/kg 2, 6
• Urine osmolality >300 mOsm/kg 2
• Urine sodium >20 mmol/L (often >40 mmol/L) 2, 6
• Evidence of volume depletion (hypotension, tachycardia, dry mucous membranes, orthostatic changes) 2
• Central venous pressure <6 cm H₂O if measured 2
• BUN and creatinine often elevated due to hypovolemia 1
• Most common in neurosurgical patients, particularly with subarachnoid hemorrhage 1, 2, 6

Role of Uric Acid and BUN in Differentiation

Serum Uric Acid

• Uric acid <4 mg/dL strongly suggests SIADH or CSW (positive predictive value 73-100%) 1, 2, 6
• Both SIADH and CSW cause increased uric acid excretion, making this marker less useful for distinguishing between them 2, 6
• Normal or elevated uric acid makes SIADH less likely and suggests hypovolemic or hypervolemic hyponatremia 1

Blood Urea Nitrogen (BUN)

• Low or low-normal BUN suggests SIADH due to mild volume expansion and increased urea clearance 1
• Elevated BUN suggests hypovolemic hyponatremia (including CSW) or hypervolemic states with reduced renal perfusion 1
• BUN/creatinine ratio >20 supports hypovolemia 1
• In CSW, BUN is typically elevated due to true volume depletion, whereas in SIADH it is low-normal 1, 2

Critical Clinical Assessment Points

Volume Status Assessment

• Physical examination alone has poor accuracy (sensitivity 41.1%, specificity 80%) for determining volume status 1, 2
• Combine clinical findings with laboratory data for accurate diagnosis 1, 2
• Look for orthostatic hypotension, dry mucous membranes, decreased skin turgor (hypovolemia) versus jugular venous distention, peripheral edema, ascites (hypervolemia) 1, 2

Common Diagnostic Pitfalls

• Relying solely on physical examination to determine volume status leads to misdiagnosis 1, 2
• Misdiagnosing CSW as SIADH results in inappropriate fluid restriction, worsening outcomes 1, 2, 6
• Obtaining ADH and natriuretic peptide levels is not supported by evidence and should not delay treatment 1, 2
• Ignoring mild hyponatremia (130-135 mmol/L) as clinically insignificant, when it increases fall risk and mortality 1

When to Pursue Full Workup

• Serum sodium <131 mmol/L warrants comprehensive evaluation including serum and urine osmolality, urine electrolytes, uric acid, and volume status assessment 1, 2, 6
• Even mild hyponatremia requires attention due to increased morbidity and mortality 1