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Khan et al. J Cancer Metastasis Treat 2019;5:71 I http://dx.doi.org/10.20517/2394-4722.2019.017 Page 3 of 12

PATHOPHYSIOLOGY OF HYPONATREMIA
Hyponatremia denotes a state of relative excess free water in relation to sodium in conjunction with
impaired free water excretion. AVP regulates water balance in the body. AVP release is regulated by
changes in effective osmolality or hypotonicity. Sodium is the major determinant of serum osmolality.
Osmoreceptors, located in the anterior hypothalamus, detect changes in effective serum osmolality and
regulate the release of vasopressin and thirst. An increase in serum osmolality activates osmoreceptors
leading to secretion of vasopressin from the posterior pituitary. The threshold for releasing vasopressin is
[10]
lower than for triggering thirst to avoid persistent thirst . Hyponatremia is a state of low effective serum
osmolality or hypotonicity. Effective serum osmolality refers to the number of osmoles that contribute
water movement between intracellular and extracellular compartments determined by the relative solute
permeability properties of the membranes separating the compartments. Total osmolality reflects the
concentration of all solutes in a given weight of water (mOsm/kg) regardless of the permeability properties
of the separating membrane. A calculated serum osmolality [calculated serum osmolality (mOsm/kg) = 2 ×
Na (mEq/L) + glucose (mg/dL)/18 + urea (mg/dL)/2.8] < 275 mOsm/kg could refer to isotonic, hypotonic or
hypertonic hyponatremia, depending on which osmoles are included in the formula, whereas a measured
serum osmolality < 275 mOsm/kg always indicates hypotonic hyponatremia.

Clarification of tonicity is important because isotonic hyponatremia does not cause cerebral edema. The
basolateral membrane of the renal collecting duct is permeable to water (aquaporin-3 and aquaporin-4
water channels). Vasopressin acts at the vasopressin-2 receptor on the cells of the renal collecting duct
leading to fusion of acquaporin-2 in the apical membrane allowing water to enter into the cells of the
collecting duct and ultimately to the circulation. Reabsorption of water from the collecting duct increases
the concentration of sodium and other electrolytes in the urine, and concentrates urine. Low serum
osmolality (normal range 285-295 mOsm/kg) decreases vasopressin release leading to excretion of free
water from renal tubules. Patients with a reset osmostat, as seen in hypovolemia (baroreceptor stimulation),
quadriplegia, and psychosis, have mild hyponatremia that is unresponsive to changes in fluid and water intake.
Patients with a reset osmostat excrete 80% of a water load (10-15 mL/kg given orally or intravenously) within
four hours, while patients with SIAD have impaired water excretion. Fractional excretion of urate [FEurate
(%) = (urine urate × serum Cr)/(serum urate × urine Cr) × 100] is also normal (4%-11%) in patients with a
[14]
reset osmostat while patients with SIAD have elevated FEurate (> 11%) . Identification of a reset osmostat
is important because the risk of severe hyponatremia is low. In addition, treatment is not necessary and
[15]
likely to be ineffective, since bringing sodium to the normal range will increase thirst . Since AVP release
is controlled by hemodynamic and nonhemodynamic stimuli, cancer patients are at risk of hyponatremia
due to hemodynamic (hypovolemia, hypotension, congestive heart failure, and nephrotic syndrome) and
non-hemodynamic stimuli (pain, stress, nausea, vomiting, hypoxemia, hypercapnia, perioperative state
[16]
and infections) .

Pseudohyponatremia (a lab artifact) is due to an inaccurate measurement of sodium in the presence of
abnormally high concentration of proteins and lipids in the blood. Larger relative proportion of plasma
is occupied by excessive lipids and proteins. In this situation, serum osmolality is actually in the normal
range since total number of solutes in the plasma remain the same. Monoclonal gammopathies can also
[10]
cause pseudohyponatremia . Patients undergoing urological and gynecological surgery can have high
serum osmolality due to mannitol and glycine absorbed in the circulation during irrigation. Effective
osmoles, e.g., mannitol, glycine and glucose (seen in uncontrolled diabetes), increase serum osmolality by
shifting water from intracellular compartments.

CLASSIFICATION OF HYPONATREMIA
Hyponatremia is classified on the basis of biochemical severity, rapidity of onset, development of symptoms,
measured serum osmolality, and volume status. Acute hyponatremia is defined as hyponatremia that is