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Page 4 of 12 Khan et al. J Cancer Metastasis Treat 2019;5:71 I http://dx.doi.org/10.20517/2394-4722.2019.017

documented to exist < 48 h. The risk of cerebral edema increases in patients with acute hyponatremia since
brain cells have less time to adapt to a hypotonic environment. Conditions predisposing cancer patients to
acute hyponatremia include a postoperative state (especially after prostate and uterine surgery), polydipsia,
thiazide diuretics, and infusion of cyclophosphamide. Brain cells adapt to hyponatremia by extruding sodium,
chloride, and organic osmoles from cells. After adaptation, a rapid increase in serum sodium, as potentially
seen after hypertonic saline administration, can cause damage to the myelin sheath leading to osmotic
demyelination. In most clinical situations in which the duration of hyponatremia is less clear, hyponatremia
[10]
should be considered chronic and managed accordingly to avoid the risk of osmotic demyelination . Mild
hyponatremia refers to serum sodium levels ranging from 130 mEq/L to 135 mEq/L; moderate hyponatremia
refers to serum sodium levels ranging from 125 mEq/L to 129 mEq/L; profound hyponatremia refers to serum
sodium levels < 125 mEq/L. Assessment of volume status in hyponatremia is challenging because of the
variability in individual clinical assessment. Furthermore, in this context it should be clarified whether
[10]
volume status refers to effective circulating volume, total body water or extracellular fluid . In addition to
absolute serum sodium levels, other factors that guide treatment of hyponatremia include symptoms and
the rate of development of hyponatremia.

EUVOLEMIC HYPONATREMIA
Euvolemic hyponatremia results from low solute intake or SIAD and is a major cause of hyponatremia
in cancer patients. Several malignancies are associated with SIAD. SIAD results from the abnormal
production (increased release from the neurohypophysis or ectopic production) or action of AVP resulting
in an excess of total body free water relative to sodium. SIAD is defined by hyponatremia (serum Na
< 135 mEq/L) and an inappropriately concentrated urine (urine osmolality > 100 mOsm/kg, usually >
300 mOsm/kg) in the presence of low serum osmolality (< 275 mOsm/kg), euvolemia, and normal renal
function. Renal sodium excretion is increased (usually > 30 mEq/L in a random urine sample) due to
decreased aldosterone production and possibly increased secretion of natriuretic peptides [17,18] , which
helps to distinguish SIAD from hypovolemic and hypervolemic hyponatremia. Urine sodium is typically
< 30 mEq/L in hypovolemic and hypervolemic hyponatremia, unless there is an underlying process
[19]
contributing to renal sodium loss such as diuretic use . Additional criteria that help to diagnose SIAD
include serum osmolality less than the urine osmolality, low serum uric acid < 4 mg/dL and serum blood
urea nitrogen (BUN) < 21.6 mg/dL, elevated fractional sodium excretion > 0.5%, fractional urea excretion >
55%, and fractional uric acid excretion > 11%.

Causes of SIAD are outlined in Table 1. SIAD is a diagnosis of exclusion. Other causes of euvolemic
hyponatremia include adrenal insufficiency and hypothyroidism. Hematocrit levels and serum
[20]
concentrations of uric acid and BUN may be decreased in SIAD due to hemodilution. These analytes
[21]
could be elevated in hypovolemic hyponatremia . In the diagnosis of SIAD, diagnostic tools that are less
useful, and potentially dangerous in the latter case, include AVP levels and water loading tests [Table 2].
Cancer patients can have a combination of SIAD and other processes that contribute to hyponatremia.
Therefore, the management of these patients is often complicated and relies on the recognition of such co-
[22]
morbidities. Hyponatremia could be a marker of occult malignancy . Patients with an unidentifiable
cause of SIAD should have a chest X-ray. Furthermore, a chest CT should be considered in patients with
a history of smoking and a MRI of the brain in patients with persistent neurologic symptoms and signs
[23]
despite correction of hyponatremia .

HYPERVOLEMIC HYPONATREMIA
Patients with congestive heart failure, nephrotic syndrome, liver and kidney disease can have hypotonic
hyponatremia with increased extracellular fluid volume due to reduced effective arterial volume that
activates baroreceptor-mediated neurohormonal release of vasopressin. Concomitant use of diuretics,