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Berardi et al. J Cancer Metastasis Treat 2019;5:79 I http://dx.doi.org/10.20517/2394-4722.2019.008 Page 5 of 33

Table 1. Causes of hyponatremia
Extracellular volume Causes of hyponatremia
Hypovolemic: increased water loss Gastrointestinal losses (vomiting, diarrhea)
Renal losses (nephropathies, M. Addison, Diuretics)
Cerebral salt wasting syndrome
Euvolemic: salt loss Syndrome of inappropriate antidiuresis
Endocrine dysfunctions (hypercortisolism, hypothyroidism)
Hypervolemic: water retention Edematogenic syndromes (cirrhosis, heart failure, kidney failure, nephrotic syndrome)

of these two different mechanisms is fundamental for the differential diagnosis between the potential
causes in order to set a correct therapeutic approach. Extracellular volume (ECV) status is fundamental to
distinguishing the mechanism underlying hyponatremia.

According to ECV status, hyponatremia can be classified in [Table 1]:
- Hypovolemic, with reduced ECV.
- Euvolemic, with normal ECV.
- Hypervolemic, with increased ECV.

Hypovolemic hyponatremia is often due to water loss, namely gastrointestinal loss (vomiting, diarrhea),
renal losses, bleeding, and cerebral salt wasting, caused by a dysfunction of hypothalamic-renal axis.

Euvolemic hyponatremia, despite being rare, is an important and frequent condition in cancer patients.
Several mechanisms induce euvolemic hyponatremia such as adrenal insufficiency, hypothyroidism, and
SIAD. SIAD is the principal cause of hyponatremia in oncological and hospitalized patients, occurring in
[26]
1%-2% of all subjects and in 30% of cancer patients . It is characterized by a deregulated AVP activity,
which induces a lower free water excretion. The relative free water surplus leads to serum euvolemic hypo-
osmolar hyponatremia. It is often due to a paraneoplastic syndrome, related to several kinds of tumors. It
is most frequently reported in patients with small-cell lung cancer, but it is also described in patients with
[26]
non-small-cell lung cancer, head and neck cancer, and, rarely, other malignancies .
[38]
SIAD may be caused by :
- Inappropriate secretion of antidiuretic hormone (ADH) from cancer cells (paraneoplastic syndrome).
- Activating mutation of ADH receptor V2.
- Inappropriate or persistent release of AVP.

Although paraneoplastic syndrome is the most frequent cause of SIAD, it should be considered that many
conditions might lead to an inappropriate release of AVP in cancer patients [39,40] :
- Concomitant drugs: diuretics, analgesics, chemotherapies, anticancer target agents, antidepressants,
antipsychotics, antiepileptics, and antiemetics.
- Central nervous system disease: expansive lesions such as neoplasms or hematomas, inflammatory
diseases (e.g., encephalitis, meningitis, etc.), degenerative diseases (e.g., Guillain-Barré syndrome), and
other rare conditions (e.g., hemorrhage, delirium tremens, hypophyseal peduncle section, transphenoidal
[41]
adenectomy , and hydrocephalus).
- Pulmonary disorders: infections, respiratory failure, chronic obstructive pulmonary disease, and active
[1]
pressure ventilation .
- Others: AIDS, senile atrophy, and idiopathic.

Hypervolemic hyponatremia is characterized by an excess of both total body sodium and water. It occurs in
edematous conditions such as cirrhosis, chronic kidney disease, nephrotic syndrome, and congestive heart
failure .
[42]