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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 19 of 33

Table 5. Causes of hypokalemia
Causes of hypokalemia
Reduced potassium intake Malnutrition, anorexia, refeeding syndrome
Gastrointestinal injuries
Vomit (caused by anticancer therapies, intestinal obstruction, etc.)
Diarrhea (caused by anticancer therapies, cancer, surgery)
Redistribution of the potassium Drugs (catecholamine, nasal decongestants, insulin, granulocyte growth factors, beta-2 agonists,
into intracellular compartment barium intoxication, theophylline, bicarbonate, verapamil)
Alkalosis
Hypothermia
Increased potassium losses Non-renal losses:
Losses (diarrhea, vomiting, fistula, laxative abuse, villous adenoma)
Profuse sweating
Extended burns
Toxic epidermal necrolysis
Renal losses:
Metabolic alkalosis
Use of diuretics
Osmotic diuresis
Renal tubular diseases (tubular acidosis, Liddle syndrome)
Endocrine dysfunctions (excess of glucocorticoids or mineralocorticoids, primary hyperaldosteronism
due to adenoma or adrenal carcinoma, renin-secreting neoplasms, ectopic secretion of ACTH)
Concomitant electrolyte disorders (hypercalcemia, hypomagnesemia)
Drugs (amphotericin B, cisplatin, ifosfamide, glucocorticoids, anti-EGFR agents, mTOR inhibitors,
eribulin, abiraterone)

ACTH: adrenocorticotropic hormone; EGFR: endothelial growth factor receptor

kallikrein hypersecretion inducing flushing, severe secretory diarrhea with cramps and hypokalemia,
tachycardia, hypotension until heart failure, and bronchial constriction [122] . Another rare syndrome due
to tumor hypersecretion of vasoactive intestinal polypeptide induces important watery diarrhea with
hypokalemia and achlorhydria [123] .

Renal losses have several potential causes. Endocrine disorders should be considered in cancer patients.
For example, Cushing syndrome can be due in rare cases to ACTH-producing tumors, especially in
patients with small-cell lung cancer, medullary thyroid carcinoma, islet cell adenoma or carcinoma,
pheochromocytoma, and ganglioneuroma, inducing an excessive production of cortisol able to blind
mineralocorticoid receptors inducing hypokalemia [124] . Another rare cause is primary aldosteronism, due to
the excessive and autonomous secretion of aldosterone by adrenal adenomas or carcinoma. This syndrome
is characterized by polydipsia, polyuria, resistant hypertension, and severe hypokalemia [125] .

Furthermore, a common cause of potassium renal losses in cancer patients is drug-related tubular toxicity.
Several chemotherapeutic agents, target therapies, and immunotherapeutic drugs [Table 5] might induce
renal injury associated to hypokalemia. Renal function should be evaluated before drug administration to
avoid further renal damage [126] . Concomitant therapies such as thiazide diuretics and glucocorticoids can
favor potassium renal losses.

Finally, some kinds of tumor induce renal damage. For example, patients with multiple myeloma producing
Bence-Jones proteins develop a progressive renal injury leading to hypomagnesemia and hypokalemia.
Acute myeloid leukemia, through secretion of lysozyme, induces renal tubular damage [127] .

In hematological patients, especially in those with marked leukocytosis (e.g., in acute myeloid leukemia),
hypokalemia can be confused with pseudo-hypokalemia, due to potassium intake in the stored blood
sample before the laboratory analysis [128] .

Management
Clinical presentation depends on severity of hypokalemia. Patients are often asymptomatic, especially
those with mild hypokalemia [129] . Symptoms and sign of hypokalemia are non-specific and due to