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Electrolyte Disorders Associated with Cancer Mitchell H Electrolyte Disorders Associated With Cancer Mitchell H. Rosner and Alan C. Dalkin Patients with malignancies commonly experience abnormalities in serum electrolytes, including hyponatremia, hypokalemia, hyperkalemia, hypophosphatemia, and hypercalcemia. In many cases, the causes of these electolyte disturbances are due to common etiologies not unique to the underlying cancer. However, at other times, these electrolyte disorders signal the pres- ence of paraneoplastic processes and portend a poor prognosis. Furthermore, the development of these electrolyte abnormal- ities may be associated with symptoms that can negatively affect quality of life and may prevent certain chemotherapeutic regimens. Thus, prompt recognition of these disorders and corrective therapy is critical in the care of the patient with cancer. Q 2014 by the National Kidney Foundation, Inc. All rights reserved. Key Words: Cancer, Hyponatremia, Hypokalemia, Hypercalcemia, Hypophosphatemia Introduction lymphoma, in which patients with serum sodium less than 137 mEq/L had a lower rate and shorter duration Electrolyte disorders are commonly encountered in the of remission after chemotherapy as compared with patient with cancer. In most cases, these disorders are as- patients with higher sodium levels.4 Likewise, hypona- sociated with etiologies seen in all types of patients and tremia may limit the use of chemotherapeutic options are not specifically linked to the malignancy or its ther- that require extensive hydration. Symptoms attributable apy (for example, diuretic-induced hyponatremia or hy- to hyponatremia, such as confusion, lethargy, and head- pokalemia). In other cases, electrolyte disorders are due ache, may also further compromise quality of life in this to paraneoplastic syndromes or are specifically associ- population. It is debatable whether hyponatremia inde- ated with chemotherapeutic regimens. When these pendently contributes to these poor outcomes or is sim- malignancy-specific electrolyte disorders are manifest, ply a marker of disease severity, progression, and they can lead to life-threatening complications that re- overall debility. A recent study would argue that the lat- quire emergent therapy. Thus, proper recognition and ter is the case, although correction of hyponatremia be- treatment of these disorders is important in the overall fore hospital discharge does seem to improve outcomes care of the patient with cancer. This review will discuss whereas persistent hyponatremia was associated with selected malignancy-associated electrolyte disorders. worse outcomes.7-10 The differential diagnosis of hyponatremia in patients Hyponatremia Associated With Cancer with cancer is extensive (Table 1) and requires a careful history, physical examination, and laboratory evaluation Hyponatremia is the most common electrolyte disorder to elucidate the etiology. It should be emphasized that the encountered in patients with malignancies. Studies symptoms related to hyponatremia may be nonspecific have reported a prevalence that ranges from approxi- and attributable to the underlying disease and its ther- mately 4% to as high as 47%.1,2 Approximately 14% of apy. Thus, clinicians should measure serum sodium hyponatremia encountered in medical inpatients is due values in patients with symptoms compatible with hypo- to an underlying malignancy-related condition.3 It is im- natremia rather than assume that the etiology is due to portant to note that nearly half of these cases represented the underlying disease. Understanding the etiology of hospital-acquired hyponatremia, suggesting that man- hyponatremia is critical in allowing proper management. agement of these patients (most likely with intravenous For example, intravenous 0.9% saline would be the ap- fluids) significantly contributes to the development of hy- propriate therapy in a patient with hypovolemic hypona- ponatremia. tremia due to vomiting but not for a patient with the Hyponatremia is clearly associated with significant syndrome of inappropriate ADH secretion (SIADH). In morbidity and mortality when it occurs in the patient some cases of drug-associated hyponatremia, simply with cancer. For instance, hospital length of stay is nearly doubled in patients with moderate to severe hyponatre- mia.1 The hazard ratio for death within 90 days after From Division of Nephrology, University of Virginia Health System, Char- lottesville, VA; and Division of Endocrinology and Metabolism, University of the diagnosis of hyponatremia was 4.74 in those patients Virginia Health System, Charlottesville, VA. with moderate hyponatremia and 3.46 in patients with Conflict of interest: M.H.R has served as a consultant to Otsuka and 1 more severe hyponatremia. Other studies have also Novartis; A.D. declares no relevant financial interests. demonstrated a marked association with hyponatremia Address correspondence to Mitchell H. Rosner, MD, Division of Nephrol- and mortality in patients with non-Hodgkin’s lym- ogy, Box 800133 HSC, University of Virginia Health System, Charlottesville, VA 22908. E-mail: [email protected] phoma, renal cell carcinoma, gastric cancer, and small- Ó 4-6 2014 by the National Kidney Foundation, Inc. All rights reserved. cell lung cancer. Hyponatremia may affect patient 1548-5595/$36.00 response to therapy, as shown in non-Hodgkin’s http://dx.doi.org/10.1053/j.ackd.2013.05.005 Advances in Chronic Kidney Disease, Vol 21, No 1 (January), 2014: pp 7-17 7 8 Rosner and Dalkin stopping the offending medication along with transient contributor to the development of severe hyponatremia free water restriction will lead to correction of the hypo- associated with cyclophosphamide is that aggressive hy- natremia. dration protocols are used to prevent hemorrhagic cysti- The most common etiology of hyponatremia that is di- tis. Cisplatin has been demonstrated to cause SIADH and rectly related to malignancy is SIADH. The diagnostic cri- to lead to a salt-losing nephropathy that can exacerbate teria for SIADH are listed in Table 2.11 This syndrome can the development of hyponatremia.23 be associated with many different types of malignancy In some cases SIADH may be subclinical with patients and antineoplastic therapies (Table 3), but it is most demonstrating only mild degrees of asymptomatic hypo- commonly seen with small-cell lung cancer, in which as natremia (serum sodium values 130-135 mEq/L). How- many as 10% to 15% of patients are hyponatremic at ever, when patients are challenged with a water load or presentation and as many as 70% of patients have hypotonic fluids, severe hyponatremia may result.24 significant elevations of plasma arginine vasopressin This has been specifically demonstrated with small-cell (AVP).12-16 Although hyponatremia may be quite severe lung cancer, in which 65% of patients had abnormalities at presentation with small-cell lung cancer, only 25% in water handling when administered a water load.12 have symptoms that can be attributable to hyponatremia, This is also consistent with the finding that a large per- suggesting that in most instances hyponatremia develops centage of hyponatremia cases encountered in patients slowly and insidiously.15 It is controversial whether the with cancer develop in the hospital setting.1 development and severity of hyponatremia correlates In patients with SIADH, it is common to see secondary with tumor burden and the extent of metastatic dis- elevations of atrial natriuretic peptide (ANP).25,26 The ease.12-16 In 1 study, the presence of SIADH did not affect elevations in ANP are due to a combination of increased response to chemotherapy or overall survival.15 However, atrial stretch secondary to the mild volume expansion other studies showed a higher mortality rate in those that occurs with AVP-induced water retention and the patients with small-cell lung direct effect of AVP to 27 cancer and a serum sodium CLINICAL SUMMARY increase ANP secretion. less than 130 mEq/L, and Nonphysiological release of hyponatremia in small-cell Electrolyte disorders in patients with cancer are common ANP by small-cell lung lung cancer patients is and can be secondary to either the cancer or its therapy. cancers has also been dem- generally a poor prognostic The most common electrolyte disorder seen in cancer onstrated, and this ANP- 6,17–19 feature. An intriguing patients is hyponatremia; this is most commonly due to driven kidney sodium loss possibility regarding the the syndrome of inappropriate ADH secretion. may also contribute to the association of SIADH with Electrolyte disorders in cancer patients are associated with development and worsen- poor outcomes in patients a poor prognosis; appropriate treatment may improve ing of hyponatremia in these with small-cell lung cancer short term outcomes and quality of life. patients.6,28,29 Thus, the is that AVPitself may directly development of hypon- stimulate tumor growth.20 atremia in patients with The next most common malignancy types associated small-cell lung cancer may be multifactorial. with SIADH are head and neck tumors (occurring in Therapeutic options for the treatment of hyponatre- 3% of these patients).21 Outside of small-cell lung cancer mia in the patient with cancer are the same as for other and head and neck cancers, most data linking SIADH causes of hyponatremia and rely on the presence of with tumor subtypes come from isolated case reports related symptoms, the duration of hyponatremia, and that may be confounded by abnormal kidney or adrenal the volume status of the patient. 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