Case-Control Study and Case Series of Pseudohyperphosphatemia during Exposure to Liposomal Amphotericin B

Abstract

A mphotericin B is a polyene antifungal indicated for the treatment of invasive fungal infections, including aspergillosis, candidiasis, cryptococcosis, and zygomycosis (1). Several generic formulations of this drug are available in the United States, including amphotericin B deoxycholate, or conventional amphotericin B (CAmB), amphotericin B colloidal dispersion (ABCD), and amphotericin B lipid complex (ABLC; Ablecet). The liposomal formulation of amphotericin B (LAmB; AmBisome) may be preferred over other formulations due to a more favorable side effect profile and enhanced tissue penetration, but it is still associated with hypokalemia, likely attributable to increased tubular permeability to monovalent cations, and hypomagnesemia, for which the mechanism is less certain (1-3). Although the drug is known to cause hypophosphatemia as well, several reports of hyperphosphatemia and pseudohyperphosphatemia have been published (1, 4-9).The first case of severe hyperphosphatemia was in a child with acute lymphocytic leukemia who was treated with LAmB for a mixed fungal infection (4). It was postulated that the electrolyte abnormality was caused by a sudden load of exogenous phosphorus coupled with inadequate clearance by the kidneys. Later, Bailey and Chan proposed the possibility of an artifactual elevation of serum phosphorus during LAmB therapy after two patients were found to have falsely elevated phosphorus levels subsequently shown to be normal by treating the serum samples with a lipemic cleansing agent (5). An ensuing case series described 4 pediatric patients who developed hyperphosphatemia while receiving LAmB (6). In that report, transitioning from LAmB to ABLC at the onset of hyperphosphatemia led to normalization of the serum phosphorus level, leading the authors to conclude that any interference with the PHOSm assay must be specific to the liposomal formulation. Another group reported that ultrafiltration of the serum may be an effective method to obtain a more accurate serum phosphorus measurement (7). Two in vitro studies demonstrated a dose-dependent, linear rise in phosphorus measurements when serum was spiked with LAmB. A 0.0072-to 0.0090-mmol/liter increase in phosphorus correlated with a 1-mg/liter increase in LAmB concentration (8,10). No effect was observed using a comparable placebo molecule without active drug, leading the authors to conclude that active drug in the liposomal formulation (LAmB) is involved in the assay interference (10). In 2008, pseudohyperphosphatemia caused by LAmB was detailed in a product corrective action statement released by Beckman and Coulter, Inc., to hospital laboratories that use Synchron chemistry systems to measure serum phosphorus by the PHOSm assay. The product information for AmBisome was updated in 2012 to reflect

Pseudohyperphosphatemia in a patient with relapsed multiple myeloma after bone marrow transplantation: A case report

“…Pseudohyperphosphatemia has also been reported in serum undergone prolonged refrigeration, the contamination of heparin or recombinant tissue plasminogen activator in the blood sample, treatment with liposomal amphotericin B, in vitro hemolysis with phosphate release from red blood cells, and the presence of hyperbilirubinemia or hyperlipidemia; however, none of these factors presented in our patient.…”

Interferences in the measurement of circulating phosphate: a literature review

“…• Liposomal Amphotericin B Six clinical reports [6,7,[9][10][11][12] containing each from one to 80 cases, analyzed 196 individuals exposed to liposomal amphotericin, who were surprisingly found to have elevated phosphate levels.…”

“…To support the hypothesis of spurious hyperphosphatemia, Bohm [11] compared the prevalence of hyperphosphatemia in 80 adults managed with liposomal amphotericin and in patients managed with triazole antifungals. The prevalence of hyperphosphatemia was found to be significantly higher in liposomal amphotericin patients both with normal (approximately 40% versus 10%) or poor renal function (approximately 60% versus 20%).…”