Analytical interference in serum iron determination reveals iron versus gadolinium transmetallation with linear gadolinium-based contrast agents

Invest Radiol. 2014 Dec;49(12):766-72. doi: 10.1097/RLI.0000000000000081.

Abstract

Objectives: The purposes of this study were to evaluate the risk for analytical interference with gadolinium-based contrast agents (GBCAs) for the colorimetric measurement of serum iron (Fe³⁺) and to investigate the mechanisms involved.

Materials and methods: Rat serum was spiked with several concentrations of all molecular categories of GBCAs, ligands, or "free" soluble gadolinium (Gd³⁺). Serum iron concentration was determined by 2 different colorimetric methods at pH 4.0 (with a Vitros DT60 analyzer or a Cobas Integra 400 analyzer). Secondly, the cause of interference was investigated by (a) adding free soluble Gd³⁺ or Mn²⁺ to serum in the presence of gadobenic acid or gadodiamide and (b) electrospray ionization mass spectrometry.

Results: Spurious decrease in serum Fe³⁺ concentration was observed with all linear GBCAs (only with the Vitros DT60 technique occurring at pH 4.0) but not with macrocyclic GBCAs or with free soluble Gd³⁺. Spurious hyposideremia was also observed with the free ligands present in the pharmaceutical solutions of the linear GBCAs gadopentetic acid and gadodiamide (ie, diethylene triamine pentaacetic acid and calcium-diethylene triamine pentaacetic acid bismethylamide, respectively), suggesting the formation of Fe-ligand chelate.Gadobenic acid-induced interference was blocked in a concentration-dependent fashion by adding a free soluble Gd³⁺ salt. Conversely, Mn²⁺, which has a lower affinity than Gd³⁺ and Fe³⁺ for the ligand of gadobenic acid (ie, benzyloxypropionic diethylenetriamine tetraacetic acid), was less effective (interference was only partially blocked), suggesting an Fe³⁺ versus Gd³⁺ transmetallation phenomenon at pH 4.0. Similar results were observed with gadodiamide. Mass spectrometry detected the formation of Fe-ligand with all linear GBCAs tested in the presence of Fe and the disappearance of Fe-ligand after the addition of free soluble Gd³⁺. No Fe-ligand chelate was found in the case of the macrocyclic GBCA gadoteric acid.

Conclusions: Macrocyclic GBCAs induced no interference with colorimetric methods for iron determination, whereas negative interference was observed with linear GBCAs using a Vitros DT60 analyzer. This interference of linear GBCAs seems to be caused by the excess of ligand and/or an Fe³⁺ versus Gd³⁺ transmetallation phenomenon.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Colorimetry / methods
  • Contrast Media / chemistry*
  • Gadolinium / chemistry*
  • Gadolinium DTPA / chemistry
  • Humans
  • Iron / blood*
  • Mass Spectrometry / methods
  • Meglumine / analogs & derivatives
  • Meglumine / chemistry
  • Organometallic Compounds / chemistry
  • Rats
  • Rats, Wistar

Substances

  • Contrast Media
  • Organometallic Compounds
  • gadobenic acid
  • Meglumine
  • gadodiamide
  • Gadolinium
  • Iron
  • Gadolinium DTPA