1. Iodine-based contrast media interference with laboratory tests

The effect of iodine-based contrast media (ICM) on clinical assays has not been systematically studied extensively. Depending on method and ICM used, interference may be clinically relevant (Morcos, 2005). M-protein analysis is paramount in the diagnosis and monitoring of monoclonal gammopathy (Dimopoulos, 2021). Several studies report interference of ICM on the spectrophotometric detection of monoclonal protein analysis by capillary zone electrophoresis with spectrophotometric detection (CZE-UV) (Quirós, 2018). ICM absorb UV-light at a similar wavelength as the peptide bonds in m-proteins, thereby mimicking the presence of (M-)proteins in the commonly used CZE analysis with UV detection. In contrast, Capaldo and co-workers (Capaldo, 2021) demonstrated that the opposite may also occur, i.e., masking an M-protein peak. In the M-protein analysis by CZE- UV, a duplication in the beta-2 fraction which was at first assigned to ICM (iomeprol) interference and the beta-1 fraction did not display any M-protein peak. Further analysis demonstrated that the iomeprol peak should appear in the beta-1-fraction and not in the beta-2-fraction. After 6 days, a new urine sample demonstrated a m-protein in the beta-1- fraction, which was masked by the iomeprol interference.

Otnes and co-workers investigated in vitro the analytical interference of two specific ICM, iodixanol and iomeprol (Otnes, 2017). They reported in the high, but clinically relevant, concentration range of the ICMs, either a positive bias (colorimetric calcium assay) or a negative bias, i.e., colorimetric iron, magnesium, and zinc assay as well as in the direct potentiometric sodium assay. Other assays did not show any interference with both ICMs. In another study, Lin and co-workers (Lin, 2006) investigated the interference of ICM on two cardiac Troponin I immunoassays (Opus Magnum (Behring Diagnostics) and the Access (Beckman Coulter, Inc)) in patients undergoing coronary angiography. In two in-vivo and two in-vitro experiments, they demonstrated a clinically relevant interference of the ICM on the cardiac levels on the Opus system, especially in the samples obtained directly after the coronary angiography procedure. The interference was absent in the sample after 30 minutes from patients with normal kidney function and lasted longer than 30 min in patients with reduced kidney function. In contrast the Access did not show any interference in the in vivo experiments. In the same study, in vitro experiments of 12 different ICMs showed a similar interference on the Opus system for all ICMs and only one (Lipiodol) on the Access system. A similar interference by iohexol on endocrine immunoassays was observed by Loh and co-workers in in-vitro experiments (Loh, 2013). They reported that soon after contrast administration iohexol may affect follicle stimulating hormone (FSH), luteinizing hormone (LH), plasma renin activity (PRA) and thyrotropin (TSH) measurements by different manufacturers. The interference on immunoassays may be explained by either the presence of an unidentified antigenic site on the contrast medium molecule blocking or cross-reacting with antibodies, dilutional effects due to the high osmolar aspects of iohexol and/or, as described before, due to spectrophotometric aspects of the ICM, interfering with UV- detection.

Next to the photometric aspects of ICM, the higher refractive index of the ICMs interference may occur in urinary analysis, e.g., specific gravity measurement (Glasson, 2012; Oyaert, 2021; Strassinger, 2008).

Besides interference on laboratory testing, sample integrity and quality may be impacted (Lippi, 2014). Since, due to the presence of ICM in the blood, the density of blood is altered, thereby potentially influencing gel cell separator characteristics resulting in incorrect plasma or serum collection (Daves, 2012; Kaleta, 2012; Spiritus, 2003).

Table 10.2.1 shows commonly demonstrated ICM interference on clinical laboratory tests. Unfortunately, there are not many systematic studies addressing CM interference on clinical laboratory tests and recommendations (Stacul, 2018) rely mainly on CM elimination. ESUR for instance recommends performing blood and urine clinical tests prior to administration of the GBCA, to circumvent interference and incorrect assessment of the patient. Post-imaging non-emergency blood and urine analysis should be delayed until the CM concentration in blood and/or urine is not present anymore. In emergency testing, blood and urine analysis can be performed, though clinicians and laboratory specialists should be aware of potential interference of CM. As is with all laboratory tests, the results should be interpreted in

relationship with the patient’s medical history and clinical examination.

Table 10.2.1 Clinical and/or analytical significant analyte interference of specific ICMs 

N.B. Interference may be manufacturer/analyser specific. For detailed information see references.

2. Gadolinium-based contrast agent interference with laboratory tests

Since the introduction of gadolinium-based contrast agents (GBCA) in 1983, these contrast agents have been used extensively. Several interferences on laboratory tests have been described, ranging from commonly used laboratory tests (Lippi, 2014) to more specialized laboratory tests (Day, 2019). One of the most reported clinically relevant interferences is the interference of GBCAs, especially gadodiamide (Normann, 1995; Prince, 2003; Prince, 2004; Zhang, 2006) and gadoversetamide (Lin, 1999) on serum calcium measurement by specific colorimetric methods, irrespective of the molecular configuration of the CA (i.e., linear or cyclic and ionic or non-ionic) (Prince, 2003). Depending on the colorimetric method used the potential bias could be either absent, positive, or negative. In principle, other methods to measure calcium, e.g., Inductively Coupled plasma Mass Spectrometry (ICP-MS) does not demonstrate clinically relevant interference.

In an in-vitro study Proctor and co-workers (Proctor, 2004) investigated the analytical interference of four GBCAs on multiple analytes and multiple analysers. They demonstrated that depending on the specific GBCA a positive and negative analytical interference is observed, which is most prominent in Angiotensin Converting Enzyme (ACE), calcium, iron, total iron binding capacity (TIBC), magnesium and zinc. Mechanistically, all the affected analytes are either endogenous divalent cations or somehow use divalent cations in the reaction of the laboratory test. Gd³⁺ can interact with the analyte of interest (e.g., transmetallation), thereby potentially interrupting the analytical process or in colorimetric assays by binding with the chromophore (Yan, 2014). In an in-vitro experiment, Otnes and co-workers demonstrated a similar interference by the GBCAs gadoxetate disodium, gadoterate meglumine, and gadobutrol on iron and zinc (negative bias) assays. Other 29 clinical tests did not display any clinically relevant interference by these GBCAs (Otnes, 2017).

In the field of trace elements and heavy metals, ICP-MS is the golden standard. Gd3+ may interfere also with this technique in multiple ways, i.e., space-charge effects, interference in the mass spectrometry analysis by double charged ions and polyatomic interference (Day, 2019). The latter can be circumvented by applying the correct analytical technique. In the study, Day and co-workers shared their experience with the clinical impact of GBCA interference in their clinical metal’s laboratory. Especially in the analysis of selenium by ICP- MS is complicated by the presence of ¹⁵⁶Gd which may be doubly charged in the ionization process and therefore has a similar m/z ratio. Moreover, the presence of excess of Gd ions may interfere with the ionization process, suppressing ions of analytes, e.g., trace elements or (toxic) heavy metals and internal standards used.

It is worth noting that many studies report interference of gadodiamide and gadoversetamide on calcium assays but these GBCAs no longer available on the European market.

Table 10.2.2 shows commonly described GBCA interference on clinical laboratory tests. Assay interference by GBCAs can be contrast agent specific, analyte specific and method specific.