Auswirkung einer Kontrastmittelgabe auf das Auftreten von DNA-Doppelstrangbrüchen bei computertomographischen Thoraxuntersuchungen

INTRODUCTION: X-ray iodinated contrast agents have a higher absorption of X-rays than soft tissue. Thus, they are suitable for a high contrast reproduction of vessels, whose density does not usually differ from the surrounding tissue. The indication-dependent use of X-ray contrast agents in computed tomography is state of the art. Nephro- and cytotoxic effects of these contrast agents, like contrast-induced nephropathy (CIN) as the most significant, are well known. Exposure to x-rays leads to an increased risk of developing cancer due to excessive DNA damage. Preliminary clinical studies indicate that the application of X-ray contrast agents increases this DNA damage during a CT examination. The proven radiation-induced DNA damages include micronuclei, chromosomal aberrations, and double-strand breaks. Double-strand breaks are the most significant cause for carcinogenesis. Their repair is more difficult than other DNA damage, and a failure of their repair can lead to cancer. DNA double-strand breaks can be visualised and quantified by assessing gamma-H2AX-foci. With this method every gamma-H2AX-focus equates to exactly one DNA double-strand break. Because of the small number of cases in earlier studies, this study should give more statistical certainty with the following question: To what extent does the application of iodinated X-ray contrast agents have a quantitative influence on the incidence of DNA double-strand breaks in patients undergoing diagnostic chest CT examinations? MATERIAL: Blood samples of 179 patients with a clinical indication for a contrast enhanced CT (cohort with contrast agent) and 66 patients with a clinical indication for an unenhanced CT (cohort without contrast agent) were analyzed prior and immediately after the CT examination. Age, size, weight, and gender did not differ significantly between both cohorts. Peripheral lymphocytes were separated from the blood samples. DNA double-strand breaks were visualised and enumerated by assessing gamma-H2AX-foci with immunefluorescence microscopy. RESULTS: The average increase of gamma-H2AX-foci per lymphocyte after the CT examination of the contrast-enhanced cohort was 0.056±0.121 foci/cell (mean±standard deviation), twice as much as the increase in the unenhanced cohort with 0.027±0.113 foci/cell. In an inferential statistic using independent t-test with directional hypothesis (one-tailed test) and alpha<0.05 this difference of means was statistically signifi�cant with p=0.044. Differences in radiation dose parameters were not statistically significant between cohorts with the exception of the dose-length product (DLP: unenhanced: 342±116 mGy*cm; contrast enhanced: 301±120 mGy*cm; p<0.05). Mean DLP was 312±120 mGy*cm for the entire patient cohort. In order to compensate for this difference in radiation dose between the two cohorts, the DNA damage was standardized to a mean radiation dose of 312 mGy*cm. This resulted in an even greater difference in the increase of foci/cell after CT scanning. The group undergoing unenhanced CT showed an increase of 0.021±0.108 foci/cell, while the contrast-enhanced group exhibited 0.077±0.160 foci/cell. This increase was 267% higher for the contrast-enhanced group. The difference was statistically significant (p=0.001). DISCUSSION: The present study showed that the presence of iodinated contrast agents during irradiation significantly increases the number of induced gamma-H2AX-foci. This is most likely an effect which is caused by the generation of additional secondary electrons when the X-rays are absorbed by the contrast agent. Due to their high density, iodinated contrast agents absorb more X-rays than human soft tissues. In addition, the generation of secondary electrons is strongly dependent on the density of the absorbing material. Therefore, these effects are synergistic, and the generation of secondary electrons is even more pronounced. These secondary electrons are the major cause of DNA damage induced by X-rays. Problems with the assessment of risk can result from the fact that the lymphocytes are irradiated only partially during the CT examination. Because of the physiological blood circulation, the irradiated lymphocytes mix with non-irradiated lymphocytes after the CT examination. This effect leads to a dilution of the radiation damage and a lower foci level. Therefore, the assessment of risk can be underestimated. However, this study, just as studies in the recent past, could show that the analysis of gamma-H2AX-foci in peripheral lymphocytes represents a useful approach to measure the induction of double-strand breaks after irradiation with diagnostic radiation doses. Finally, the indication and the dosing of iodinated X-ray contrast agents has to be assessed even more carefully, and alternative diagnostic procedures should be considered.