This study quantitatively evaluated liver and spleen attenuation in patients with and without amiodarone treatment using TNC and VNC from spectral-detector CT. Patients that were being treated with amiodarone showed higher values of liver attenuation and LAI in TNC images. This is in line with previous studies13,18,19 and case reports7,28,29 suggesting a connection between amiodarone treatment and elevated liver attenuation. Besides the aforementioned case reports, there is only one recent study examining the influence of amiodarone treatment on liver attenuation in CT. The study from Matsuda et al. showed an increase of mean liver attenuation of 9.7 HU in 25 patients after amiodarone treatment had been initiated. This is in line with our investigation that revealed also an increase of liver attenuation by 5.0 HU and an increase of LAI by 7.1 HU. Our results and earlier studies suggest that the parenchymal attenuation increase might be caused by the iodine bound to amiodarone molecule accumulated in the liver, similar to the way iodinated contrast media increases attenuation7,13,14,15,16,30,31,32.
VNC-Chest and -Abdomen derived from spectral-detector CT in a cohort of TAVR planning patients not receiving amiodarone treatment showed accurate removal of iodine in both contrast phases (CTA-Chest and -Abdomen) with attenuation values very similar to TNC. In general, for quantitative liver assessment VNC might therefore serve as a replacement to unenhanced CT examinations when potential limitations of this technique are considered33,34. For example, Durieux et al. 2018 evaluated VNC images for abdominal depiction from a third generation dual-source dual-energy CT and pointed out that despite high accuracies of attenuation values for the liver and spleen with mean attenuation differences between 0–2 HU, there have been substantial differences in fluid, fat and renal tissue with mean differences as high as 32 HU. Other recent dual-energy studies also showed accurate iodine subtraction by VNC for depiction of the liver23,24,35,36. Further, overestimation of fat by VNC has also been reported for spectral-detector CT by Ananthakrishnan et al. and Sauter et al., which could negatively impact attenuation based diagnosis of pathologies with increased fat content, such as liver steatosis, as recently shown by Haji-Momeninan et al. in a second-generation dual-source CT scanner23,24,35. For depiction of the liver, Haji-Momenian et al. reported mean attenuation differences in liver between TNC and VNC of 5.4 ± 8.4 HU in 48 patients24. Our study showed differences between TNC and VNC of 1.8 ± 4.6 HU for CTA-Chest and −1.1 ± 5.9 HU in CTA-Abdomen in liver. These smaller differences in accuracy between the dual-energy CT solutions available might to some extend also be explained by their technical approaches. The spectral-detector CT, for example, separates high and low energy photons on the detector level so that acquired data are exactly matched temporally and spatially. Thereby material decomposition is enabled in the raw data domain21,23,37,38.
Dual-energy CT allows for identification of iodine containing voxels. In a second step, the iodine component of a predefined voxel can be measured and accurately subtracted to create VNC images. This approach should be equally valid for iodinated contrast media and iodine bound to amiodarone21 which have similar molecular structures. The iodine molecules are connected to a benzene ring and iodine atoms have a comparable share of the total molecular mass9,10,11,12,13,14,15,16. In our study, contrary to TNC, liver attenuation and LAI in VNC of CTA-Chest and -Abdomen examinations did not differ significantly between patients treated and not treated with amiodarone, suggesting that VNC also subtracts iodine from iodine-containing amiodarone accumulation in the liver. These initial findings were then verified in a phantom scan, in which VNC of TNC were able to subtract attenuation of iodine-containing amiodarone. Further, the results from our first analysis could be confirmed in an additional patient cohort, for which, unlike to our initial patient cohort, also VNC reconstructions of TNC images were available. In line with our initial results VNC was also able to reduce liver attenuation and LAI in patients treated with amiodarone to a level comparable to patients not treated with amiodarone.
Our patient cohort only included five patients with reduced liver attenuation and LAI indicating liver steatosis, therefore we could not add a further pathology focused analysis on liver steatosis. Still, our data suggests that VNC could be relevant in these patients. In the group of amiodarone patients, VNC led to a mean decrease of LAI of around 10 HU compared to TNC, potentially representing artificially high attenuation in TNC from the iodine in amiodarone. This difference can be relevant in amiodarone patients when it obscures potential liver damage reflected by liver steatosis1,7,8. The LAI is predictive for a liver fat fraction of >30% and image-based diagnosis of liver steatosis when the difference is less than −10 HU39,40,41, hence a mean difference of 10 HU could possibly lead to many misclassified patients. Due to its toxicity amiodarone is also known to independently induce steatohepatitis30 which can then result in liver cirrhosis, drastically increasing risk of mortality1,7,8. Further, liver steatosis, that is caused for other reasons than amiodarone, is common in a general population with non-alcoholic liver steatosis as its most common subtype and an incidence of 15% in general population24,42. A severe liver fat fraction of ≥30% is considered to have relevant clinical implications43,44 but could be obscured in amiodarone patients due to amiodarone accumulation in liver24,45,46. As described above, VNC can also overestimate attenuation of fat; therefore, it needs to be considered that VNC can negatively affect CT attenuation-based diagnosis of liver steatosis in CT imaging24.
For patients with increased liver attenuation undergoing amiodarone treatment, material decomposition and TNC might give radiologists and clinicians more confidence to identify amiodarone as the cause of increased liver attenuation7,28,29, potentially allowing for more precise monitoring of liver attenuation and earlier adaption of drug treatment. Identification and quantification of amiodarone in the liver might also be useful as additional guidance for amiodarone treatment, as tissue levels have been suggested to be useful to anticipate toxic liver damage and treatment efficacy7,18,29. Differences in liver attenuation between TNC and VNC could be used as a measure to quantify amiodarone accumulation in the liver21,47. Thus, spectral imaging might serve as a quantitative biomarker for treatment monitoring in patients before and/or under amiodarone with and with-out fatty liver disease, which should be evaluated in future studies.
The study has some limitations that need to be considered. Spectral imaging data for the unenhanced chest acquisition (TNC) is not routinely saved at our institution, therefore creation of VNC images from this phase was not possible in the initial cohort. However, to address this shortcoming we changed our image reconstruction protocol and included an additional cohort in which VNC was also reconstructed from TNC scans; however, we refrained from conducting a pooled analysis as in the initial patient group VNC was performed on contrast enhanced CT scans and in the additional patient group VNC was performed on unenhanced scans. In this cohort we were able to show that VNC of TNC can reliably reduce increased liver density due to amiodarone deposition. As frequently applied in comparable studies, we used ROI-based measurements of mean attenuation22,23,24,25,35. Still, a volumetric assessment of attenuation covering an entire organ might be less susceptible for any measuring bias. To minimize mismeasurement, we used two ROI for spleen and four ROI for the liver with a standardized size and averaged the results. Further, we placed ROIs in the same anatomical locations in each image set with the help of screenshots of the initial placement.
In conclusion, patients treated with amiodarone showed significantly higher liver attenuation in TNC. In patients not treated with amiodarone VNC accurately subtracted contrast-agent related iodine in contrast-enhanced examinations. Also, VNC depicted comparable liver attenuation in patients treated and untreated with amiodarone indicating that VNC subtracted iodine resulting contrast injection as well as from hepatic amiodarone deposits.