Cirrhosis can damage liver cells, increase spleen volume, and lead to portal hypertension, so we mainly assessed the liver, spleen and portal vein. Our research was conducted with 15-min HBP images, and we believed that this time period could meet the needs for diagnosing liver diseases and shorten the examination time of patients.
The liver parenchyma SI can be used to estimate liver function, which has been widely described. The hepatobiliary phase of Gd-EOB-DTPA-enhanced images is due to the selective uptake of membrane-bound organic anion transporters (OATP1 B1/B3) [16-18]. Normal hepatocytes can use these transporters to uptake Gd-EOB-DTPA, and the amount of Gd-EOB-DTPA peaked on the 20-min HBP images; the number of impaired transporters and functional capacity of these transporters could reduce the uptake of Gd-EOB-DTPA into hepatocytes [19], subsequently affecting the liver signal. Our data showed that liver parenchyma SI gradually decreases with increasing liver function damage. Previous studies [19-21] have also indicated that the severity of cirrhosis can significantly affect the absorption of gadolinium and then affect the degree of liver enhancement, which was consistent with our research.
The spleen does not contain the organic anion transporters described above, and Gd-EOB-DTPA only shows the characteristics of a nonspecific extracellular space contrast agent. Our research indicates that the SI of the spleen cannot reflect liver function, and the mean value of the spleen signal is equally likely in each group. In addition, we found that in most of the cases in this study, the spleen signal increased gradually from right to left on both pro-enhanced images or 15-min HBP images (Fig. 4), leading to an increase in the mean signal value of the spleen. The reason behind this phenomenon remains unclear and may be related to the uneven magnetic field or the hemodynamics of the spleen.
In our study, the portal vein SI constantly and slightly increased from the normal liver to Child–Pugh class C cirrhotic liver, but there were no differences among groups. Zhang reported that the LPC can effectively indicate the severity of liver function [22], and their data on portal vein SI are similar to our research. A previous study suggested that the delayed hyperintensity in the portal vein can potentially be used to reflect hepatobiliary function [23], the subjects in that study were mostly patients with extrahepatic cholestasis. There was no delayed hyperintensity in the portal vein in any of the subjects in this study, and the direct bilirubin levels in all groups were lower than the cut-off value of 2.18 mg/dl, except for one patient in group C (2.38 mg/dl). We think that is the main reason for the difference between studies. Hepatobiliary phase images among the groups are shown in Fig. 5. A study proved that hepatic uptake and biliary elimination of bilirubin compete against Gd-EOB-DTPA uptake, and hyperbilirubinemia will lead to decreased absorption and clearance of Gd-EOB-DTPA, which can also lead to delayed contrast agent clearance from the blood [24]. However, we hold that the bilirubin level in patients with cirrhosis may not be as high as that in patients with extrahepatic cholestasis, and hepatocytes may be able to withstand this competition in patients with cirrhosis.
Unlike that of enhanced CT, the signal intensity of enhanced MRI has a nonlinear relationship with the concentration of contrast agent, and most studies have used a reference tissue (spleen) to correct the liver signal. As we have seen, only one study has examined the relationship between LPC and LSC [25]. Their results showed that LPC was strongly correlated with LSC, and the LPC of each group was lower than the LSC. The authors believed that this was due to the portal vein SI, which can more reflect the blood pool than the spleen. Our research also showed a strong correlation between LPC and LSC among groups, but the LPC was greater than the LSC. The reasons for this difference may be as follows: (1) the different underlying causes might lead to the different patterns of uptake and excretion of Gd-EOB-DTPA since our patients mainly had hepatitis B cirrhosis, and their patients mainly had chronic liver disease; and (2) the MRI devices and imaging sequences were different.
To the best of our knowledge, no one has studied PSC yet, and our research proved for the first time that PSC cannot reflect liver function in patients with cirrhosis. As discussed before, the portal vein SI consistently and slightly increased from normal liver to Child–Pugh class C cirrhotic liver, but there were no differences among groups, and the mean value of the spleen signals was likely equal across groups. It is possible that there is no difference in PSC among groups.
Some studies have used ICG to reflect liver function because there is a direct correlation between ICG clearance and hepatocytes, and this parameter can provide more complete information on liver uptake and excretion function [26-28]. We did not analyze ICG because of operational difficulties. We quantitatively analyzed the correlations between MRI data and liver function parameters. In this study, the liver parenchyma SI, LPC and LSC were weakly to moderately correlated with laboratory markers. Zhang also demonstrated a weak to moderate correlation between LPC and laboratory markers [22], which was consistent with our research. We also found that the liver parenchyma SI, LPC and LSC were negatively correlated with hepatic function scores (Child–Pugh score and MELD score), and the correlation coefficients of the parameters, in order from largest to smallest, was as follows: LPC, LSC, and the liver parenchyma SI. The reason may be that the changing trend of the portal vein signal strengthens the correlation between LPC and liver function.
Receiver operating characteristic analysis showed that the order of the AUCs of the parameters, from largest to smallest, was as follows: LPC, LSC, and the liver parenchyma SI (0.892, 0.889, 0.836); however, the differences in AUCs among LPC, LSC and the liver parenchyma SI were not significant. This illustrated that these parameters have the same ability to distinguish between group 1 and group 2.
These results suggested that LPC might be a more useful alternative imaging biomarker for evaluating liver function than LSC and the liver parenchyma SI. Takatsu found that LPC could be used as a substitute for LSC for a simple assessment of the degree of hepatic contrast enhancement [25], which is consistent with our research. In addition, the authors also believed that LPC can be especially useful in cases of splenectomy and Gamna–Gandy bodies [25]. However, we thought this conclusion needed further verification because of the small number of patients who underwent splenectomy (n = 6) and those with Gamna–Gandy bodies (n = 7), and these patients were Child–Pugh class B.
In addition, nuclear medicine tracers that assess liver function have also been reported, mainly 99mTc-galactosyl human serum albumin (GSA) and 99mTc-mebrofenin. GSA is an asialoglycoprotein analog, and mebrofenin is an iminodiacetic acid (IDA) analog [29]. The tracers 99mTc-GSA and 99mTc-mebrofenin can be specifically absorbed by hepatocytes after being injected into the body. The combination of SPECT and CT allows for 3D distribution analysis and more exact measurements. Therefore, these tracers can be used to accurately and quantitatively analyze the liver function reserve of each liver segment. However, the disadvantages are obvious, such as the fusion method of SPECT image and CT image has not been standardized, radiation exposure and low image resolution. Rassam et al. compared dynamic gadoxetate-enhanced MRI and 99mTc-mebrofenin hepatobiliary scintigraphy with SPECT for the assessment of liver function and found that the mebrofenin uptake rate (MUR) and the mean Gd-EOB-DTPA uptake rate (KI) of the whole liver correlated strongly with liver function and that there was a moderate correlation between RE and the MUR [30]. Geisel et al. also found that RE and the hepatic uptake index (HUI) correlate with MUR [31]. These studies suggested that the assessment of liver function with Gd-EOB-DTPA MRI is comparable with imaging with 99mTc-mebrofenin or GSA. Compared with signal intensity, quantitative parameters such as KI, T1 values and T2* values (obtained from T1 mapping [9] and T2*mapping [32], respectively) can reflect liver function more accurately, but the data acquisition obstacles and the uncertainty of the optimum pharmacokinetic model and most suitable parameters might limit their application. Nevertheless, these results indicate that GD-EOB-DTPA MRI will be an ideal choice for preoperative liver function evaluations.
Our study had several limitations. First, the severity of cirrhosis was not grouped based on liver biopsy results. Second, we did not classify the causes of cirrhosis, and the different causes might lead to different patterns of uptake and excretion of Gd-EOB-DTPA. Third, it was difficult to avoid selection bias because of the retrospective nature of this study. Fourth, this study included a small number of patients with Child–Pugh class C disease, who have a poor physical condition and decompensated cirrhosis and cannot undergo the examination; thus, further prospective and multicenter studies that include more patients with Child–Pugh class C disease are needed, and classify the causes of cirrhosis. Finally, this study only evaluated whole liver function. In clinical work, segmental liver function is more meaningful than whole liver function. Therefore, we will measure and explore segmental liver function according to liver segment in the future.