Cirrhosis can damage liver cells, increase the spleen volume, and lead to portal hypertension. Therefore, we mainly assessed the liver, spleen and portal vein. Our research was conducted using 15-min HBP images, and we believed that this period could meet the needs to diagnose 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 take up 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 the liver parenchyma SI gradually decreased 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, a finding that was consistent with ours.
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 data indicate that the SI of spleen cannot reflect liver function, and the mean value of the spleen signal is equally likely in each group. Additionally, we found that, in most cases in this study, the spleen signal increased gradually from right to left on both pro-enhanced images and 15-min HBP images (Fig. 4), leading to an increase in the mean signal value of the spleen. The cause remains unclear and may be related to the uneven magnetic field or hemodynamic of the spleen.
In our study, the portal vein SI constantly and slightly increased from normal livers to Child–Pugh class C cirrhotic livers, but no difference was found among the groups. Zhang reported that LPC could effectively indicate the severity of liver function [22], and their data on portal vein SI are similar to ours. A previous study suggested that the delayed hyperintensity in the portal vein can potentially be used to reflect hepatobiliary function [23]; however, the subjects in that study were mostly patients with extrahepatic cholestasis. We found no delayed hyperintensity in the portal vein in any of the subjects in our study, and the direct bilirubin levels in all the 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. The 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 the decreased absorption and clearance of Gd-EOB-DTPA, which can also cause 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 withstand this competition in patients with cirrhosis.
Unlike that of enhanced CT, the signal intensity of enhanced MRI has a nonlinear relationship with the contrast agent concentration, and most studies have used a reference tissue (spleen) to correct the liver signal. Only one study has examined the relationship between LPC and LSC [25]. Their results showed that LPC strongly correlates with LSC, and the LPC of each group was lower than that of LSC. The authors believed that the cause might be 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 the groups, but LPC was greater than LSC. The reasons for this difference may be as follows: (1) different causes might have led to the different patterns of uptake and excretion of Gd-EOB-DTPA: 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 our best knowledge, no study has investigated the value of PSC in evaluating liver function in cirrhosis. Our research proved, for the first time, that PSC cannot reflect liver function in patients with cirrhosis. As discussed previously, the portal vein SI constantly and slightly increased from normal livers to Child–Pugh class C cirrhotic livers, but no differences were found among the groups, and the mean value of the spleen signals was likely equal across the groups. No difference in PSC may exist among the groups.
Some studies have used ICG to reflect liver function because a direct correlation has been found between ICG clearance and hepatocytes, and this parameter can provide more complete information on liver uptake and excretion function [26-28]. We did not analyse ICG because of operational difficulties. We quantitatively analysed the correlations between the 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], consistent with our findings. 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 the largest to smallest, was as follows: LPC, LSC, and the liver parenchyma SI. The cause 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 the largest to smallest, was as follows: LPC, LSC, and the liver parenchyma SI (0.892, 0.889, and 0.836, respectively). However, the differences in AUCs among LPC, LSC and the liver parenchyma SI were not significant. Thus, these parameters have the same ability to distinguish between group 1 and group 2.
These results suggest that LPC may be a more useful alternative imaging biomarker to evaluate 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], consistent with our findings. Additionally, the authors believed that LPC could be particularly 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 had undergone splenectomy (n = 6) and those with Gamna–Gandy bodies (n = 7), and all of these patients had Child–Pugh class B disease.
Additionally, nuclear medicine tracers that assess liver function have been reported, mainly 99mTc-galactosyl human serum albumin (GSA) and 99mTc-mebrofenin. GSA is an asialoglycoprotein analogue, and mebrofenin is an iminodiacetic acid (IDA) analogue [29]. The tracers 99mTc-GSA and 99mTc-mebrofenin can be specifically absorbed by hepatocytes after injection into the body. The combination of SPECT and CT allows for 3D distribution analysis and more precise measurements. Therefore, these tracers can be used to accurately and quantitatively analyse the liver function reserve of each liver segment. However, the disadvantages are obvious, such as the fusion method of SPECT images and CT images not being standardized, radiation exposure and low image resolution. Rassam et al. compared dynamic gadoxetate-enhanced MRI and 99mTc-mebrofenin hepatobiliary scintigraphy with SPECT to assess liver function and found that the mebrofenin uptake rate (MUR) and mean Gd-EOB-DTPA uptake rate (KI) of the whole liver correlated strongly with liver function and that a moderate correlation exists between RE and MUR [30]. Geisel et al. also found that RE and the hepatic uptake index (HUI) correlate with MUR [31]. These studies suggest that the assessment of liver function with Gd-EOB-DTPA MRI is comparable to imaging with 99mTc-mebrofenin or GSA. Compared with the 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, uncertainty of the optimum pharmacokinetic model and most suitable parameters might limit their application. Nevertheless, these results indicate that GD-EOB-DTPA MRI is an ideal choice for preoperative liver function evaluation.
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 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 multicentre studies that include more patients with Child–Pugh class C disease are needed and that classify the causes of cirrhosis. Finally, this study only evaluated whole liver function. Clinically, 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.