DOI: https://doi.org/10.21203/rs.3.rs-1633667/v1
To investigate the clinical value of liver-to-portal ratio (LPR) on adequate hepatobiliary phase (HBP) defined by 2016 Gastrointestinal and Abdominal Radiology (ESGAR) consensus statement to assess liver function.
Between March 2020 and February 2022, a total of 115 subjects with liver disease were referred by physicians for Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) were prospectively enrolled in the study. Eighty of the 115 subjects were cirrhotic, then all subjects were divided into 4 subgroups according to Child-Pugh (C-P) classification (non-cirrhosis: 35, C-P A: 30, C-P B: 35, C-P C: 15). Two radiologists used 4-point scale to determine the adequate HBP for all subjects, and the LPR on adequate HBP was calculated by other two radiologists. Spearman rank correlation coefficient was used to analyze the correlation between C-P classification and LPR on adequate HBP. The differences in delay time and LPR on adequate HBP among four subgroups were analyzed by One-way ANOVA and Dunnett’s multiple comparisons. Intraclass correlation coefficient (ICC) and κ-statistics were used to test the consistency of measurements and HBP adequacy between radiologists, respectively.
The correlation between the delay time of adequate HBP and liver function was positive (r = 0.802, P < 0.01), while the LPR decreased with severity of cirrhosis (r = -0.562, P < 0.01). the difference in delay time and LPR were significant among four subgroups (P < 0.01), however, the LPR on adequate HBP between C-P B subgroup and C-P C subgroup wasn’t statistically significant (P > 0.05). ICC = 0.93 (95%Cl: 0.92–0.94) and κ-value (0.87) demonstrated that the measurements and interpretation of HBP were good between radiologists.
Prolonged delay time benefits patients with cirrhosis to obtain adequate HBP, and the LPR decreases with the severity of cirrhosis, however the downward trend of LPR is attenuated with more severe liver impairment. The efficacy of LPR on adequate HBP to assess moderate-to-severe cirrhosis decreased.
Gadoxetic acid disodium (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) is widely used in clinical practice, and its specific hepatobiliary phase (HBP) can significantly improve the detection of small lesions compared with dynamic contrast enhanced (DCE)-MRI based on traditional extracellular space contrast media[1–4]. Gd-based contrast media can shorten the relaxation time of T1 and T2, whereby functional MRI can be used for assessing liver function on HBP[5–9]. Additionally, based on the pharmacokinetic mechanism of Gd-EOB-DTPA in vivo, several studies demonstrated that the biliary system enhancement, liver-to-spleen ratio, relative enhancement ratio of liver, and liver-to-portal vein ratio (LPR) are all associated with liver function, and the LPR is considered as the most effective ratio parameter for evaluating liver function[10–17]. We empirically collect HBP at 20 min after intravenous administration[18, 19], however, the 20-min delay time be time-consuming for the total MRI examination duration. With the in-depth study of optimizing HBP delay time by many investigators, it is believed that the personalized delay time based on different cirrhosis classifications is beneficial, i.e., 10-min delay time for patients without cirrhosis, 15-min delay time for mild cirrhosis patients and 20-min or extend to 30 min for severely cirrhotic patients[20–26], nevertheless, the genetic polymorphisms of organic anion transport polypeptides 8 (OATP8) may lead to optimized HBP delay time not being suitable for all patients with different cirrhosis[27]. Moreover, the optimized and adequate HBP not only increases the authenticity of the means for assessing liver function, but also improves the conspicuity of hepatic focal lesions. The 2016 European Society of Gastrointestinal and Abdominal Radiology (ESGAR) consensus statement defines the conditions for adequate HBP, i.e., biliary imaging after Gd-EOB-DTPA into vivo, meanwhile, the signal intensity (SI) between hepatic parenchyma and intrahepatic vascular has been significantly reversed[28]. Furthermore, it is reasonable to deem that optimized and adequate HBP can be more effective in detecting liver lesions and assessing liver function in one-stop-shop Gd-EOB-DTPA-enhanced MRI. However, the HBP delay time is fixed in most previous reports of using MRI-related parameters to assess liver function in different subgroups (e.g., 15 or 20 min)[16, 17]. To our knowledge, the LPR on optimized and sufficient HBP have not been proposed in patients with different liver impairment. Combined with the optimized & adequate HBP defined by the 2016 ESGAR consensus statement and previous studies, we aimed to investigate the LPR on adequate HBP in different liver function to broaden our understanding of the efficacy in evaluating liver function.
The prospective study was approved by the review board of 8th Medical Center of the General Hospital of the Chinese PLA and obtained the written informed consent of all subjects. All methods were carried out in accordance with relevant guidelines and regulations.
Subjects
Between March 2020 and February 2022, a total of 135 subjects with liver disease who were referred by physicians for Gd-EOB-DTPA-enhanced MRI were prospectively enrolled in the study. The Child-Pugh (C-P) grading and renal function (eGFR<30mL·min-1/1.73m²)[29, 30] were obtained within 1 week of the MRI examination. The inclusion criteria were as follows: (1) Gd-EOB-DTPA-enhanced MRI was referred by physicians to clarify hepatic lesions, (2) Older than 18 years, (3) No contraindications to MRI and no allergy to Gd-EOB-DTPA, (4) normal renal function; the exclusion criteria were as follows: (1) Liver without focal lesions,(2) Failure to cooperate with Gd-EOB-DTPA-enhanced MRI, (3) Contrast agent extravasation, (4) Obvious artifacts on HBP imaging, (5) Portal vein embolism, (6) Administration of rifampicin and/or erythromycin during the examination[31, 32].
One hundred and fifteen subjects were enrolled in the final investigation, and 80 of 115 subjects were cirrhotic (type B viral cirrhosis: 65, type C viral cirrhosis: 6, alcoholic cirrhosis: 7, immune hepatitis: 2). Subsequently, 115 patients were divided into four subgroups according to C-P classification [non-cirrhosis subgroup (n=35), C-P A subgroup (n=30), C-P B subgroup (n=35), C-P C subgroup (n=15)]. The flowchart of all subjects was provided in Fig. 1. The final diagnosis of all hepatic focal lesions was based on histopathology after hepatic resection or aspiration biopsy and CT/MRI follow-up[26, 33].
MRI scanning protocol
All subjects underwent Gd-EOB-DTPA-enhanced MRI performed on a 3.0T MRI scanner (Magnetom Skyra, Siemens Healthcare, Erlangen, Germany) in our medical center. Subjects were instructed to fast for 4 hours before the Gd-EOB-DTPA-enhanced MRI, and all subjects were also trained to hold their breath to ensure the quality of HBP imaging before the MRI examination. Subjects were positioned supine with a phased array receiver coil to finish the scanning. The MRI scanning protocol contained location scan, T1WI (in/oppose phase), pre-contrast T1WI three-dimensional Volumetric Interpolated Breath-hold Examination (3D-VIBE), Arterial phase (25 sec), Portal vein phase (65 sec), Transitional phase (2-3 min)[34]. In order to obtain adequate and optimized HBP for all subjects according to the 2016 ESGAR consensus statement for reference standards, we collected 8 HBP at intervals of 5 minutes within 5-40 minutes after intravenous injection. T2-fs-DIXON and EPI-DWI were obtained after HBP[35]. Administration of Gd-EOB-DTPA (Bayer AG, Berlin, Germany, 10 ml, 0.025 mmol/Kg) based on weight was injected at a rate of 2 mL/s via a power injector (Tennessee XD2003, Ulm, Germany) followed by a 20mL saline flush at a rate of 3mL/s. The MRI parameters was shown in Table 1.
Sequences | Planes | TR (ms) | TE (ms) | FOV (mm) | Slice (mm) | FA | Matrix |
---|---|---|---|---|---|---|---|
Location | Coronal/Axial/Sagittal | 7.8 | 3.69 | 430 | 6 | 20° | - |
T2 haste bh | Coronal | 1800 | 89 | 380 | 6 | 160° | 256×256 |
T1 in/opp bh | Axial | 166 | 1.23 | 380 | 6 | 70° | 320×180 |
T1 VIBE fs bh (pre-contrast, DCE, HBP) | Axial | 4.06 | 1.89 | 380 | 3 | 9° | 340×274 |
T2-fs-DIXON | Axial | 3000 | 79 | 380 | 6 | 180° | 256×132 |
EPI-DWI (b = 50、800) | Axial | 5600 | 58 | 400 | 6 | 90° | 160×160 |
TR, repetition time; TE, echo time; FOV, field of view; FA, flip angle; bh, breath hold; fs, fat saturate; EPI, echo planar imaging; HBP, Hepatobiliary phase (5, 10, 15, 20, 25, 30, 35, 40 min). |
Collection of adequate HBP
Two radiologists with 9 and 15 years of experience in abdominal MRI assessed independently all subjects’ HBP datasets using 4-point scale (1: poor, 2: insufficient, 3: good, 4: excellent)[36] based to the 2016 ESGAR consensus statement, then the HBP was determined as adequate HBP which be initially rated 3 or 4 points by both radiologists (Fig. 2). Both radiologists were blind with all clinical information of subjects.
Measurement and calculation of LPR
The other two radiologists with 6 and 14 years of experience in abdominal MRI measured the SI of liver and portal vein (SIliver, SIportal vein) using region of interest (ROI) on all adequate HBP respectively. Obvious artifacts, hepatic lesions, blood vessels and bile ducts should be avoided when setting ROI.
The SIliver took the mean SI of forth liver lobes at the hepatic hilar level (ROI=100mm2). SIliver = (SILMlobe + SILLlobe + SIRAlobe + SIRPlobe) / 4.
The SIportal vein was also measured at the hepatic hilar level, and the area of the ROI was determined by the actual size of the portal trunk (Fig. 3). Ultimately, SIliver and SIprotal vein was the mean of ROI measured by two radiologists.
LPR=SIliver / SIportal vein.
Statistical analysis
All statistical analysis was analyzed by SPSS (version 22.0; Chicago, IL USA). The normal distribution of the continuous data was tested by Shapiro-Wilk's test, then normally distributed data were expressed as mean ± standard deviation (Mean ± SD). Spearman rank correlation coefficient was used to analyze the correction between C-P classification and delay time & LPR of adequate HBP. Differences in LPR and delay time of HBP among four subgroups were assessed by one-way ANOVA and Dunnett's multiple comparisons. The reproducibility of measurements was assessed by intraclass correlation coefficient (ICC), and κ-statistics was used to analyze the consistency of the interpretation for HBP adequacy between radiologists, The evaluation of consistency based on κ-value was as follows: 0.01-0.20, poor agreement; 0.21-0.40, fair agreement; 0.41-0.60, moderate agreement; 0.61-0.80, good agreement; 0.81-0.99, excellent agreement; 1.00, perfect agreement. P value < 0. 05 indicated statistically significant.
A total of 130 liver focal lesions were detected. Eight of the 115 subjects had multiple liver lesions. Thirty-nine focal lesions were detected in non-cirrhosis subgroup [13 cysts, 12 hemangiomas, 4 focal nodular hyperplasia (FNH), 4 hepatocellular carcinomas (HCCs), 6 liver metastases], 34 lesions were found in C-P A subgroup [15 HCCs, 4 regenerative nodules (RNs), 5 hemangiomas], 39 (20 HCCs, 15 RNs and 4 cysts) and 18 (12 HCCs, 4 RNs and 2 hemangiomas) focal lesions were found in C-P B subgroup and C-P C subgroup respectively (Table 2). The final diagnosis of FNH, RNs (20/25), cysts, hemangiomas and HCCs (50/54) were decided by typical medical imaging findings, and remaining RNs and HCCs were diagnosed by histopathology. The hepatic metastases were diagnosed in combination with typical imaging findings and a history of primary tumors[26].
Clinical information | Value |
---|---|
Non-cirrhosis subgroup | (35/115) |
Sex(M/F) | (25/10) |
Age (Mean ± SD) | (49.74 ± 2.34) |
Cyst | 13 |
Hemangioma | 12 |
FNH | 4 |
HCCs | 4 |
Hepatic metastases | 6 |
C-P A subgroup | (30/115) |
Sex(M/F) | (18/12) |
Age (Mean ± SD) | (53.10 ± 1.58) |
HCCs | 18 |
RNs | 6 |
Cyst | 11 |
Hemangioma | 12 |
C-P B subgroup | (35/115) |
Sex(M/F) | (27/8) |
Age (Mean ± SD) | (62.31 ± 1.15) |
HCCs | 20 |
RNs | 15 |
Cyst | 4 |
C-P C subgroup | (15/115) |
Sex(M/F) | (9/6) |
Age (Mean ± SD) | (55.67 ± 2.60) |
HCCs | 12 |
RNs | 4 |
Hemangioma | 2 |
C-P, Child-Pugh; FNH, focal nodular hyperplasia; RNs, regenerative nodules; HCCs, hepatocellular carcinomas; SD, standard deviation |
The delay time of adequate HBP were 11.28 ± 2.22min, 16.00 ± 2.75min, 19.57 ± 4.09min, and 23.33 ± 4.08min in four subgroups. The correlation between the delay time of adequate HBP and liver function classification was positive (r = 0.802, P < 0.01). The difference in delay time was significant among four subgroups (F = 61.87, P < 0.01) (Fig. 4).
The correlation between the LPR on adequate HBP and liver function classification was negative (r = − 0.562, P < 0.01). The differences in LPR were also significant among four subgroups (F = 18.57, P < 0.05), and Dunnett’s multiple comparisons demonstrated that the difference in LPR between C-P B subgroup and C-P C subgroup wasn’t statistically significant (P > 0.05), whereas, the differences between the remaining subgroups were significant (P < 0.05) (Fig. 5, Table 3).
Subgroups | LPR | F, P | P-value of Dunnett’s multiple comparisons | |||||
---|---|---|---|---|---|---|---|---|
non-cirrhosis | 1.59 ± 0.30 | 18.57, < 0.01 | 0.015a | 0.017b | 0.059c | < 0.01d | < 0.01e | < 0.01f |
C-P A | 1.41 ± 0.17 | |||||||
C-P B | 1.30 ± 0.06 | |||||||
C-P C | 1.23 ± 0.08 | |||||||
a non-cirrhosis subgroup VS C-P A subgroup | ||||||||
b C-P A subgroup VS C-P B subgroup | ||||||||
c C-P B subgroup VS C-P C subgroup | ||||||||
d non-cirrhosis subgroup VS C-P B subgroup | ||||||||
e non-cirrhosis subgroup VS C-P C subgroup | ||||||||
f C-P A subgroup VS C-P C subgroup | ||||||||
LPR, liver-to-portal vein ratio; C-P, Child-Pugh; HBP, Hepatobiliary phase |
ICC = 0.93 (95%Cl: 0.92–0.94) demonstrated that the measurements between two radiologists had good reproducibility, and κ-value (0.87) also showed the consistency in assessing HBP is good.
In the present study, we obtained the personalized delay time of adequate HBP defined by the 2016 ESGAR consensus statement in patients with different hepatic function and the delay time is similar to the optimized HBP delay time based on liver function (non-cirrhotic patients: minimum 10–15 min, cirrhotic patients: minimum 20 min)[23, 26]. The correlation between delay time of adequate HBP and C-P classification indicated that patients with severe cirrhosis need a longer delay time for obtaining adequate HBP, which is consistent with previous reports[23, 24]. The reason for the prolong delay time may be the transport mechanisms of Gd-EOB-DTPA, i.e., as the degree of cirrhosis worsens, the absorption efficiency of Gd-EOB-DTPA by liver cells decreases, and a longer delay time may increase the uptake of contrast agent by the liver parenchyma[24, 37]. Additionally, the liver portal hypertension caused by cirrhosis also affects the uptake of contrast medium by OATP 8 in the hepatic blood sinuses[38, 39].
In cirrhotic patients, the LPR on adequate HBP id reduced due to the dual effect of decreased hepatic parenchymal uptake and changes in portal venous pressure, and the LPR is negatively correlated with severity of cirrhosis, which is also consistent with previous studies with a fixed HBP delay time (15 min and 20 min)[15, 16], but what’s inconsistent is a weakening of the downward trend of LPR on adequate HBP in patients with severe cirrhosis. A longer delay time may be the main reason for the weakening of the decline in LPR on adequate HBP in moderate to severe cirrhotic patients, however a relatively short delay may reduce the benefit from HBP in patients with cirrhosis. In clinical practice, a fixed optimized HBP delay time usually doesn’t adequately display liver lesions, and additional HBP datasets with longer delay time are necessary for patients with impaired liver function. The 2016 ESGAR consensus statement provides us with a feasible HBP acquisition strategy, and the 2018 version LI-RADS also emphasizes the importance of the obvious difference of SI between the hepatic parenchyma and intrahepatic vascular for the acquisition of adequate HBP[40]. Consensus-based LPR expands our understanding of the relationship between LPR and liver function, i.e., LPR on adequate HBP may be difficult to distinguish between patients with moderate and severe cirrhosis.
Our study had several limitations. Firstly, considering the operability of the MRI scanning protocol, we didn’t obtain more HBP datasets within 40 min. Secondly, we didn’t investigate on a low-field MRI scanner. Thirdly, our study only investigated the whole liver function according to C-P grading, however, segmental liver function is more meaningful than total liver function in patients with decompensated cirrhosis.
The delay time for obtaining adequate HBP prolongs with severity of cirrhosis, and the LPR on adequate HBP decreases with the severity of cirrhosis, however the downward trend of LPR is attenuated with more severe cirrhosis. The efficacy of LPR on adequate HBP to assess moderate-to-severe cirrhosis decreased.
Gd-EOB-DTPA
MRI
HBP
DCE
LPR
C-P
OATP8
ESGAR.
Ethics approval and consent to participate
This study complies with the Declaration of Helsinki. The prospective study was approved by the review board of 8th Medical Center of the General Hospital of the Chinese PLA and obtained the written informed consent of all subjects. All methods were carried out in accordance with relevant guidelines and regulations.
Consent for publication
Not applicable.
Availability of data and materials
The datasets generated and analysed during the current study are not publicly available due the security of data but are available from the corresponding author on reasonable request.
Competing interests
Not applicable.
Funding
This study has received funding by National Natural Science Foundation of China (NO.81671680).
Authors' contributions
All authors contributed to the paper. Xiaodong Yuan and Chao Wang conceived. Xiaodong Yuan, Chao Wang, Ning Wu, Weirong Sun and Yuan Tian provided a comprehensive background review and analyzed data. Chao Wang and Yuan Tian wrote the first draft and prepared Figures and Tables. Xiaodong Yuan signifcantly amended the manuscript. All authors read and approved the final manuscript.
Acknowledgements
Not applicable.
Author details
1 Department of Graduate, Hebei North University, No. 11 Zuanshi South Road, Gaoxin District, Zhangjiakou City 075000, Hebei Province, China.
2 Department of Radiology, the 8th Medical Center of the General Hospital of the Chinese PLA, 17 Heishanhu Road, Haidian District, 100091, Beijing, China.