Gadobenate Dimeglumine-enhanced Magnetic Resonance Imaging In Predicting Esophageal Varices And Liver Function In Patients With Hepatitis B Cirrhosis

Chronic hepatitis B virus(HBV)infection is a worldwide public health problem.About 30%of the world's population has serological evidence of past or current HBV infection'.According to the report of World Health Organization(WHO),there were approximately 257 million chronic HBV infections in the world in 2015,but the epidemic intensity varies greatly in different regions.China is a high-endemic area of HBV,which owns the most HBV infected patients in the world,about 7 million2.In 2014,the Chinese Center for Disease Control and Prevention estimated that the current prevalence rate of hepatitis B surface antigen(HBsAg)in the general population in China is still as high as 5%to 6%.There are about 70 million cases with chronic HBV infection,of which about 20 million to 30 million are patients with chronic inflammatory diseases of the liver caused by chronic HBV infection2.HBV infection can cause long-lasting damage to the liver.Due to repeated tissue repair and autoimmune reactions,chronic liver disease gradually progresses to the compensatory and decompensated phases of hepatitis B cirrhosis.Among those with perinatal acquired HBV infection,40%of men and 15%of women will die of hepatitis B cirrhosis or hepatocellular carcinoma(HCC)1.Unlike our country,chronic hepatitis C infection is the most common cause of liver cirrhosis in the United States and many other Western countries3,so its research on liver cirrhosis mostly focuses on hepatitis C cirrhosis.The cause of liver cirrhosis has a great influence on the development of the disease,the appearance of complications,and the treatment.Our study pays attention to the national conditions of our country and focuses on patients with hepatitis B cirrhosis.According to whether there are serious complications such as portal hypertension(PH),ascites,esophago-gastric varices(EGV),and hepatic encephalopathy,liver cirrhosis is divided into a compensatory phase and a decompensated phase.Once the above complications occur,it is diagnosed as decompensated cirrhosis4,and Child-Pugh grade is usually B or C.After the portal pressure of patients with decompensated liver cirrhosis increases to a certain level,it will lead to the establishment of collateral circulation,which will shunt portal blood flow to the systemic circulation.The most common one is EGV,whose incidence is reported to be about 50%5.A number of studies have shown that EGV appears and worsens as the course of liver cirrhosis progresses.Christensen et al.6 followed up 532 patients with cirrhosis for 12 years and found that the cumulative incidence of EGV increased from the initial 12%to the final 90%.Cales and Pasal et al.7 showed that during the 16 months of follow-up,20%of patients without EGV developed EGV,and 42%of patients with small EGV developed large EGV.Studies have shown that the annual rate of life-threatening acute EGV bleeding(EGVB)is 5-15%8.In the past thirty years,great progress has been made in the treatment of PH and EGVB,including the application of somatostatin and its analogues,the preventive use of antibiotics,emergency endoscopic treatment,and remedial transjugular intrahepatic portosystemic shunting(TIPS),but it is still a difficult problem in clinical work.A national study of patients with acute EGVB in the UK in 20149 showed that it only accounted for about 10%of patients with acute upper gastrointestinal bleeding.But 54%of EGVB occured during normal working hours,73%of patients with EGVB required infusion of red blood cell,35%of patients needed plasma infusion,the rebleeding rate was still as high as 26%after treatment,and the mortality rate within 30 days was 15%.Therefore,the EGVB guidelines10-12 for cirrhosis and portal hypertension in many countries recommend endoscopy for all patients with confirmed liver cirrhosis to assess the presence and severity of EGV,and recommend the primary prevention of severe esophageal varice(EV),including oral non-selective beta-blocker(NSBB)and endoscopic variceal ligation(EVL)to reduce the risk of bleeding and related complication.Endoscopy is the gold standard for diagnosis and evaluation of EGV.However,as an invasive tool,the examination process is painful and can cause complications such as gastrointestinal bleeding,infection,cardiovascular and cerebrovascular accidents,sedation and anesthesia accidents,and patients with liver cirrhosis need to be assessed by gastroscopy regularly,which greatly reduces the compliance of patients.Therefore,clinicians have been looking for non-invasive monitoring tools for EGV to replace gastroscopy.Although studies have shown that capsule endoscopy(CE)13,transient elastrography(TE)14,and serological indicators15 can assess EV,all of them have not got recognition,due to the lack of large-scale prospective studies,the high heterogeneity of the research subjects and poor consistency between observers and the lack of relatively uniform cutoffs.In recent years,magnetic resonance imaging(MRI)and magnetic resonance elastrography(MRE)had been reported to evaluate the severity of EV.Studies have shown that the ratio of right hepatic lobe volume measured by MRI to albumin can not only identify the presence of cirrhosis16,but as the disease worsens,that is,Child-Pugh classification progresses,the ratio increases,and it can be used to predict EV.The sensitivity,specificity and area under receiver operating characteristic curve(AUROC)are 80%,83.5%and 0.8916 respectively.The study of Razek et al.17 showed that the spleen apparent diffusion coefficient of MRI of normal volunteers,patients with liver cirrhosis without EV,and patients with liver cirrhosis with EV were significantly different,and when the application of 1.15×10-3 mm2/S and 1.29×10-3 mm2/s is used as the cutoff value,the AUROC are 0.872 and 0.889 respectively.The sensitivity of MRE combined with or without enhanced MRI in diagnosing EV is 88.9%and 96%,and the specificity is 56.4%,60.0%,respectively.However,when patients are complicated with other portosystemic shunts,false positive results are prone to occur,and liver iron deposition or large amount of ascites may lead to false negative result18,19.Research from Morisaka20 shows that MRE can distinguish whether patients have EVs,but it cannot distinguish the volume of EVs.The research methods involved in the above studies require additional scanning sequences and complex post-processing software,which limits their wide application in clinical work.In order to improve the accuracy of diagnosing EV,the method of simultaneously applying multiple indicators is often used.In summary,in order to improve the accuracy of diagnosis and facilitate the promotion in future clinical work,we also apply liver MRI and related serological indicators,hoping to find a non-invasive,highly accurate and repeatable scoring model to replace gastroscope in EV screening.Hepatic vein pressure gradient(HVPG)is the gold standard reflecting portal vein pressure21.HVPG>10mmHg indicates the presence of clinically significant portal hypertension and possible EV22;HVPG>12mmHg indicates a higher risk of EGVB23;HVPG>16mmHg is closely related to high mortality24.In patients with EGVB,HVPG>20mmHg is an independent risk factor affecting prognosis25.However,the measurement of HVPG requires the insertion of a catheter into the hepatic vein through the internal jugular vein,which is obtained by measuring the wedging pressure and free pressure of the hepatic vein.It is an invasive operation and requires high operator requirements,so it can only be used in very few hospitals,which limits its routine clinical application.Clinicians are committed to finding diagnostic tools for non-invasive evaluation of HVPG,such as TE and endoscopy,but they all proved to be ineffective.The previous research of our team showed that by measuring the liver and spleen volume by contrast enhanced computed tomogtaphy(CECT),and by evaluating EV by endoscopy,we obtained the score model for non-invasive evaluation of HVPG:HVPG=13.651-6.187 × 1n(liver volume/spleen volume)+2.755×EV score under endoscopy(small EV:1 point;large EV:2 points)26.Research shows that this score can predict HVPG non-invasively and accurately.In this study,this HVPG scoring model was used to predict HVPG to evaluate whether Gd-BOPTA-enhanced liver MRI can predict HVPG.The liver reserve function refers to the repair and regeneration capacity of the liver after partial resection or damage caused by various pathogenic factors.It is mainly determined by the total number of functional liver cells,blood-liver exchange volume,and liver cell microsomal function27.Hepatic insufficiency is impaired liver reserve function and is the main cause of death in patients with decompensated cirrhosis after liver resection.Preoperative evaluation of liver reserve function is of great significance for reducing the incidence of postoperative liver failure28.However,the commonly used tools include indocyanine green clearance rate29,computed tomography volumetric measurement method30,clinical scoring systems such as Child-Pugh score31,model for end-stage liver disease(model for end-stage liver disease,MELD)32,etc.It just evaluates the overall function of the liver.The studies of Patel et al.33 and Zhao et al.34 found that Gd-BOPTA-enhanced MRI can not only reflect liver function,but also assess liver function reserve through hepatobiliary specific phase.The study by Zhao et al34 showed that Gd-BOPTA-enhanced MRI had the potential to quantitatively evaluate liver function and liver reserve function by the degree of liver parenchymal enhancement in hepatobiliary phase.At the same time,the application of Gd-BOPTA-enhanced MRI in the study to assess liver reserve function can assess not only the overall liver function,but also local liver function.However,the etiology of patients with decompensated cirrhosis in their study included not only hepatitis B virus infection,but also hepatitis C virus infection,heavy alcohol,and immune factors.The etiology of liver cirrhosis has a clear influence on the course of the disease.Therefore,this study is dedicated to observe whether Gd-BOPTA-enhanced MRI can be used to assess the liver reserve function of patients with hepatitis B cirrhosis.HCC is the fifth most common tumor in the world and the second leading cause of death from cancer35.As a high-risk group of HCC,patients with liver cirrhosis are recommended to receive HCC monitoring by various guidelines.The occurrence of HCC is a complex,multi-step evolution process.HCC under the background of liver cirrhosis has mostly experienced the gradual progression of cirrhotic nodules,low-grade dysplastic nodules,high-grade dysplastic nodules,early HCC to advanced HCC36.Gd-BOPTA has important application value for the qualitative diagnosis of HCC-related nodules.Therefore,for patients with liver cirrhosis with nodules,it is recommended to use Gd-BOPTA-enhanced MRI to obtain hepatobiliary-specific phase images,and integrate the artery phase and hepatobiliary-specific phase to define the nature of the nodules and improve the diagnostic accuracy37.MRI has no radiation,high tissue resolution,and can realize multi-directional and multi-sequence imaging.It is generally believed that dynamic enhanced multi-phase MRI scan is better than enhanced CT38 in identifying benign and malignant intrahepatic lesions.At the same time,the detection rate of small liver cancer increased from 65%to 87%36,39,40 by using hepatobiliary-specific contrast agent scanning.MRI enhancement contrast agents are divided into hepatocyte specific ones and hepatocyte non-specific ones.The former mainly include gadoxetic acid disodium and gadobenate dimeglumine(Gd-BOPTA),which can be taken up by functional liver cells specifically and then excreted through the biliary tract,and thus has a biphasic enhancing effect.The advantage of hepatocyte specific enhancement contrast agents lies in hepatobiliary-specific phase,which shown good applications in disease detection,qualitative diagnosis,and biliary system display41.For patients with chronic liver disease,the above two hepatocyte-specific MRI contrast agents have the same liver parenchymal enhancement effect and liver cancer detection rate.The difference lies in 34:(1)Gd-BOPTA has stronger hepatic artery and portal vein enhancement effect;(2)The price of Gd-BOPTA is only about 1/4 of the former;(3)The hepatobiliary specific phase of Gd-BOPTA is 90-120 minutes after Gd-BOPTA injection,while Gd-BOPTA disodium is about 20 minutes.Due to its significant advantages,Gd-BOPTA has received more and more attention in recent years,and its clinical application has become more and more extensive41.Therefore,in this study,Gd-BOPTA was selected as a liver MRI contrast agent.The items that need to be closely monitored during follow-up of patients with liver cirrhosis include liver function,portal pressure,degree of EV,and the occurrence of HCC.This study focused on the high prevalence of HBV in our country,and aimed to explore whether it is available in non-invasive evaluation of EV,HVPG and liver reserve function in hepatitis B cirrhosis patients.We found that Gd-BOPTA-enhanced MRI combined with serological indicators could predict EV non-invasively,and patients in the validation group proved that the EV model is accurate and repeatable.Meantime,it also played an important role in predicting HVPG,evaluating liver reserve function,and monitoring HCC.It can be used as a tool in the follow-up of hepatitis B cirrhosis patients,simultaneously achieving the purpose of evaluating liver reserve function,predicting portal pressure and EV severity,and monitoring the occurrence of HCC.Part 1 Gadobenate dimeglumine-enhanced magnetic resonance imaging in predicting the severity of esophageal varices in patients with hepatitis B cirrhosis Aim:To explore the effectiveness of gadobenate dimeglumine(Gd-BOPTA)-enhanced magnetic resonance imaging(MRI)in predicting high-risk esophageal varices(EV)in patients with hepatitis B cirrhosis.Methods:First,71 patients with hepatitis B cirrhosis who met the inclusion and exclusion criteria were retrospectively included as the training group.The univariate and multivariate analysis were used to obtain serological and MRI indicators related to high-risk EV,and then the high-risk EV score model was derived.Then,30 eligible patients with hepatitis B cirrhosis were prospectively included as the validation group to evaluate the accuracy and repeatability of the high-risk EV score model derived in this study.Results:Platelet count(P=0.033),portal vein width(P=0.040)and RE(P=0.046)were identified as independent predictors of high-risk EV.Based on these parameters,the EV score model was calculated as:-6.483+15.612 ×portal vein width(cm)+2.251×RE-0.176 × platelet count(×109/L).The area under the receiver operating characteristic curve of the training group was 0.903.At a cut-off value of<-2.74,the negative predictive value was 92.86%,while the positive predictive value was as high as 94.44%when the cut-off was set at>4.00.Its accuracy was confirmed with the validation set.Conclusions:The high-risk EV scoring model established on the basis of Gd-BOPTA-enhanced MRI and serum indexes could non-invasively and accurately assess high-risk EVs in patients with hepatitis B cirrhosis.Based on this model,different follow-up strategies were established for patients with hepatitis B cirrhosis,which avoided the need for endoscopic screening for each patient.Part 2 Gadobenate dimeglumine-enhanced magnetic resonance imaging in predicting the portal vein pressure in patients with hepatitis B cirrhosisAim:To explore if gadobenate dimeglumine(Gd-BOPTA)-enhanced magnetic resonance imaging(MRI)can be used to predict the portal vein pressure?Methods:First,71 and 30 patients with hepatitis B cirrhosis who met the inclusion and exclusion criteria were retrospectively and prospectively included as the training group and verification group,respectively.All patients complted Gd-BOPTA-enhanced MRI and we could got liver parenchymal relative enhancement(RE).By calculating the volume of liver and spleen through enhanced computed tomography(CECT)of the upper abdomen and calculating the score of esophageal varices through upper gastrointestinal endoscopy,we could reckon hepatic vein pressure gradient(HVPG)by the HVPG scoring model from our previous research.Then,whether there was a correlation between RE and HVPG was analysed.Results:56 patients in the training group and 30 patientsin the validation group performed CECT.The scatter plot analysis showed that there was a negative correlation between HVPG and RE in both the training group and the validation group(training group:r=-0.6266,P=0.000;validation group:r=-0.5971,P=0.000).Conclusions:Gd-BOPTA-enhanced MRI could be used to predict portal vein in patients with hepatitis B cirrhosis.Part 3 The efficacy of gadobenate dimeglumine-enhanced magnetic resonance imaging in evaluating liver function in patients with hepatitis B cirrhosisAim:To observe the role of gadobenate dimeglumine(Gd-BOPTA)-enhanced magnetic resonanceimaging(MRI)in evaluating liver function in patients with hepatitis B cirrhosis?Methods:71 patients with hepatitis B cirrhosis who met the inclusion and exclusion criteria were retrospectively included.According to the Child-Pugh classification,the patients were divided into three groups:Child-Pugh A group,Child-Pugh B group,and Child-Pugh C group.The relative enhancement ratio(RE)of the liver parenchyma of Gd-BOPTA enhanced MRI in three groups was calculated and compared.Results:The RE was respectively 0.46±0.07,0.37±0.11,0.23±0.10 in Child-Pugh A,B and C group.Differences existed between any two group(P=0.000).Conclusion:Gd-BOPTA-enhance MRI could evaluate liver function in patients with hepatitis B cirrhosis,including not only the overall liver function but also the regional liver function.