Application Of Two-dimensional Shear Wave Elastography In The Evaluation Of Disease Progression And Curative Effect Of Primary Biliary Cholangitis

Objective:Primary biliary cholangitis(PBC)is an autoimmune-mediated chronic cholestatic liver disease characterized by interlobular bile duct damage.As a disease of which prevalence varied widely across regions in the whole world,study reported that overall prevalence of PBC was 118.75 cases per million every year in the Asia-Pacific region,lower than that of other regions.PBC was previously thought to be very rare in China,but the incidence and prevalence of PBC are still on the rise in China and even in the world.PBC usually occurs in middle-aged and elderly women.The typical clinical manifestations of PBC include fatigue,pruritus,jaundice,intolerance,epigastric discomfort,and pain.Serological manifestations were elevated alkaline phosphatase(ALP)and glutamine transpeptidase(GGT),and positive specific autoimmune-related antibodies such as anti-mitochondrial antibody(AMA),anti-speckled protein 100 antibody(SP100),and anti-glycoprotein 210 antibody(GP210).Ursodeoxycholic acid(UDCA)is currently recommended as the first-line treatment for PBC.However,30～40%patients still show incomplete biochemical response to UDCA treatment.As same as liver disease caused by other reasons,PBC could develop into liver fibrosis and cirrhosis,portal hypertension complications such as esophageal and gastric varices,ascites,even liver carcinoma and death.Timely treatment and regular monitoring are very important to PBC patients.Two-dimensional shear wave elastography(2D-SWE)is a new ultrasonic elastography technique which has been widely used in recent years.2D-SWE mainly includes two basic principles:(1)the pressure is the acoustic radiation force that can generate the shear wave.Since the propagation velocity of the shear wave is directly related to the stiffness of the tissue,it can reflect the stiffness of the tissue;(2)In combination with the ultrasonic imaging system,real-time ultrasonic imaging can be provided to display the shear wave propagation.2D-SWE can be used to measure liver stiffness(LS).In recent years,a growing number of studies have shown that 2D-SWE plays a certain role in the field of chronic liver disease,including the diagnosis of fibrosis,portal hypertension and gastroesophageal varices,and the evaluation of response to drug treatment.At present,there are few studies about 2D-SWE in the evaluation of disease progression in PBC.Therefore,this study aims in the role of 2D-SWE in PBC patients,including assessing the degree of liver fibrosis and gastroesophageal varices,and predicting response to UDCA treatment.Materials and Methods:In this study,patients diagnosed with PBC admitted to West China Hospital of Sichuan University between September 2016 and December 2020 were collected and followed up for a long period of time.This study was divided into three parts.The first part included PBC patients with LS measured by 2D-SWE and liver biopsy results at the time of diagnosis.The degree of liver fibrosis and inflammatory activity were staged according to the Scheuer scoring system.The second part included PBC patients with LS values and esophagogastroduodenoscopy(EGD)results.According to the Baveno VI guidelines for portal hypertension,low-risk varices were defined as Grade I varices,and high-risk varices were defined as Grade I varices with red sign,Grade II and III varices.And the third part included PBC patients with LS values at baseline and followed up for at least 6 months.Clinical data of these patients were collected for analysis.The following criteria were used to evaluate the response to UDCA treatment in PBC patients:ALP>1.5×ULN;AST>1.5 x ULN;Bilirubin>ULN indicates poor response,otherwise complete response.Descriptive statistics were expressed as median and interquartile range from 25th to 75th quartile,IQR.Qualitative variables were expressed as number(percentages).Comparisons between quantitative variables were estimated by using Kruskal-Wallis or Mann-Whitney test,when appropriate.Receiver operating characteristic curves(ROCs)of relationship between LS value and the degree of liver fibrosis and varices were drawn.Optimal cutoff values were identified from the Youden’s Index.The cutoff values of LS for ruling out and ruling in different degree of liver fibrosis and all-size varices or high-risk varices were defined with>90%sensitivity and>90%specificity,respectively.Areas under the receiver operating characteristic curves(AUROCs)were used to describe the diagnostic efficacy of non-invasive models for evaluating different degree of liver fibrosis and varices and prognosis of PBC patients,then were compared by using De Long test.Z test was used to compare the effect of G0-G1subgroup and G2-G4 subgroup on the degree of liver fibrosis diagnosed by LS values.A criteria of varices missed rate less than 10%and a high-risk varices missed rate less than 5%was considered the best criteria for EGD saving.Univariate and multivariate logistic regression analyses were used to analyze the independent influencing factors for advanced liver fibrosis,all-size varices and high-risk varices,and poor response to UDCA in PBC patients.P values<0.05 were considered statistically significant.Results:1.In the first part,234 PBC patients with LS values measured by 2D-SWE and liver biopsy results were collected.Finally,205 patients met the inclusion and exclusion criteria for analysis.The LS values(r=0.690,P<0.0001),APRI score(r=0.280,P<0.0001),FIB-4 index(r=0.406,P<0.0001)and AST/ALT ratio(r=0.319,P<0.0001)were all positively correlated with liver fibrosis stage,and there were statistically significant differences between different liver fibrosis stages(all P<0.0001).The AUROCs for significant fibrosis(S≥2),advanced fibrosis(S≥3),and cirrhosis(S=4)were 0.79(95%CI:0.72-0.84),0.95(95%CI:0.91-0.97),and0.97(95%CI:0.94-0.99),respectively.The optimal cutoff values were 7.9k Pa,11.6k Pa,and 13.9k Pa,respectively.Compared with serological assessment models of liver fibrosis such as APRI score,FIB-4 index and AST/ALT ratio,LS values were more effective in the diagnosis of different degrees of liver fibrosis with statistical difference(all P<0.05).There was no statistical significance in the diagnosis of significant fibrosis,advanced fibrosis,or cirrhosis in PBC patients by the LS values in the G0-G1 subgroup and the G2-G4 subgroup(AUROC:0.74 vs.0.81,1.00 vs.0.94,1.00 vs.0.96,all P>0.05).PLT(odds ratio(OR)=0.98,95%CI:0.97-1.00)and LS value(OR=1.91,95%CI:1.51-2.41)were independent risk factors for diagnosing S≥3.The accuracy of LS values in predicting significant liver fibrosis was97/121(80.17%),predicting advanced liver fibrosis was 38/42(90.48%),predicting liver cirrhosis was 21/22(95.45%),and the overall accuracy of predicting liver fibrosis was 109/199(57.29%).2.In the second part,324 PBC patients with LS values measured by 2D-SWE and results of esophagogastroduodenoscopy were collected.Finally,248 patients met the inclusion and exclusion criteria for analysis.The LS value measured by 2D-SWE showed promising predictive ability in detecting gastroesophageal varices(AUROC=0.84,95%CI:0.79-0.88)and high-risk varices(AUROC=0.87,95%CI:0.82-0.91).When detecting all-size varices,there were no statistically significant difference between AUROCs of LS values and FIB-4(0.80,95%CI:0.74-0.84)(P=0.18),Mayo risk score(0.81,95%CI:0.75-0.86)(P=0.40),NVP score(0.86,95%CI:0.81-0.90)(P=0.34),PLT(0.79,95%CI:0.74-0.84)(P=0.20)or ALB(0.79,95%CI:0.73-0.84)(P=0.12).But AUROC of LS values was significantly higher than that of APRI(0.70,95%CI:0.64-0.75)(P=0.0002).When detecting high-risk varices,AUROC of LS values was significantly higher than that of APRI(0.70,95%CI:0.63-0.75)(P<0.0001),FIB-4(0.78,95%CI:0.72-0.83)(P=0.0038)and PLT(0.75,95%CI:0.69-0.80)(P<0.0001).But there were no statistically significant difference between AUROCs of LS values and Mayo risk score(0.84,95%CI:0.79-0.88)(P=0.30),NVP score(0.88,95%CI:0.83-0.92)(P=0.64)or ALB(0.54,95%CI:0.45-0.61)(P=0.34).PLT(OR=0.98,95%CI:0.98-0.99;P<0.0001),ALB(OR=0.85,95%CI:0.77-0.95;P=0.003),GLB(OR=1.08,95%CI:1.00-1.16;P=0.04),GGT(OR=0.998,95%CI:0.995-1.000;P=0.04),CR(OR=1.03,95%CI:1.00-1.21;P=0.03)and LS values(OR=1.12,95%CI:1.03-1.21;P=0.005)were independent risk factors for varices in PBC patients.PLT(OR=0.99,95%CI:0.98 1.00;P=0.002),ALB(OR=0.82,95%CI:0.74-0.91;P<0.0001)and LS values(OR=1.09,95%CI:0.98-1.00;P=0.01)were independent risk factors for high risk varices in PBC patients.The criteria based on LS value and PLT value can be used for screening varices in PBC patients.The criteria of LS value<20.0 k Pa and PLT>110×10~9/L saved relatively high rate of EGD screening(44.76%)and could be the best criteria for avoiding EGD to screening varices in PBC patients.PLT>110×10~9/L and ALB>40 g/L saved higher rate of EGD screening(39.11%)than NVP score<0.3,NVP score<0.5,PLT>140×10~9/L and Mayo risk score<4.5.3.In the third part,507 PBC patients were collected.The final 299 patients who had LS at baseline and were followed up for at least 6 months met the inclusion and exclusion criteria,including 250 PBC patients who were followed up for at least 12months.The positive rate of AMA in PBC patients with at least 6 months follow-up was 67.22%,which was significantly lower than that reported in other studies.The poor response to UDCA rate of PBC patients was 43.14%.Compared with the response group,the levels of TB,DB,GLB,AST,ALT,ALP,GGT,TBA,Ig M and CHOL in patients with poor response group were higher,while the levels of Hb,WBC and ALB were lower,and there were no statistical differences in other indicators.Among PBC patients followed up for at least 12 months,the rates of poor response to UDCA at 3,6,and 12 months were 46.0%,42.8%,and 34.4%,respectively.The rate of poor response at 12 months was not statistically different from that at 6 months(P=0.054),but was statistically significant from that at 3 months(P=0.0082).ALP(0.006),TB(P=0.012)and LS values(P=0.019)were independent risk factors for drug non-response in PBC patients after 12 months of UDCA treatment.This result is consistent with the findings of PBC patients treated with UDCA for 6 months.Based on logistic regression analysis result of UDCA therapy for six months,the Huaxi model with ALP,TB and LS values could be used to evaluate the non-response of PBC patients after UDCA treatment.The predictive efficacy of Huaxi score was higher than that of ALBI score,European score,Globe score,Mayo score and Newcastle score,with statistically difference(all P<0.05).Conclusion:The LS values measured by 2D-SWE and serological non-invasive evaluation models for liver fibrosis such as APRI score,FIB-4 index and AST/ALT ratio were positively correlated with the degree of liver fibrosis in PBC patients.LS values have better diagnostic efficacy than the liver fibrosis serological models in the diagnosis of the degree and stage of liver fibrosis in PBC patients,especially in advanced liver fibrosis and cirrhosis.The degree of inflammation had no effect on the diagnostic efficacy of LS values.2D-SWE is an accurate,convenient,reliable non-invasive method to assess the degree of liver fibrosis in PBC patients and has broad clinical application prospects.2D-SWE is also an effective non-invasive method to predict the presence of gastroesophageal varices and high-risk gastroesophageal varices needed treatment in PBC patients.The criteria based on LS value and PLT value can be used for screening varices in PBC patients.The criteria of LS value<20.0 k Pa and PLT>110×10~9/L could be the best criteria for avoiding EGD to screening varices.When there is no 2D-SWE results,the criteria of PLT>110×10~9/L and ALB>40 g/L can be used as a potential method to avoid EGD screening in patients with PBC.LS value can be used as one of the indicators to predict poor response to UDCA treatment in PBC patients.ALP,TB,and LS values are independent risk factors for poor response to UDCA.The Huaxi score containing these three indicators can be used to predict response to UDCA in PBC patients.