Assessment of the utility of two-dimensional shear wave elastography and superb microvascular imaging in postoperative patients with biliary atresia

Assessment of the utility of two-dimensional shear wave elastography and superb microvascular imaging in postoperative patients with biliary atresia | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Assessment of the utility of two-dimensional shear wave elastography and superb microvascular imaging in postoperative patients with biliary atresia Satoru Oita, Miki Toma, Koji Hirono, Takayuki Masuko, Toru Shimizu, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4841588/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 08 Aug, 2024 Read the published version in Pediatric Surgery International → Version 1 posted 7 You are reading this latest preprint version Abstract Purpose We aimed to investigate whether prediction of liver fibrosis using two-dimensional shear wave elastography (2D-SWE) and vascular tree grading using superb microvascular imaging (SMI) are useful for postoperative follow-up in patients with biliary atresia (BA). Methods We retrospectively collected data from medical records of 134 patients who underwent ultrasound examination with 2D-SWE or SMI, including 13 postoperative patients with BA and 121 non-BA patients. We investigated the distribution of liver stiffness values with SWE and vascular tree grading with SMI and evaluated correlations between these findings and biochemical indices of liver fibrosis in postoperative BA patients. Results The SWE values of the BA group were not significantly different from that of any other disease groups in non-BA patients. In postoperative BA patients, SWE values correlated significantly with aspartate aminotransferase to platelet ratio index (Spearman rank correlation coefficient [r s ] = 0.6380, p = 0.0256) and with the Fib-4 index (r s =0.6526, p = 0.0214). SMI vascular tree grading of the BA group was significantly higher than that of the choledochal cyst group (p = 0.0008) and other hepatobiliary disorder group (p = 0.0030). In postoperative BA patients, SMI vascular tree grading was not positively correlated with any biochemical marker of fibrosis. Conclusion 2D-SWE appears to be useful for follow-up in postoperative BA patients. Biliary atresia Shear wave elastography Superb microvascular imaging Ultrasound Liver fibrosis Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Biliary atresia (BA) is a devastating neonatal cholangiopathy characterized by inflammation, progressive fibrosis, and obstruction of both the extra- and intrahepatic bile ducts, leading to end-stage liver failure [ 1 – 3 ]. Even in patients who undergo successful hepatoportoenterostomy, more than half eventually develop cirrhosis and require liver transplantation before adulthood [ 4 , 5 ]. Assessment of liver fibrosis plays an important role in the prediction of survival following hepatoportoenterostomy. Liver biopsy remains the current standard for assessing liver fibrosis, despite limitations in its accuracy and adverse effects associated with the procedure. Considering that iterative liver biopsies are invasive and impractical, noninvasive alternatives are needed [ 6 – 9 ]. Shear wave elastography (SWE) is a noninvasive method to measure liver stiffness. It works by generating shear waves within the tissue and then measuring their propagation speed. Because the speed of propagation is influenced by the tissue’s elasticity, SWE can be used to assess the stiffness or elasticity of tissues. Several groups have addressed the utility of SWE for diagnosis and management of BA [ 10 – 18 ]. SWE can be further classified into transient elastography, point shear wave elastography, and two-dimensional shear wave elastography (2D-SWE) [ 19 , 20 ]. 2D-SWE is integrated into a diagnostic ultrasound system and uses an acoustic radiation force impulse (ARFI) to measure tissue stress [ 21 ]. Therefore, 2D-SWE has advantages: it can use real-time grayscale imaging mode for assessing morphological changes or avoiding vessels and can provide a real-time quantitative map without stress concentration artifacts [ 12 ]. A recent meta-analysis addressed the utility of 2D-SWE for predicting liver fibrosis in patients with BA [ 18 ]. This meta-analysis, including six studies with 470 patients, revealed that 2D-SWE performs well in determining advanced fibrosis and cirrhosis in patients with BA (summary sensitivity and specificity was 88% and 85%, respectively, for advanced fibrosis, and 80% and 82% for cirrhosis). However, in this meta-analysis, only one study (24 patients) assessed patients with BA following hepatoportoenterostomy, whereas the remaining five (446 patients) focused on patients before hepatoportoenterostomy. The authors noted the limitation that the small sample size made it impossible to assess the performance of 2D-SWE in diagnosing liver fibrosis in post-hepatoportoenterostomy patients with BA. The evaluation of 2D-SWE in postoperative patients with BA remains incomplete. Superb microvascular imaging (SMI) is a novel ultrasound Doppler imaging mode that is designed to improve blood flow visualization, especially slow flow signals from microscopic vessels, using advanced noisy signal suppression. SMI allows for the detailed visualization of the vascular structures of lesions without the use of a contrast agent [ 8 , 22 ]. SMI can be performed in two modes: (1) color SMI (cSMI), a color information mode, and (2) monochrome SMI (mSMI), a monochrome mode that improves the sensitivity by subtracting background information [ 23 ]. A few studies have shown that SMI can predict fibrosis stage by detecting vascular changes caused by liver fibrosis [ 22 , 24 , 25 ]. To our knowledge, no report has used SMI to predict fibrosis in BA patients. Tosun and Uslu [ 26 ] reported that both SWE and SMI had good diagnostic performance in determining the degree of liver fibrosis in patients with chronic hepatitis B, and that the efficacy of SMI was better than that of SWE. Moreover, in children, especially infants, accurate measurement using SWE can be technically difficult due to motion artifact caused by respiratory movements or crying. In the present study, we assessed the usefulness of SWE and SMI for predicting liver fibrosis in patients with BA and compared the two techniques. Patients and Methods 1. Study population From September 2017, when we started using SWE and SMI, until October 2023, we collected data from all patients who underwent ultrasound examinations with liver elasticity measurements using SWE or morphological assessments of the liver surface vascular tree using SMI. This included both patients with BA following surgery and non-BA patients. The non-BA patients were collected as a reference group because of the lack of established normal ranges for SWE values and normal SMI findings in postoperative patients with BA and other pediatric cholestatic diseases [ 18 ]. 2. Data collection A retrospective chart review and data collection were performed after receiving institutional review board approval. We collected patient characteristics, including sex, age at the time of ultrasound examination, and SWE values or vascular tree grading with SMI. In postoperative BA patients, we also collected age at the time of hepatoportoenterostomy and laboratory parameters as biochemical markers of fibrosis. The collected data included platelet count (Plt), serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transferase P (γ-GTP), total bilirubin (T-Bil), direct bilirubin (D-Bil), prothrombin time, and albumin (Alb) levels. We then calculated the AST to platelet ratio index (APRi), Fib-4 index, and BA liver fibrosis (BALF) score or infant BA liver fibrosis (iBALF) score as follows: APRi = (AST [U/L]/upper limit of normal)/(platelet count [10 9 /L]) × 100 [ 27 ] Fib-4 index = age (years) × AST [U/L]/(platelets [10 9 /L] × (ALT [U/L])1/2) [ 28 ] BALF score = 7.196 + 1.438 × Log e [T-Bil (mg/dL)] + 0.434 × Log e [γ-GTP (IU/L)] – 3.491 × Log e [Alb (g/dL)] – 0.670 × Log e [age (years)] [ 29 ] iBALF score = 8 + 1.185 × Log e [T-Bil (mg/dL)] – 1.882 × Log e [Plt (10 9 /L)] + 1.093 × Log e [age (days)] [ 30 ] A serum AST level of 31 IU/L was used as the upper limit of normal. APRi scores of < 0.5 and < 1.0 have been found to have negative predictive values of 90% for hepatic fibrosis and 100% for cirrhosis, respectively [ 27 ]. The Fib-4 index had been shown to predict portal hypertension at diagnosis in children with cystic fibrosis liver disease [ 28 ]. BALF and iBALF scores are new fibrosis scores specifically for BA patients developed by Tomita et al. [ 29 , 30 ] using a retrospective analysis of native liver histology examinations of patients with BA. We utilized the BALF score for patients ≥ 1 year old, and the iBALF score for patients < 1 year old. Direct serum fibrosis markers included serum levels of hyaluronic acid and type IV collagen. The biochemical serum fibrosis marker results and ultrasound examination were typically obtained on the same day. If the examinations were not performed on the same day, we accepted results obtained within 30 days of each other. 3. Ultrasound examination All ultrasound examinations were performed by two sonographers using an Aplio i800 ultrasound system (Canon Medical Systems Corp., Otawara, Japan) equipped with a convex transducer (5.5 MHz) or a linear transducer (9.0 MHz). Liver elasticity measurements were obtained via the intercostal/subcostal approach performed during a short breath, if possible, or else during one normal, gentle breathing cycle. The target region for measurement was usually set in segment 5, which is the most common region for liver biopsy. Elasticity results were expressed in kilopascals (kPa). The most important parameter for assessing the reliability of SWE evaluation is the interquartile range (IQR), which reflects the variability of the validated measures. Only measurements with IQR/median ratios ≤ 0.3, as calculated by the machine, were considered acceptable [ 26 , 31 ]. SMI images were obtained from the peripheral liver part of the right anterior sector, approximately 2 cm below the liver capsule [ 24 , 26 ]. The vascular tree was qualitatively evaluated using mSMI. We graded the changes of vascular tree structures and divided results into four main classes with reference to previous studies [ 22 , 24 , 25 ]. According to this classification, the normal vascular tree structure was defined as Grade 0; thinning in the distal branches of the vascular tree as Grade 1; marked tortuosity in distal branches as Grade 2; blunting of distal small branches as Grade 3; and, in addition to the findings of Grade 3, blunting of larger branches as Grade 4 [ 24 ]. 4. Statistical analysis Statistical analysis was performed using JMP Pro 16.0.0 software (SAS Institute Inc., Cary, NC, USA). If multiple measurements were performed on the same patient, the data to be used were determined in the following order of priority: (1) fewer deficient data, and (2) the most recent examination date (i.e., when more proficiency in the technique had been obtained). We used non-parametric tests (Wilcoxon test or Kruskal-Wallis test) to compare multiple groups. For post hoc multiple comparisons, we used the Steel-Dwass test. Correlations for continuous variables were evaluated using the Spearman rank correlation coefficient. A p-value < 0.05 was considered statistically significant. 5. Compliance with ethical standards This study was performed in line with the principles of the Declaration of Helsinki. This study was approved by the Institutional Review Board of Ibaraki Children’s Hospital (approval number 2023IRB-39). Results 1. Patient population Between September 2017 and October 2023, 134 patients (median age, 10 years; range, 0 to 30 years) underwent ultrasound examination with SWE or SMI, including 13 postoperative BA patients and 121 non-BA patients. In the BA patients, 12 patients underwent SWE, and all 13 patients underwent SMI. In non-BA patients, 108 patients underwent SWE, 54 patients underwent SMI, and 43 patients underwent both SWE and SMI. We broadly divided non-BA patients into following eight groups; (1) choledochal cyst (n=19); (2) fatty liver (n=28); (3) other hepatobiliary disorder (n=38: 5 cases of parenteral nutrition-associated liver disease; 4 cases of hepatitis B; 3 cases of undiagnosed neonatal cholestasis; 2 cases each of autoimmune hepatitis, Alagille syndrome, hepatic fibrosis, non-syndromic paucity of interlobular bile ducts, drug-induced liver injury; 1 case each of hepatitis C, progressive familial intrahepatic cholestasis type 1, primary sclerosing cholangitis, portosystemic shunt, thrombotic thrombocytopenic purpura, traumatic liver injury, post-liver transplantation, Dubin-Johnson syndrome, traumatic stricture of the distal common bile duct, Epstein-Barr virus infectious mononucleosis; and 6 cases of undiagnosed liver dysfunction); (4) metabolic disorder (n=4: 2 cases of glycogen storage disease and 1 case each of ornithine transcarbamylase deficiency and Bardet-Biedl syndrome; (5) cardiovascular disorders (n=23: 22 cases of Fontan-associated liver disease [FALD] and 1 case of idiopathic pulmonary arterial hypertension/heritable pulmonary arterial hypertension; (6) hematologic disorder (n=6: 4 cases of graft-versus-host disease and 1 case each of spherocytosis and congenital erythropoietic porphyria; (7) renal disorders (n=2, 1 case each of multicystic dysplastic kidney and renal hypoplasia); and (8) endocrine disorders (n=1, 1 case of autoimmune thyroiditis). Demographic data of patients are available in Online Resource 1. Out of 13 BA patients, 4 patients were clinically determined to have an indication for liver transplantation. All ultrasound examinations in BA patients were performed before liver transplantation in this study. 2. Liver stiffness values and vascular tree grading distribution in BA patients and non-BA patients First, we compared the distribution of liver elasticity values and vascular tree grading for the BA group with each disease group, because the normal range of liver stiffness values and vascular tree grading in postoperative patients with BA has not yet been clearly established. Fig. 1 shows the distribution of liver elasticity values with SWE for each disease group. The SWE values differed significantly across disease groups, as demonstrated by the Kruskal-Wallis test (p<0.0001). However, median SWE values did not differ significantly between the BA group and any of the other groups by pairwise comparisons using the Steel-Dwass test. Few patients in the BA group had high SWE values. Interestingly, significant differences were found between the cardiovascular disorder group and the fatty liver group (p=0.0001), the other hepatobiliary disorder group (p=0.0056), and the choledochal cyst group (p=0.0004). Fig. 2 shows the distribution of vascular tree grading with SMI for each disease group. The SMI grading was significantly different across disease groups (p=0.0006), as demonstrated by the Kruskal-Wallis test. The SMI grading of the BA group was significantly higher than that of the choledochal cyst group (p=0.0008) and the other hepatobiliary disorder group (p=0.0030), as revealed by pairwise comparisons using the Steel-Dwass test. All BA patients except one had an SMI grade of 1 or above. No significant differences were found for the other disease groups. 3. Correlation between liver stiffness value with SWE or vascular tree grading with SMI and biochemical indices of liver fibrosis. Next, we focused on the 13 BA patients and investigated the correlation between liver stiffness values with SWE or vascular tree grading with SMI and biochemical indices of liver fibrosis, including APRi, Fib-4 index, BALF/iBALF score, serum type IV collagen level, and serum hyaluronic acid level. Table 1 shows the demographic data and laboratory parameters of BA patients. Fig. 3 shows the distribution of liver stiffness values with SWE and biochemical indices of liver fibrosis. The median SWE value of the BA patients was 4.7 (range: 2.9-12.4) kPa. Eight patients (67%) had a value ≤ 5 kPa and a high probability of being normal [31]. SWE values were significantly positively correlated with APRi (Spearman rank correlation coefficient [r s ]=0.6380, p=0.0256) and Fib4 index (r s =0.6526, p=0.0214) but were not correlated with BALF/iBALF score (r s =0.0244, p=0.9467), type 4 collagen (r s =0.2067, p=0.5667), or hyaluronic acid (r s =0.2073, p=0.5655). Fig. 4 shows the distribution of vascular tree grading score with SMI and biochemical indices of liver fibrosis. The distribution of BA patients by vascular tree grading was as follows: Grade 0: 1 patient (7.7%), Grade 1: 7 patients (53.9%), Grade 2: 3 patients (23.1%), Grade 3: 2 patients (15.4%), and Grade 4: no patients. SMI grading was significantly negatively correlated with BALF/iBALF score (r s =-0.6164, p=0.0434) but was not correlated with APRi (r s =-0.4146, p=0.1590), Fib4 index (r s =0.1025, p=0.7389), type 4 collagen (r s =-0.3887, p=0.2374), or hyaluronic acid (r s =-0.2498, p=0.4589). 4. Predictive value of liver stiffness value with SWE/vascular tree grading with SMI for liver transplantation in BA patients Finally, we evaluated whether liver elasticity with SWE/vascular tree grading with SMI could predict the need for liver transplantation in patients with BA. We divided the BA patients into two groups: patients who had a clinical indication for liver transplantation and those who did not. Subsequently, we compared SWE values and SMI gradings between the two groups. There was no significant different between transplant and non-transplant groups in SWE value (p=0.1250) or SMI grading (p=0.9326). Discussion SWE has been studied extensively in adult liver disease, with studies in pediatric liver disease emerging only recently [32]. The consensus statement for elastography diagnosis was reviewed recently [31]. The consensus panel proposes a vendor-neutral “rule of four” (5, 9, 13, 17 kPa) for the ARFI techniques for viral etiologies and non-alcoholic fatty liver disease: a value ≤ 5 kPa (1.3 m/sec) has high probability of being normal; a value < 9 kPa (1.7 m/sec) rules out compensated advanced chronic liver disease (cACLD) in the absence of other known clinical signs; values 9–13 kPa (1.7–2.1 m/sec) are suggestive of cACLD but may need further testing for confirmation; values > 13 kPa (2.1 m/sec) rule in cACLD; and values > 17 kPa (2.4 m/sec) are suggestive of clinically significant portal hypertension [31]. For other causes, such as alcoholic hepatitis, primary biliary cirrhosis, Wilson disease, autoimmune hepatitis, sclerosing cholangitis, and drug-induced liver disease, there is insufficient data to draw a conclusion [31]. In our data, although the cardiovascular disorders group showed a higher level, BA did not show significantly higher levels compared to other groups, with most cases having values < 9 kPa. Recommendations for performing liver stiffness measurements using the ARFI technique include the following points as major potential confounding factors: (1) liver severe inflammation indicated by AST and/or ALT elevation > 5 times the upper limit of normal; (2) obstructive cholestasis; (3) liver congestion; (4) acute hepatitis; and (5) infiltrative liver disease [31]. These factors all lead to overestimation of the stage of fibrosis [31]. Depending on these factors, the patient’s condition at the examination would influence the SWE value. The evaluation of SWE values needs to take these factors into account. In BA patients post-hepatoportoenterostomy, a recent meta-analysis by Wagner et al. [17] revealed that SWE has high diagnostic performance for evaluating cirrhosis. The study conducted by Chen et al. [10] (including 24 patients) is the only study to investigate the predictive accuracy of 2D-SWE in liver fibrosis in postoperative BA patients, not in preoperative BA patients. They revealed that APRi scores and SWE values were positively correlated with fibrosis stage of liver biopsy evaluated by METAVIR score [10]. They then calculated the areas under the receiver operating characteristic curves, sensitivity, and specificity of 2D-SWE for advanced fibrosis, which were 0.81, 77.8%, and 80%, respectively. In the present study, the 2D-SWE values in BA patients post-hepatoportoenterostomy were positively correlated with some fibrotic markers (APRi, Fib-4 index). 2D-SWE is also considered a useful tool for monitoring postoperative liver fibrosis in BA patients. However, the BALF/iBALF score did not correlate with the 2D-SWE value, unlike APRi and Fib-4 index in the current study. The BALF score is the first non-invasive fibrosis marker developed for post-surgical BA patients based on liver histology findings, including the findings of percutaneous needle biopsy examinations obtained from patients with good postoperative courses [29]. It is necessary to continue exploring which indicators reflect the unique pathology of postoperative BA patients and which indicators are optimal for predicting outcomes. Chen et al. [10] reported cut-off values of 2D-SWE for diagnosis of significant fibrosis, advanced fibrosis, and cirrhosis of 9.4, 10.8, and 24.4 kPa, respectively, in postoperative BA patients, whereas another study reported cut-off values of 12.1, 13.5, and 15.7 kPa in preoperative BA patients [10, 12]. These results may be influenced by obstructive cholestasis. A cut-off value for SWE to diagnose advanced fibrosis or cirrhosis in post-surgical BA patients must be established separately from that in preoperative patients or in patients with other cholestatic liver disease, and this will require further study. In this study, only one case had an SWE value greater than 9.4 kPa. To our knowledge, this is the first series investigating the performance of SMI for the evaluation of liver fibrosis in patients with BA. In the present study, SMI grade in the BA group was significantly higher than that of the choledochal cyst group and the other hepatobiliary disorder group, despite no significant difference in SWE values compared with the other disease groups. All BA patients except one was Grade 1 or above, including those without high SWE values. In contrast to previous reports in patients with chronic hepatitis [8, 22, 24, 26], we could not find a positive correlation with several fibrosis indices in BA patients. Although the BALF/iBALF scores showed a significant negative correlation with SMI grade, it is difficult to hypothesize scenarios where the elasticity of the liver decreases as vascular findings worsen, or where vascular observations improve as the elasticity of the liver increases. It is reasonable to interpret this result as an error due to factors such as sample size, causing a lack of positive correlation rather than a presence of negative correlation. Based on these our results, we discuss the following considerations. In chronic fibrotic disease, portal vein branches are distorted and compressed by connective tissue and an increased number of tortuous arterioles surround cirrhotic nodules [33]. Vascularity is decreased and the intrahepatic vessels typically show coiling and corkscrewing [34]. Because SMI is able to demonstrate changes of the vascular tree structure that occur in the cirrhotic liver, including thinning and increased tortuosity of peripheral vessels as well as blunting at various levels of the vascular tree, SMI can distinguish mild and severe forms of fibrosis [24]. In the context of BA, Masuya et al. reported narrowing of the portal veins with an increase in the number of capillaries, and medial hypertrophy with an increase in the number of endothelial cells in the hepatic arteries [35]. They also reported that portal vein diameter was not significantly correlated with the degree of fibrosis [35]. From these results, Masuya et al. conclude that these vascular lesions are considered essential in BA and may not occur secondary to liver fibrosis. Moreover, Harumatsu et al. [36] reported that microvascular proliferation of the portal vein branches in the liver of BA patients is associated with a better long‑term clinical outcome. Analyzing our data in the present study, SWE value and SMI grading showed a positive correlation in patients with FALD but not in those with BA (Online Resource 1). The changes in the vascular tree structure demonstrated in the liver of BA patients may be pathologically different from those that occur in cirrhotic chronic fibrotic liver disease such as chronic hepatitis. Therefore, SMI may not be suitable for long-term follow-up of BA patients because vascular tree grading does not reflect liver fibrosis (unlike chronic fibrotic liver disease). In the present study, all BA patients except one was Grade 1 or above, including those without high SWE values. This finding may reflect the hypothesis suggested by Masuya et al. These results are interesting in understanding the etiology of BA and the pathophysiology leading to postoperative cirrhosis. SMI findings of the vascular tree may have potential application in the diagnosis of BA. There are several limitations in the present study. First, this is a retrospective study with a small sample size and does not include a healthy control group. The comparison groups consisted of diverse patients with various diseases. Patient condition (including those in the BA group), such as age and the degree of their cirrhosis, varied. Second, the lack of pathological findings on the liver biopsy performed at the same time as ultrasound examination is a major limitation. It is very challenging to repeat postsurgical liver biopsy examinations to monitor progression of fibrosis in pediatric clinical practice. To answer the clinical question of how to noninvasively and appropriately predict liver condition and identify those patients who need a transplant in postoperative patients with BA, well-designed prospective observational studies are necessary. This involves setting appropriate normal and cholestasis controls, standardizing the methods and timing of measurements, collecting liver biopsy samples, and obtaining longitudinal data, among other considerations. Conclusion We conducted a retrospective study to investigate whether liver stiffness measurement using 2D-SWE and vascular tree grading using SMI were associated with liver fibrosis in postoperative BA patients. SWE values in BA patients post-hepatoportoenterostomy were positively correlated with APRi and Fib-4 index; however, BALF/iBALF score was not correlated with 2D-SWE values in this study. 2D-SWE appears to be an informative tool for following liver fibrosis in postoperative BA patients, but these findings need to be carefully examined in a cohort specifically focused on this group. SMI vascular tree grading in BA patients post-hepatoportoenterostomy was significantly higher than that of the choledochal cyst group and the other hepatobiliary disorder group but was not positively correlated with any marker of liver fibrosis. Changes in the vascular tree structure demonstrated in the liver of patients with BA may be pathologically different from those that occur in patients with chronic hepatitis, as previously reported. Further detailed prospective studies with appropriate controls and a larger sample size are warranted. Declarations 1. Funding and competing interests This work received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. None of the authors have any relevant financial or non-financial interests to disclose. 2. Ethics approval This study was performed in line with the principles of the Declaration of Helsinki. 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World J Gastroenterol 22:6057–6064. https://doi.org/10.3748/wjg.v22.i26.6057 Gabriel M, Tomczak J, Snoch-Ziółkiewicz M, et al (2016) Comparison of Superb Micro-Vascular Ultrasound Imaging (SMI) and Contrast-Enhanced Ultrasound (CEUS) for Detection of Endoleaks After Endovascular Aneurysm Repair (EVAR). Am J Case Rep 17:43–46. https://doi.org/10.12659/ajcr.895415 Balık AÖ, Kılıçoğlu ZG, Görmez A, Özkara S (2019) Radiology-pathology correlation in staging of liver fibrosis using superb microvascular imaging. Diagn Interv Radiol 25:331–337. https://doi.org/10.5152/dir.2019.18231 Smith GW, Westgaard T, Björn-Hansen R (1971) Hepatic venous angiography in the evaluation of cirrhosis of the liver. Ann Surg 173:469–480. https://doi.org/10.1097/00000658-197104000-00001 Tosun M, Uslu H (2022) Comparison of superb microvascular imaging and shear wave elastography for assessing liver fibrosis in chronic hepatitis B. Ultrasonography 41:394–402. https://doi.org/10.14366/usg.21136 Grieve A, Makin E, Davenport M (2013) Aspartate Aminotransferase-to-Platelet ratio index (APRi) in infants with biliary atresia: prognostic value at presentation. J Pediatr Surg 48:789–795. https://doi.org/10.1016/j.jpedsurg.2012.10.010 Leung DH, Khan M, Minard CG, et al (2015) Aspartate aminotransferase to platelet ratio and fibrosis-4 as biomarkers in biopsy-validated pediatric cystic fibrosis liver disease. Hepatology 62:1576–1583. https://doi.org/10.1002/hep.28016 Tomita H, Masugi Y, Hoshino K, et al (2014) Long-term native liver fibrosis in biliary atresia: development of a novel scoring system using histology and standard liver tests. J Hepatol 60:1242–1248. https://doi.org/10.1016/j.jhep.2014.01.028 Tomita H, Fuchimoto Y, Fujino A, et al (2015) Development and Validation of a Novel Fibrosis Marker in Biliary Atresia during Infancy. Clin Transl Gastroenterol 6:e127. https://doi.org/10.1038/ctg.2015.55 Barr RG, Wilson SR, Rubens D, et al (2020) Update to the Society of Radiologists in Ultrasound Liver Elastography Consensus Statement. Radiology 296:263–274. https://doi.org/10.1148/radiol.2020192437 Thumar V, Squires JH, Spicer PJ, et al (2018) Ultrasound Elastography Applications in Pediatrics. Ultrasound Q 34:199–205. https://doi.org/10.1097/RUQ.0000000000000379 Yamamoto T, Kobayashi T, Phillips MJ (1984) Perinodular arteriolar plexus in liver cirrhosis. Scanning electron microscopy of microvascular casts. Liver 4:50–54. https://doi.org/10.1111/j.1600-0676.1984.tb00907.x Bosniak MA, Phanthumachinda P (1966) Value of arteriography in the study of hepatic disease. Am J Surg 112:348–355. https://doi.org/10.1016/0002-9610(66)90202-9 Masuya R, Muraji T, Ohtani H, et al (2019) Morphometric demonstration of portal vein stenosis and hepatic arterial medial hypertrophy in patients with biliary atresia. Pediatr Surg Int 35:529–537. https://doi.org/10.1007/s00383-019-04459-4 Harumatsu T, Muraji T, Masuya R, et al (2019) Microvascular proliferation of the portal vein branches in the liver of biliary atresia patients at Kasai operation is associated with a better long-term clinical outcome. Pediatr Surg Int 35:1437–1441. https://doi.org/10.1007/s00383-019-04579-x Tables Table 1: Baseline characteristics of patients with biliary atresia Variable Value (n=13) Sex (female/male) 9:4 Age at hepatoportoenterostomy (days) 54 (30–83) Age at examination (years) 7 (0–21) Plt (×10 9 /L) 190 (78–471) AST (U/L) 31 (13–424) ALT (U/L) 48 (10–419) γ-GTP (U/L) 47 (9–1286) T-Bil (mg/dL) 0.7 (0.4–3.1) D-Bil (mg/dL) 0.1 (0–1.5) Alb (g/dL) 4.2 (2.7–4.8) PT (%) 89 (70–158) Data are shown as median (minimum–maximum). Plt: platelet count; AST: aspartate aminotransferase; ALT: alanine aminotransferase; γ-GTP: gamma glutamyl transferase P; T-Bil: total bilirubin; D-Bil: direct bilirubin; Alb: albumin; PT: prothrombin time. Additional Declarations No competing interests reported. Supplementary Files OnlineResource1.pdf Online Resource 1: Demographic data of all patients *Data are shown as median (minimum–maximum). OnlineResource2.jpeg Online Resource 2: Correlation (Spearman correlation coefficient, r s ) between liver elasticity (kPa) and vascular tree grading in (a) BA patients (r s =-0.2594, p=0.4159), and (b) FALD patients (r s =0.5999, p=0.0181). BA: biliary atresia, FALD: Fontan-associated liver disease Cite Share Download PDF Status: Published Journal Publication published 08 Aug, 2024 Read the published version in Pediatric Surgery International → Version 1 posted Editorial decision: Accepted 02 Aug, 2024 Reviews received at journal 02 Aug, 2024 Reviewers agreed at journal 02 Aug, 2024 Reviewers invited by journal 02 Aug, 2024 Editor assigned by journal 02 Aug, 2024 Submission checks completed at journal 02 Aug, 2024 First submitted to journal 01 Aug, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4841588","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":335132803,"identity":"2f7cd003-272b-453e-a756-ed191b049035","order_by":0,"name":"Satoru Oita","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzElEQVRIiWNgGAWjYDAC+QMMBxIMbORA7AMPiNIiwcB44ENBmjFYSwKRWpgPzvhwOLEBxCFKi/zs7oTDPAaH0+eHHX4ItMVOTreBgBbGOWc3ALWk5268nWYA1JJsbHaAgBZmhlyQFuvcjbMTQFoOJG4jpIUNooU53XB2+gfitPBI5G44OMPAOUFeOodIWyR4zm448MEgzXCDdE4BMIKI8It8e+/mDwl/bOTlZ6dv/vChwk6OoBY4MACrNCBWOdi6BlJUj4JRMApGwYgCAKabSu7SMdi5AAAAAElFTkSuQmCC","orcid":"","institution":"Ibaraki Children’s Hospital","correspondingAuthor":true,"prefix":"","firstName":"Satoru","middleName":"","lastName":"Oita","suffix":""},{"id":335132804,"identity":"07db1e3d-617d-4b5b-9c98-393a23eb6345","order_by":1,"name":"Miki Toma","email":"","orcid":"","institution":"Ibaraki Children’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Miki","middleName":"","lastName":"Toma","suffix":""},{"id":335132805,"identity":"d0b654b9-6b10-4daf-b578-c27d073b1638","order_by":2,"name":"Koji Hirono","email":"","orcid":"","institution":"Ibaraki Children’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Koji","middleName":"","lastName":"Hirono","suffix":""},{"id":335132807,"identity":"4486a7f5-8304-4890-95ba-0a1761fa157d","order_by":3,"name":"Takayuki Masuko","email":"","orcid":"","institution":"Ibaraki Children’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Takayuki","middleName":"","lastName":"Masuko","suffix":""},{"id":335132809,"identity":"0f55f3fa-fcdf-48ed-95a1-f53eb4d0c712","order_by":4,"name":"Toru Shimizu","email":"","orcid":"","institution":"Ibaraki Children’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Toru","middleName":"","lastName":"Shimizu","suffix":""},{"id":335132813,"identity":"c5b60982-d384-4f93-a309-4bbe3ed704f4","order_by":5,"name":"Sakika Shimizu","email":"","orcid":"","institution":"Ibaraki Children’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Sakika","middleName":"","lastName":"Shimizu","suffix":""},{"id":335132814,"identity":"bb6807dc-867e-4d13-bb38-ed69f597a62f","order_by":6,"name":"Kojiro Miyajima","email":"","orcid":"","institution":"Ibaraki Children’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kojiro","middleName":"","lastName":"Miyajima","suffix":""},{"id":335132815,"identity":"851d3298-daad-4152-849f-79fa0ceea9c4","order_by":7,"name":"Nobuyoshi Asai","email":"","orcid":"","institution":"Ibaraki Children’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Nobuyoshi","middleName":"","lastName":"Asai","suffix":""},{"id":335132817,"identity":"e2721d61-eb00-4aeb-9e1f-65aa728a73fc","order_by":8,"name":"Toshihiro Yanai","email":"","orcid":"","institution":"Ibaraki Children’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Toshihiro","middleName":"","lastName":"Yanai","suffix":""}],"badges":[],"createdAt":"2024-08-01 10:53:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4841588/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4841588/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00383-024-05804-y","type":"published","date":"2024-08-08T15:57:29+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":64146573,"identity":"896bf4a6-45be-41bd-b2c6-52fe6c8272a8","added_by":"auto","created_at":"2024-09-08 19:58:59","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1471333,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution of liver stiffness values assessed using shear wave elastography (SWE) for each disease group.\u003c/p\u003e\n\u003cp\u003e** p\u0026lt;0.01, *** p\u0026lt;0.001 (Steel-Dwass test)\u003c/p\u003e","description":"","filename":"Fig1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4841588/v1/da9ca825c3c52a351362220e.jpeg"},{"id":64145493,"identity":"273b74e9-61a9-4fca-8ec8-3c1fb7e02426","added_by":"auto","created_at":"2024-09-08 19:50:59","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1308893,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution of vascular tree grading assessed using superb microvascular imaging (SMI) for each disease group.\u003c/p\u003e\n\u003cp\u003e** p\u0026lt;0.01, *** p\u0026lt;0.001 (Steel-Dwass test)\u003c/p\u003e","description":"","filename":"Fig2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4841588/v1/080afe5eff12d1533596163f.jpeg"},{"id":64145498,"identity":"ecd4c09b-98dd-4441-8e18-8804912f80b0","added_by":"auto","created_at":"2024-09-08 19:50:59","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1382972,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelation (Spearman correlation coefficient, r\u003csub\u003es\u003c/sub\u003e) between liver stiffness (kPa) and each parameter of fibrosis: (a) APRi (r\u003csub\u003es\u003c/sub\u003e=0.6380, p=0.0256); (b) Fib-4 index (r\u003csub\u003es\u003c/sub\u003e=0.6526, p=0.0214); (c) BALF/iBALF score (r\u003csub\u003es\u003c/sub\u003e=0.0244, p=0.9467); (d) type IV collagen (ng/mL) (r\u003csub\u003es\u003c/sub\u003e=0.2067, p=0.5667); and (e) hyaluronic acid (ng/mL) (r\u003csub\u003es\u003c/sub\u003e=0.2073, p=0.5655).\u003c/p\u003e\n\u003cp\u003eAPRi: aspartate aminotransferase to platelet ratio index; BALF score: biliary atresia liver fibrosis score; iBALF score: infant biliary atresia liver fibrosis score\u003c/p\u003e","description":"","filename":"Fig3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4841588/v1/51ff405cd3610e844aa1230d.jpeg"},{"id":64145495,"identity":"419f8b2e-6171-4f35-acad-046c4e9eda18","added_by":"auto","created_at":"2024-09-08 19:50:59","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1345240,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelation (Spearman correlation coefficient, r\u003csub\u003es\u003c/sub\u003e) between vascular tree grading and each parameter of fibrosis: (a) APRi (r\u003csub\u003es\u003c/sub\u003e=-0.4146, p=0.1590); (b) Fib-4 index (r\u003csub\u003es\u003c/sub\u003e=0.1025, p=0.7389); (c) BALF/iBALF score (r\u003csub\u003es\u003c/sub\u003e=-0.6164, p=0.0434); (d) type IV collagen (ng/mL) (r\u003csub\u003es\u003c/sub\u003e=-0.3887, p=0.2374); and (e) hyaluronic acid (ng/mL) (r\u003csub\u003es\u003c/sub\u003e=-0.2498, p=0.4589).\u003c/p\u003e\n\u003cp\u003eAPRi: aspartate aminotransferase to platelet ratio index; BALF score: biliary atresia liver fibrosis score; iBALF score: infant biliary atresia liver fibrosis score\u003c/p\u003e","description":"","filename":"Fig4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4841588/v1/ae9b2ccf39663d8b76c797f9.jpeg"},{"id":64146574,"identity":"d1618668-5e73-4fa5-acd0-2247c5abb013","added_by":"auto","created_at":"2024-09-08 19:59:05","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":6028787,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4841588/v1/97c16c8e-431a-49a0-9ff7-b40e1232d5b5.pdf"},{"id":64146571,"identity":"7fdcfad8-7ccf-47cb-a7ea-2143990a12bb","added_by":"auto","created_at":"2024-09-08 19:58:59","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":58480,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eOnline Resource 1\u003c/strong\u003e: Demographic data of all patients\u003c/p\u003e\n\u003cp\u003e*Data are shown as median (minimum–maximum).\u003c/p\u003e","description":"","filename":"OnlineResource1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4841588/v1/d2ce93b9202b5bd6ba394e53.pdf"},{"id":64146572,"identity":"ef7e37b9-e40c-4f07-bead-b6bc493a2ad9","added_by":"auto","created_at":"2024-09-08 19:58:59","extension":"jpeg","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":1496653,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eOnline Resource 2\u003c/strong\u003e: Correlation (Spearman correlation coefficient, r\u003csub\u003es\u003c/sub\u003e) between liver elasticity (kPa) and vascular tree grading in (a) BA patients (r\u003csub\u003es\u003c/sub\u003e=-0.2594, p=0.4159), and (b) FALD patients (r\u003csub\u003es\u003c/sub\u003e=0.5999, p=0.0181).\u003c/p\u003e\n\u003cp\u003eBA: biliary atresia, FALD: Fontan-associated liver disease\u003c/p\u003e","description":"","filename":"OnlineResource2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4841588/v1/76aeb563ff458d7af1e99e01.jpeg"}],"financialInterests":"No competing interests reported.","formattedTitle":"Assessment of the utility of two-dimensional shear wave elastography and superb microvascular imaging in postoperative patients with biliary atresia","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBiliary atresia (BA) is a devastating neonatal cholangiopathy characterized by inflammation, progressive fibrosis, and obstruction of both the extra- and intrahepatic bile ducts, leading to end-stage liver failure [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e–\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Even in patients who undergo successful hepatoportoenterostomy, more than half eventually develop cirrhosis and require liver transplantation before adulthood [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAssessment of liver fibrosis plays an important role in the prediction of survival following hepatoportoenterostomy. Liver biopsy remains the current standard for assessing liver fibrosis, despite limitations in its accuracy and adverse effects associated with the procedure. Considering that iterative liver biopsies are invasive and impractical, noninvasive alternatives are needed [\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e–\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eShear wave elastography (SWE) is a noninvasive method to measure liver stiffness. It works by generating shear waves within the tissue and then measuring their propagation speed. Because the speed of propagation is influenced by the tissue’s elasticity, SWE can be used to assess the stiffness or elasticity of tissues. Several groups have addressed the utility of SWE for diagnosis and management of BA [\u003cspan additionalcitationids=\"CR11 CR12 CR13 CR14 CR15 CR16 CR17\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e–\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. SWE can be further classified into transient elastography, point shear wave elastography, and two-dimensional shear wave elastography (2D-SWE) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. 2D-SWE is integrated into a diagnostic ultrasound system and uses an acoustic radiation force impulse (ARFI) to measure tissue stress [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Therefore, 2D-SWE has advantages: it can use real-time grayscale imaging mode for assessing morphological changes or avoiding vessels and can provide a real-time quantitative map without stress concentration artifacts [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. A recent meta-analysis addressed the utility of 2D-SWE for predicting liver fibrosis in patients with BA [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. This meta-analysis, including six studies with 470 patients, revealed that 2D-SWE performs well in determining advanced fibrosis and cirrhosis in patients with BA (summary sensitivity and specificity was 88% and 85%, respectively, for advanced fibrosis, and 80% and 82% for cirrhosis). However, in this meta-analysis, only one study (24 patients) assessed patients with BA following hepatoportoenterostomy, whereas the remaining five (446 patients) focused on patients before hepatoportoenterostomy. The authors noted the limitation that the small sample size made it impossible to assess the performance of 2D-SWE in diagnosing liver fibrosis in post-hepatoportoenterostomy patients with BA. The evaluation of 2D-SWE in postoperative patients with BA remains incomplete.\u003c/p\u003e \u003cp\u003eSuperb microvascular imaging (SMI) is a novel ultrasound Doppler imaging mode that is designed to improve blood flow visualization, especially slow flow signals from microscopic vessels, using advanced noisy signal suppression. SMI allows for the detailed visualization of the vascular structures of lesions without the use of a contrast agent [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. SMI can be performed in two modes: (1) color SMI (cSMI), a color information mode, and (2) monochrome SMI (mSMI), a monochrome mode that improves the sensitivity by subtracting background information [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. A few studies have shown that SMI can predict fibrosis stage by detecting vascular changes caused by liver fibrosis [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. To our knowledge, no report has used SMI to predict fibrosis in BA patients.\u003c/p\u003e \u003cp\u003eTosun and Uslu [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] reported that both SWE and SMI had good diagnostic performance in determining the degree of liver fibrosis in patients with chronic hepatitis B, and that the efficacy of SMI was better than that of SWE. Moreover, in children, especially infants, accurate measurement using SWE can be technically difficult due to motion artifact caused by respiratory movements or crying.\u003c/p\u003e \u003cp\u003eIn the present study, we assessed the usefulness of SWE and SMI for predicting liver fibrosis in patients with BA and compared the two techniques.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003cp\u003e\u003c/p\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003c/div\u003e\u003cp\u003e\u003c/p\u003e \u003c/div\u003e \n\n"},{"header":"Patients and Methods","content":"\u003ch2\u003e1. Study population\u003c/h2\u003e\u003cp\u003eFrom September 2017, when we started using SWE and SMI, until October 2023, we collected data from all patients who underwent ultrasound examinations with liver elasticity measurements using SWE or morphological assessments of the liver surface vascular tree using SMI. This included both patients with BA following surgery and non-BA patients. The non-BA patients were collected as a reference group because of the lack of established normal ranges for SWE values and normal SMI findings in postoperative patients with BA and other pediatric cholestatic diseases [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e\u003ch2\u003e2. Data collection\u003c/h2\u003e\u003cp\u003e A retrospective chart review and data collection were performed after receiving institutional review board approval. We collected patient characteristics, including sex, age at the time of ultrasound examination, and SWE values or vascular tree grading with SMI. In postoperative BA patients, we also collected age at the time of hepatoportoenterostomy and laboratory parameters as biochemical markers of fibrosis. The collected data included platelet count (Plt), serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transferase P (γ-GTP), total bilirubin (T-Bil), direct bilirubin (D-Bil), prothrombin time, and albumin (Alb) levels. We then calculated the AST to platelet ratio index (APRi), Fib-4 index, and BA liver fibrosis (BALF) score or infant BA liver fibrosis (iBALF) score as follows:\u003c/p\u003e\u003cul\u003e \u003cli\u003e \u003cp\u003eAPRi = (AST [U/L]/upper limit of normal)/(platelet count [10\u003csup\u003e9\u003c/sup\u003e/L]) × 100 [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eFib-4 index = age (years) × AST [U/L]/(platelets [10\u003csup\u003e9\u003c/sup\u003e/L] × (ALT [U/L])1/2) [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eBALF score = 7.196 + 1.438 × Log\u003csub\u003ee\u003c/sub\u003e [T-Bil (mg/dL)] + 0.434 × Log\u003csub\u003ee\u003c/sub\u003e [γ-GTP (IU/L)] – 3.491 × Log\u003csub\u003ee\u003c/sub\u003e [Alb (g/dL)] – 0.670 × Log\u003csub\u003ee\u003c/sub\u003e [age (years)] [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eiBALF score = 8 + 1.185 × Log\u003csub\u003ee\u003c/sub\u003e [T-Bil (mg/dL)] – 1.882 × Log\u003csub\u003ee\u003c/sub\u003e [Plt (10\u003csup\u003e9\u003c/sup\u003e/L)] + 1.093 × Log\u003csub\u003ee\u003c/sub\u003e [age (days)] [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e\u003cp\u003eA serum AST level of 31 IU/L was used as the upper limit of normal. APRi scores of \u0026lt; 0.5 and \u0026lt; 1.0 have been found to have negative predictive values of 90% for hepatic fibrosis and 100% for cirrhosis, respectively [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. The Fib-4 index had been shown to predict portal hypertension at diagnosis in children with cystic fibrosis liver disease [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. BALF and iBALF scores are new fibrosis scores specifically for BA patients developed by Tomita et al. [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] using a retrospective analysis of native liver histology examinations of patients with BA. We utilized the BALF score for patients ≥ 1 year old, and the iBALF score for patients \u0026lt; 1 year old.\u003c/p\u003e\u003cp\u003eDirect serum fibrosis markers included serum levels of hyaluronic acid and type IV collagen. The biochemical serum fibrosis marker results and ultrasound examination were typically obtained on the same day. If the examinations were not performed on the same day, we accepted results obtained within 30 days of each other.\u003c/p\u003e\u003ch2\u003e3. Ultrasound examination\u003c/h2\u003e\u003cp\u003eAll ultrasound examinations were performed by two sonographers using an Aplio i800 ultrasound system (Canon Medical Systems Corp., Otawara, Japan) equipped with a convex transducer (5.5 MHz) or a linear transducer (9.0 MHz).\u003c/p\u003e\u003cp\u003e Liver elasticity measurements were obtained via the intercostal/subcostal approach performed during a short breath, if possible, or else during one normal, gentle breathing cycle. The target region for measurement was usually set in segment 5, which is the most common region for liver biopsy. Elasticity results were expressed in kilopascals (kPa). The most important parameter for assessing the reliability of SWE evaluation is the interquartile range (IQR), which reflects the variability of the validated measures. Only measurements with IQR/median ratios ≤ 0.3, as calculated by the machine, were considered acceptable [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eSMI images were obtained from the peripheral liver part of the right anterior sector, approximately 2 cm below the liver capsule [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The vascular tree was qualitatively evaluated using mSMI. We graded the changes of vascular tree structures and divided results into four main classes with reference to previous studies [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. According to this classification, the normal vascular tree structure was defined as Grade 0; thinning in the distal branches of the vascular tree as Grade 1; marked tortuosity in distal branches as Grade 2; blunting of distal small branches as Grade 3; and, in addition to the findings of Grade 3, blunting of larger branches as Grade 4 [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e\u003ch2\u003e4. Statistical analysis\u003c/h2\u003e\u003cp\u003eStatistical analysis was performed using JMP Pro 16.0.0 software (SAS Institute Inc., Cary, NC, USA). If multiple measurements were performed on the same patient, the data to be used were determined in the following order of priority: (1) fewer deficient data, and (2) the most recent examination date (i.e., when more proficiency in the technique had been obtained). We used non-parametric tests (Wilcoxon test or Kruskal-Wallis test) to compare multiple groups. For post hoc multiple comparisons, we used the Steel-Dwass test. Correlations for continuous variables were evaluated using the Spearman rank correlation coefficient. A p-value \u0026lt; 0.05 was considered statistically significant.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e5. Compliance with ethical standards\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eThis study was performed in line with the principles of the Declaration of Helsinki. This study was approved by the Institutional Review Board of Ibaraki Children’s Hospital (approval number 2023IRB-39).\u0026nbsp;\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e1.\u0026nbsp; \u0026nbsp;Patient population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBetween September 2017 and October 2023, 134 patients (median age, 10 years; range, 0 to 30 years) underwent ultrasound examination with SWE or SMI, including 13 postoperative BA patients and 121 non-BA patients. In the BA patients, 12 patients underwent SWE, and all 13 patients underwent SMI. In non-BA patients, 108 patients underwent SWE, 54 patients underwent SMI, and 43 patients underwent both SWE and SMI.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe broadly divided non-BA patients into following eight groups; (1) choledochal cyst (n=19); (2) fatty liver (n=28); (3) other hepatobiliary disorder (n=38: 5 cases of parenteral nutrition-associated liver disease; 4 cases of hepatitis B; 3 cases of undiagnosed neonatal cholestasis; 2 cases each of autoimmune hepatitis, Alagille syndrome, hepatic fibrosis, non-syndromic paucity of interlobular bile ducts, drug-induced liver injury; 1 case each of hepatitis C, progressive familial intrahepatic cholestasis type 1, primary sclerosing cholangitis, portosystemic shunt, thrombotic thrombocytopenic purpura, traumatic liver injury, post-liver transplantation, Dubin-Johnson syndrome, traumatic stricture of the distal common bile duct, Epstein-Barr virus infectious mononucleosis; and 6 cases of undiagnosed liver dysfunction); (4) metabolic disorder (n=4: 2 cases of glycogen storage disease and 1 case each of ornithine transcarbamylase deficiency and Bardet-Biedl syndrome; (5) cardiovascular disorders (n=23: 22 cases of Fontan-associated liver disease [FALD] and 1 case of idiopathic pulmonary arterial hypertension/heritable pulmonary arterial hypertension; (6) hematologic disorder (n=6: 4 cases of graft-versus-host disease and 1 case each of spherocytosis and congenital erythropoietic porphyria; (7) renal disorders (n=2, 1 case each of multicystic dysplastic kidney and renal hypoplasia); and (8) endocrine disorders (n=1, 1 case of autoimmune thyroiditis). Demographic data of patients are available in Online Resource 1.\u003c/p\u003e\n\u003cp\u003eOut of 13 BA patients, 4 patients were clinically determined to have an indication for liver transplantation. All ultrasound examinations in BA patients were performed before liver transplantation in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.\u0026nbsp; \u0026nbsp;Liver stiffness values and vascular tree grading distribution in BA patients and non-BA patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFirst, we compared the distribution of liver elasticity values and vascular tree grading for the BA group with each disease group, because the normal range of liver stiffness values and vascular tree grading in postoperative patients with BA has not yet been clearly established.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFig. 1 shows the distribution of liver elasticity values with SWE for each disease group. The SWE values differed significantly across disease groups, as demonstrated by the Kruskal-Wallis test (p\u0026lt;0.0001). However, median SWE values did not differ significantly between the BA group and any of the other groups by pairwise comparisons using the Steel-Dwass test. Few patients in the BA group had high SWE values. Interestingly, significant differences were found between the cardiovascular disorder group and the fatty liver group (p=0.0001), the other hepatobiliary disorder group (p=0.0056), and the choledochal cyst group (p=0.0004).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFig. 2 shows the distribution of vascular tree grading with SMI for each disease group. The SMI grading was significantly different across disease groups (p=0.0006), as demonstrated by the Kruskal-Wallis test. The SMI grading of the BA group was significantly higher than that of the choledochal cyst group (p=0.0008) and the other hepatobiliary disorder group (p=0.0030), as revealed by pairwise comparisons using the Steel-Dwass test. All BA patients except one had an SMI grade of 1 or above. No significant differences were found for the other disease groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.\u0026nbsp; \u0026nbsp;Correlation between liver stiffness value with SWE or vascular tree grading with SMI and biochemical indices of liver fibrosis.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNext, we focused on the 13 BA patients and investigated the correlation between liver stiffness values with SWE or vascular tree grading with SMI and biochemical indices of liver fibrosis, including APRi, Fib-4 index, BALF/iBALF score, serum type IV collagen level, and serum hyaluronic acid level. Table 1 shows the demographic data and laboratory parameters of BA patients.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFig. 3 shows the distribution of liver stiffness values with SWE and biochemical indices of liver fibrosis. The median SWE value of the BA patients was 4.7 (range: 2.9-12.4) kPa. Eight patients (67%) had a value \u0026le; 5 kPa and a high probability of being normal [31]. SWE values were significantly positively correlated with APRi (Spearman rank correlation coefficient [r\u003csub\u003es\u003c/sub\u003e]=0.6380, p=0.0256) and Fib4 index (r\u003csub\u003es\u003c/sub\u003e=0.6526, p=0.0214) but were not correlated with BALF/iBALF score (r\u003csub\u003es\u003c/sub\u003e=0.0244, p=0.9467), type 4 collagen (r\u003csub\u003es\u003c/sub\u003e=0.2067, p=0.5667), or hyaluronic acid (r\u003csub\u003es\u003c/sub\u003e=0.2073, p=0.5655).\u003c/p\u003e\n\u003cp\u003eFig. 4 shows the distribution of vascular tree grading score with SMI and biochemical indices of liver fibrosis. The distribution of BA patients by vascular tree grading was as follows: Grade 0: 1 patient (7.7%), Grade 1: 7 patients (53.9%), Grade 2: 3 patients (23.1%), Grade 3: 2 patients (15.4%), and Grade 4: no patients. SMI grading was significantly negatively correlated with BALF/iBALF score (r\u003csub\u003es\u003c/sub\u003e=-0.6164, p=0.0434) but was not correlated with APRi (r\u003csub\u003es\u003c/sub\u003e=-0.4146, p=0.1590), Fib4 index (r\u003csub\u003es\u003c/sub\u003e=0.1025, p=0.7389), type 4 collagen (r\u003csub\u003es\u003c/sub\u003e=-0.3887, p=0.2374), or hyaluronic acid (r\u003csub\u003es\u003c/sub\u003e=-0.2498, p=0.4589).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4.\u0026nbsp; \u0026nbsp;Predictive value of liver stiffness value with SWE/vascular tree grading with SMI for liver transplantation in BA patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFinally, we evaluated whether liver elasticity with SWE/vascular tree grading with SMI could predict the need for liver transplantation in patients with BA. We divided the BA patients into two groups: patients who had a clinical indication for liver transplantation and those who did not. Subsequently, we compared SWE values and SMI gradings between the two groups. There was no significant different between transplant and non-transplant groups in SWE value (p=0.1250) or SMI grading (p=0.9326).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eSWE has been studied extensively in adult liver disease, with studies in pediatric liver disease emerging only recently [32]. The consensus statement for elastography diagnosis was reviewed recently [31]. The consensus panel proposes a vendor-neutral \u0026ldquo;rule of four\u0026rdquo; (5, 9, 13, 17 kPa) for the ARFI techniques for viral etiologies and non-alcoholic fatty liver disease: a value\u0026nbsp;\u0026le; 5 kPa (1.3 m/sec) has high probability of being normal; a value \u0026lt; 9 kPa (1.7 m/sec) rules out compensated advanced chronic liver disease (cACLD) in the absence of other known clinical signs; values 9\u0026ndash;13 kPa (1.7\u0026ndash;2.1 m/sec) are suggestive of cACLD but may need further testing for confirmation; values \u0026gt; 13 kPa (2.1 m/sec) rule in cACLD; and values \u0026gt; 17 kPa (2.4 m/sec) are suggestive of clinically significant portal hypertension [31]. For other causes, such as alcoholic hepatitis, primary biliary cirrhosis, Wilson disease, autoimmune hepatitis, sclerosing cholangitis, and drug-induced liver disease, there is insufficient data to draw a conclusion [31]. In our data, although the cardiovascular disorders group showed a higher level, BA did not show significantly higher levels compared to other groups, with most cases having values \u0026lt; 9 kPa.\u003c/p\u003e\n\u003cp\u003eRecommendations for performing liver stiffness measurements using the ARFI technique include the following points as major potential confounding factors: (1) liver severe inflammation indicated by AST and/or ALT elevation \u0026gt; 5 times the upper limit of normal; (2) obstructive cholestasis; (3) liver congestion; (4) acute hepatitis; and (5) infiltrative liver disease [31]. These factors all lead to overestimation of the stage of fibrosis [31]. Depending on these factors, the patient\u0026rsquo;s condition at the examination would influence the SWE value. The evaluation of SWE values needs to take these factors into account.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn BA patients post-hepatoportoenterostomy, a recent meta-analysis by Wagner et al. [17] revealed that SWE has high diagnostic performance for evaluating cirrhosis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe study conducted by Chen et al. [10] (including 24 patients) is the only study to investigate the predictive accuracy of 2D-SWE in liver fibrosis in postoperative BA patients, not in preoperative BA patients. They revealed that APRi scores and SWE values were positively correlated with fibrosis stage of liver biopsy evaluated by METAVIR score [10]. They then calculated the areas under the receiver operating characteristic curves, sensitivity, and specificity of 2D-SWE for advanced fibrosis, which were 0.81, 77.8%, and 80%, respectively. In the present study, the 2D-SWE values in BA patients post-hepatoportoenterostomy were positively correlated with some fibrotic markers (APRi, Fib-4 index). 2D-SWE is also considered a useful tool for monitoring postoperative liver fibrosis in BA patients. However, the BALF/iBALF score did not correlate with the 2D-SWE value, unlike APRi and Fib-4 index in the current study. The BALF score is the first non-invasive fibrosis marker developed for post-surgical BA patients based on liver histology findings, including the findings of percutaneous needle biopsy examinations obtained from patients with good postoperative courses [29]. It is necessary to continue exploring which indicators reflect the unique pathology of postoperative BA patients and which indicators are optimal for predicting outcomes.\u003c/p\u003e\n\u003cp\u003eChen et al. [10] reported cut-off values of 2D-SWE for diagnosis of significant fibrosis, advanced fibrosis, and cirrhosis of 9.4, 10.8, and 24.4 kPa, respectively, in postoperative BA patients, whereas another study reported cut-off values of 12.1, 13.5, and 15.7 kPa in preoperative BA patients [10, 12]. These results may be influenced by obstructive cholestasis. A cut-off value for SWE to diagnose advanced fibrosis or cirrhosis in post-surgical BA patients must be established separately from that in preoperative patients or in patients with other cholestatic liver disease, and this will require further study. In this study, only one case had an SWE value greater than 9.4 kPa.\u003c/p\u003e\n\u003cp\u003eTo our knowledge, this is the first series investigating the performance of SMI for the evaluation of liver fibrosis in patients with BA.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the present study, SMI grade in the BA group was significantly higher than that of the choledochal cyst group and the other hepatobiliary disorder group, despite no significant difference in SWE values compared with the other disease groups. All BA patients except one was Grade 1 or above, including those without high SWE values. In contrast to previous reports in patients with chronic hepatitis [8, 22, 24, 26], we could not find a positive correlation with several fibrosis indices in BA patients. Although the BALF/iBALF scores showed a significant negative correlation with SMI grade, it is difficult to hypothesize scenarios where the elasticity of the liver decreases as vascular findings worsen, or where vascular observations improve as the elasticity of the liver increases. It is reasonable to interpret this result as an error due to factors such as sample size, causing a lack of positive correlation rather than a presence of negative correlation.\u003c/p\u003e\n\u003cp\u003eBased on these our results, we discuss the following considerations. In chronic fibrotic disease, portal vein branches are distorted and compressed by connective tissue and an increased number of tortuous arterioles surround cirrhotic nodules [33]. Vascularity is decreased and the intrahepatic vessels typically show coiling and corkscrewing [34]. Because SMI is able to demonstrate changes of the vascular tree structure that occur in the cirrhotic liver, including thinning and increased tortuosity of peripheral vessels as well as blunting at various levels of the vascular tree, SMI can distinguish mild and severe forms of fibrosis [24].\u003c/p\u003e\n\u003cp\u003eIn the context of BA, Masuya et al. reported narrowing of the portal veins with an increase in the number of capillaries, and medial hypertrophy with an increase in the number of endothelial cells in the hepatic arteries [35]. They also reported that portal vein diameter was not significantly correlated with the degree of fibrosis [35]. From these results, Masuya et al. conclude that these vascular lesions are considered essential in BA and may not occur secondary to liver fibrosis. Moreover, Harumatsu et al. [36] reported that microvascular proliferation of the portal vein branches in the liver of BA patients is associated with a better long‑term clinical outcome. Analyzing our data in the present study, SWE value and SMI grading showed a positive correlation in patients with FALD but not in those with BA (Online Resource 1). The changes in the vascular tree structure demonstrated in the liver of BA patients may be pathologically different from those that occur in cirrhotic chronic fibrotic liver disease such as chronic hepatitis. Therefore, SMI may not be suitable for long-term follow-up of BA patients because vascular tree grading does not reflect liver fibrosis (unlike chronic fibrotic liver disease).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the present study, all BA patients except one was Grade 1 or above, including those without high SWE values. This finding may reflect the hypothesis suggested by Masuya et al. These results are interesting in understanding the etiology of BA and the pathophysiology leading to postoperative cirrhosis. SMI findings of the vascular tree may have potential application in the diagnosis of BA.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThere are several limitations in the present study. First, this is a retrospective study with a small sample size and does not include a healthy control group. The comparison groups consisted of diverse patients with various diseases. Patient condition (including those in the BA group), such as age and the degree of their cirrhosis, varied. Second, the lack of pathological findings on the liver biopsy performed at the same time as ultrasound examination is a major limitation. It is very challenging to repeat postsurgical liver biopsy examinations to monitor progression of fibrosis in pediatric clinical practice. To answer the clinical question of how to noninvasively and appropriately predict liver condition and identify those patients who need a transplant in postoperative patients with BA, well-designed prospective observational studies are necessary. This involves setting appropriate normal and cholestasis controls, standardizing the methods and timing of measurements, collecting liver biopsy samples, and obtaining longitudinal data, among other considerations.\u0026nbsp;\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eWe conducted a retrospective study to investigate whether liver stiffness measurement using 2D-SWE and vascular tree grading using SMI were associated with liver fibrosis in postoperative BA patients. SWE values in BA patients post-hepatoportoenterostomy were positively correlated with APRi and Fib-4 index; however, BALF/iBALF score was not correlated with 2D-SWE values in this study. 2D-SWE appears to be an informative tool for following liver fibrosis in postoperative BA patients, but these findings need to be carefully examined in a cohort specifically focused on this group. SMI vascular tree grading in BA patients post-hepatoportoenterostomy was significantly higher than that of the choledochal cyst group and the other hepatobiliary disorder group but was not positively correlated with any marker of liver fibrosis. Changes in the vascular tree structure demonstrated in the liver of patients with BA may be pathologically different from those that occur in patients with chronic hepatitis, as previously reported. Further detailed prospective studies with appropriate controls and a larger sample size are warranted.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e1. \u0026nbsp; Funding and competing interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. None of the authors have any relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2. \u0026nbsp; Ethics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was performed in line with the principles of the Declaration of Helsinki. This study was approved by the Institutional Review Board of Ibaraki Children\u0026rsquo;s Hospital (approval number 2023IRB-39).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3. \u0026nbsp; Consent to participate and publish\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study utilized an opt-out consent model, where patients or parents of patient were considered participants unless they opted out.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank Dr. Hirota Saito of the pediatric department in our hospital for his advice in grouping non-BA patients.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBezerra JA, Wells RG, Mack CL, et al (2018) Biliary atresia: Clinical and research challenges for the twenty-first century. Hepatology 68:1163\u0026ndash;1173. https://doi.org/10.1002/hep.29905\u003c/li\u003e\n\u003cli\u003eAsai A, Miethke A, Bezerra JA (2015) Pathogenesis of biliary atresia: defining biology to understand clinical phenotypes. Nat Rev Gastroenterol Hepatol 12:342\u0026ndash;352. https://doi.org/10.1038/nrgastro.2015.74\u003c/li\u003e\n\u003cli\u003eMcKiernan PJ, Baker AJ, Kelly DA (2000) The frequency and outcome of biliary atresia in the UK and Ireland. Lancet 355:25\u0026ndash;29. https://doi.org/10.1016/S0140-6736(99)03492-3\u003c/li\u003e\n\u003cli\u003eNizery L, Chardot C, Sissaoui S, et al (2016) Biliary atresia: Clinical advances and perspectives. Clin Res Hepatol Gastroenterol 40:281\u0026ndash;287. https://doi.org/10.1016/j.clinre.2015.11.010\u003c/li\u003e\n\u003cli\u003eNio M (2017) Japanese Biliary Atresia Registry. Pediatr Surg Int 33:1319\u0026ndash;1325. https://doi.org/10.1007/s00383-017-4160-x\u003c/li\u003e\n\u003cli\u003eGunadi, Sirait DN, Budiarti LR, et al (2020) Histopathological findings for prediction of liver cirrhosis and survival in biliary atresia patients after Kasai procedure. Diagn Pathol 15:79. https://doi.org/10.1186/s13000-020-00996-y\u003c/li\u003e\n\u003cli\u003eMuthukanagarajan SJ, Karnan I, Srinivasan P, et al (2016) Diagnostic and Prognostic Significance of Various Histopathological Features in Extrahepatic Biliary Atresia. J Clin Diagn Res 10:EC23-7. https://doi.org/10.7860/JCDR/2016/19252.8035\u003c/li\u003e\n\u003cli\u003eKoyama N, Hata J, Sato T, et al (2017) Assessment of hepatic fibrosis with superb microvascular imaging in hepatitis C virus-associated chronic liver diseases. Hepatol Res 47:593\u0026ndash;597. https://doi.org/10.1111/hepr.12776\u003c/li\u003e\n\u003cli\u003eZhou W, Li X, Zhang N, et al (2021) The combination of conventional ultrasound and shear-wave elastography in evaluating the segmental heterogeneity of liver fibrosis in biliary atresia patients after Kasai portoenterostomy. Pediatr Surg Int 37:1099\u0026ndash;1108. https://doi.org/10.1007/s00383-021-04920-3\u003c/li\u003e\n\u003cli\u003eChen S, Liao B, Zhong Z, et al (2016) Supersonic shearwave elastography in the assessment of liver fibrosis for postoperative patients with biliary atresia. Sci Rep 6:31057. https://doi.org/10.1038/srep31057\u003c/li\u003e\n\u003cli\u003eHwang J, Yoon HM, Kim KM, et al (2021) Assessment of native liver fibrosis using ultrasound elastography and serological fibrosis indices in children with biliary atresia after the Kasai procedure. Acta Radiol 62:1088\u0026ndash;1096. https://doi.org/10.1177/0284185120948489\u003c/li\u003e\n\u003cli\u003eChen H, Zhou L, Liao B, et al (2021) Two-Dimensional Shear Wave Elastography Predicts Liver Fibrosis in Jaundiced Infants with Suspected Biliary Atresia: A Prospective Study. Korean J Radiol 22:959\u0026ndash;969. https://doi.org/10.3348/kjr.2020.0885\u003c/li\u003e\n\u003cli\u003eGalina P, Alexopoulou E, Mentessidou A, et al (2021) Diagnostic accuracy of two-dimensional shear wave elastography in detecting hepatic fibrosis in children with autoimmune hepatitis, biliary atresia and other chronic liver diseases. Pediatr Radiol 51:1358\u0026ndash;1368. https://doi.org/10.1007/s00247-020-04959-9\u003c/li\u003e\n\u003cli\u003eDing C, Wang Z, Peng C, et al (2022) Diagnosis of liver cirrhosis with two-dimensional shear wave elastography in biliary atresia before Kasai portoenterostomy. Pediatr Surg Int 38:209\u0026ndash;215. https://doi.org/10.1007/s00383-021-05044-4\u003c/li\u003e\n\u003cli\u003eDuan X, Yang L, Wen R, et al (2022) Sound touch elastography for assessing cirrhosis preoperatively in infants with biliary atresia: Comparison with serum fibrosis biomarkers. Front Pediatr 10:989293. https://doi.org/10.3389/fped.2022.989293\u003c/li\u003e\n\u003cli\u003eDuan X, Peng Y, Yang L, et al (2020) Value of shear wave elastography for the evaluation of hepatics fibrosis in infants with biliary atresia before Kasai portoenterostomy. Chinese Journal of Ultrasonography 143\u0026ndash;148\u003c/li\u003e\n\u003cli\u003eWagner ES, Abdelgawad HAH, Landry M, et al (2022) Use of shear wave elastography for the diagnosis and follow-up of biliary atresia: A meta-analysis. World J Gastroenterol 28:4726\u0026ndash;4740. https://doi.org/10.3748/wjg.v28.i32.4726\u003c/li\u003e\n\u003cli\u003eDong B, Duan Y, Wang H, et al (2023) Performance of two-dimensional shear wave elastography for detecting advanced liver fibrosis and cirrhosis in patients with biliary atresia: a systematic review and meta-analysis. Pediatr Radiol. https://doi.org/10.1007/s00247-023-05796-2\u003c/li\u003e\n\u003cli\u003eSigrist RMS, Liau J, Kaffas AE, et al (2017) Ultrasound Elastography: Review of Techniques and Clinical Applications. Theranostics 7:1303\u0026ndash;1329. https://doi.org/10.7150/thno.18650\u003c/li\u003e\n\u003cli\u003eOzturk A, Grajo JR, Dhyani M, et al (2018) Principles of ultrasound elastography. Abdom Radiol (NY) 43:773\u0026ndash;785. https://doi.org/10.1007/s00261-018-1475-6\u003c/li\u003e\n\u003cli\u003eBamber J, Cosgrove D, Dietrich CF, et al (2013) EFSUMB guidelines and recommendations on the clinical use of ultrasound elastography. Part 1: Basic principles and technology. Ultraschall Med 34:169\u0026ndash;184. https://doi.org/10.1055/s-0033-1335205\u003c/li\u003e\n\u003cli\u003eKuroda H, Abe T, Kakisaka K, et al (2016) Visualizing the hepatic vascular architecture using superb microvascular imaging in patients with hepatitis C virus: A novel technique. World J Gastroenterol 22:6057\u0026ndash;6064. https://doi.org/10.3748/wjg.v22.i26.6057\u003c/li\u003e\n\u003cli\u003eGabriel M, Tomczak J, Snoch-Zi\u0026oacute;łkiewicz M, et al (2016) Comparison of Superb Micro-Vascular Ultrasound Imaging (SMI) and Contrast-Enhanced Ultrasound (CEUS) for Detection of Endoleaks After Endovascular Aneurysm Repair (EVAR). Am J Case Rep 17:43\u0026ndash;46. https://doi.org/10.12659/ajcr.895415\u003c/li\u003e\n\u003cli\u003eBalık A\u0026Ouml;, Kılı\u0026ccedil;oğlu ZG, G\u0026ouml;rmez A, \u0026Ouml;zkara S (2019) Radiology-pathology correlation in staging of liver fibrosis using superb microvascular imaging. Diagn Interv Radiol 25:331\u0026ndash;337. https://doi.org/10.5152/dir.2019.18231\u003c/li\u003e\n\u003cli\u003eSmith GW, Westgaard T, Bj\u0026ouml;rn-Hansen R (1971) Hepatic venous angiography in the evaluation of cirrhosis of the liver. Ann Surg 173:469\u0026ndash;480. https://doi.org/10.1097/00000658-197104000-00001\u003c/li\u003e\n\u003cli\u003eTosun M, Uslu H (2022) Comparison of superb microvascular imaging and shear wave elastography for assessing liver fibrosis in chronic hepatitis B. Ultrasonography 41:394\u0026ndash;402. https://doi.org/10.14366/usg.21136\u003c/li\u003e\n\u003cli\u003eGrieve A, Makin E, Davenport M (2013) Aspartate Aminotransferase-to-Platelet ratio index (APRi) in infants with biliary atresia: prognostic value at presentation. J Pediatr Surg 48:789\u0026ndash;795. https://doi.org/10.1016/j.jpedsurg.2012.10.010\u003c/li\u003e\n\u003cli\u003eLeung DH, Khan M, Minard CG, et al (2015) Aspartate aminotransferase to platelet ratio and fibrosis-4 as biomarkers in biopsy-validated pediatric cystic fibrosis liver disease. Hepatology 62:1576\u0026ndash;1583. https://doi.org/10.1002/hep.28016\u003c/li\u003e\n\u003cli\u003eTomita H, Masugi Y, Hoshino K, et al (2014) Long-term native liver fibrosis in biliary atresia: development of a novel scoring system using histology and standard liver tests. J Hepatol 60:1242\u0026ndash;1248. https://doi.org/10.1016/j.jhep.2014.01.028\u003c/li\u003e\n\u003cli\u003eTomita H, Fuchimoto Y, Fujino A, et al (2015) Development and Validation of a Novel Fibrosis Marker in Biliary Atresia during Infancy. Clin Transl Gastroenterol 6:e127. https://doi.org/10.1038/ctg.2015.55\u003c/li\u003e\n\u003cli\u003eBarr RG, Wilson SR, Rubens D, et al (2020) Update to the Society of Radiologists in Ultrasound Liver Elastography Consensus Statement. Radiology 296:263\u0026ndash;274. https://doi.org/10.1148/radiol.2020192437\u003c/li\u003e\n\u003cli\u003eThumar V, Squires JH, Spicer PJ, et al (2018) Ultrasound Elastography Applications in Pediatrics. Ultrasound Q 34:199\u0026ndash;205. https://doi.org/10.1097/RUQ.0000000000000379\u003c/li\u003e\n\u003cli\u003eYamamoto T, Kobayashi T, Phillips MJ (1984) Perinodular arteriolar plexus in liver cirrhosis. Scanning electron microscopy of microvascular casts. Liver 4:50\u0026ndash;54. https://doi.org/10.1111/j.1600-0676.1984.tb00907.x\u003c/li\u003e\n\u003cli\u003eBosniak MA, Phanthumachinda P (1966) Value of arteriography in the study of hepatic disease. Am J Surg 112:348\u0026ndash;355. https://doi.org/10.1016/0002-9610(66)90202-9\u003c/li\u003e\n\u003cli\u003eMasuya R, Muraji T, Ohtani H, et al (2019) Morphometric demonstration of portal vein stenosis and hepatic arterial medial hypertrophy in patients with biliary atresia. Pediatr Surg Int 35:529\u0026ndash;537. https://doi.org/10.1007/s00383-019-04459-4\u003c/li\u003e\n\u003cli\u003eHarumatsu T, Muraji T, Masuya R, et al (2019) Microvascular proliferation of the portal vein branches in the liver of biliary atresia patients at Kasai operation is associated with a better long-term clinical outcome. Pediatr Surg Int 35:1437\u0026ndash;1441. https://doi.org/10.1007/s00383-019-04579-x\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1:\u003c/strong\u003e Baseline characteristics of patients with biliary atresia\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eValue (n=13)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSex (female/male)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9:4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAge at\u0026nbsp;hepatoportoenterostomy (days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e54 (30\u0026ndash;83)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAge at examination (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7 (0\u0026ndash;21)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePlt (\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e190 (78\u0026ndash;471)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAST (U/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e31 (13\u0026ndash;424)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eALT (U/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e48 (10\u0026ndash;419)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026gamma;-GTP (U/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e47 (9\u0026ndash;1286)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eT-Bil (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.7 (0.4\u0026ndash;3.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eD-Bil (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.1 (0\u0026ndash;1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAlb (g/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4.2 (2.7\u0026ndash;4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePT\u0026nbsp;(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e89 (70\u0026ndash;158)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eData are shown as median (minimum\u0026ndash;maximum).\u003c/p\u003e\n\u003cp\u003ePlt: platelet count; AST: aspartate aminotransferase; ALT: alanine aminotransferase; \u0026gamma;-GTP: gamma glutamyl transferase P; T-Bil: total bilirubin; D-Bil: direct bilirubin; Alb: albumin; PT: prothrombin time.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"pediatric-surgery-international","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pesi","sideBox":"Learn more about [Pediatric Surgery International](http://link.springer.com/journal/383)","snPcode":"383","submissionUrl":"https://submission.nature.com/new-submission/383/3","title":"Pediatric Surgery International","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Biliary atresia, Shear wave elastography, Superb microvascular imaging, Ultrasound, Liver fibrosis","lastPublishedDoi":"10.21203/rs.3.rs-4841588/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4841588/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eWe aimed to investigate whether prediction of liver fibrosis using two-dimensional shear wave elastography (2D-SWE) and vascular tree grading using superb microvascular imaging (SMI) are useful for postoperative follow-up in patients with biliary atresia (BA).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe retrospectively collected data from medical records of 134 patients who underwent ultrasound examination with 2D-SWE or SMI, including 13 postoperative patients with BA and 121 non-BA patients. We investigated the distribution of liver stiffness values with SWE and vascular tree grading with SMI and evaluated correlations between these findings and biochemical indices of liver fibrosis in postoperative BA patients.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe SWE values of the BA group were not significantly different from that of any other disease groups in non-BA patients. In postoperative BA patients, SWE values correlated significantly with aspartate aminotransferase to platelet ratio index (Spearman rank correlation coefficient [r\u003csub\u003es\u003c/sub\u003e]\u0026thinsp;=\u0026thinsp;0.6380, p\u0026thinsp;=\u0026thinsp;0.0256) and with the Fib-4 index (r\u003csub\u003es\u003c/sub\u003e=0.6526, p\u0026thinsp;=\u0026thinsp;0.0214). SMI vascular tree grading of the BA group was significantly higher than that of the choledochal cyst group (p\u0026thinsp;=\u0026thinsp;0.0008) and other hepatobiliary disorder group (p\u0026thinsp;=\u0026thinsp;0.0030). In postoperative BA patients, SMI vascular tree grading was not positively correlated with any biochemical marker of fibrosis.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003e2D-SWE appears to be useful for follow-up in postoperative BA patients.\u003c/p\u003e","manuscriptTitle":"Assessment of the utility of two-dimensional shear wave elastography and superb microvascular imaging in postoperative patients with biliary atresia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-09-08 19:50:54","doi":"10.21203/rs.3.rs-4841588/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accepted","date":"2024-08-02T09:10:31+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-02T09:08:13+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"340165079514415562491512844803786995236","date":"2024-08-02T09:06:54+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-08-02T09:03:35+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-08-02T09:03:03+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-08-02T08:06:39+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pediatric Surgery International","date":"2024-08-01T10:50:22+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pediatric-surgery-international","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pesi","sideBox":"Learn more about [Pediatric Surgery International](http://link.springer.com/journal/383)","snPcode":"383","submissionUrl":"https://submission.nature.com/new-submission/383/3","title":"Pediatric Surgery International","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"c0289dce-1a83-4688-bc03-c8cf3916f3f9","owner":[],"postedDate":"September 8th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-09-08T19:50:54+00:00","versionOfRecord":{"articleIdentity":"rs-4841588","link":"https://doi.org/10.1007/s00383-024-05804-y","journal":{"identity":"pediatric-surgery-international","isVorOnly":false,"title":"Pediatric Surgery International"},"publishedOn":"2024-08-08 15:57:29","publishedOnDateReadable":"August 8th, 2024"},"versionCreatedAt":"2024-09-08 19:50:54","video":"","vorDoi":"10.1007/s00383-024-05804-y","vorDoiUrl":"https://doi.org/10.1007/s00383-024-05804-y","workflowStages":[]},"version":"v1","identity":"rs-4841588","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4841588","identity":"rs-4841588","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}