Early detection of liver fibrosis with serum Mac-2 binding protein glycosylation-modified isomer (M2BPGi) during follow-up intestinal failure patients without intestinal failure–associated liver disease (IFALD)

Early detection of liver fibrosis with serum Mac-2 binding protein glycosylation-modified isomer (M2BPGi) during follow-up intestinal failure patients without intestinal failure–associated liver disease (IFALD) | 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 Early detection of liver fibrosis with serum Mac-2 binding protein glycosylation-modified isomer (M2BPGi) during follow-up intestinal failure patients without intestinal failure–associated liver disease (IFALD) Takehisa Ueno, Koki Takase, Koichi Deguchi, Kazunori Masahata, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2047447/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 6 You are reading this latest preprint version Abstract Purpose Mac-2 binding protein glycosylation-modified isomer (M2BPGi) is a new marker for hepatic fibrosis progression. We examined the relationship between serum M2BPGi levels and liver histological findings in intestinal failure (IF) patients without IF-associated liver disease (IFALD). Methods This study included IF patients without IFALD followed at our hospital. All patients underwent routine liver biopsies per protocol every 1–2 years. We examined M2BPGi levels and histological findings in relation to aspartate aminotransferase (AST) to platelet ratio index, fibrosis-4 index, and AST/ALT ratio. Liver fibrosis was evaluated based on the METAVIR score. Results Total 18 liver biopsies out of 8 patients were included. The median age was 11.5 years. Mean M2BPGi was 0.44 cutoff index (COI) in patients with F0 fibrosis; 0.78 COI in patients with F1 fibrosis; and 1.63 COI in patients with F2 fibrosis. Mean M2BPGi was significantly higher in patients with F2 versus F1 or F0 fibrosis ( P < 0.016 and P < 0.028, respectively). M2BPGi levels were more strongly correlated with fibrosis stage than with other conventional fibrosis markers. Conclusion Serum M2BPGi is a novel marker of liver fibrosis in patients with IF. It is useful for follow-up prior to IFALD. Serum M2BPGi levels can support the interpretation of liver status. Mac-2 binding protein glycosylation-modified isomer (M2BPGi) Liver Fibrosis Intestinal failure–associated liver disease (IFALD) Intestinal failure Liver biopsy Figures Figure 1 Figure 2 Figure 3 Introduction Intestinal failure (IF) is the inability of the gut to absorb nutrition, mostly due to short gut syndrome or motility disorder. Patients with IF are usually dependent on parenteral nutrition (PN). PN is a definitive therapy for these children. Home PN is the standard of care for children with IF [ 1 ]. The prognosis of persistent IF has improved due to the development of PN. However, prolonged PN causes numerous complications, including catheter-related sepsis and vital organ disorder. Some patients might develop IF-associated liver disease (IFALD). IFALD is a potentially life-threatening complication [ 2 ]. IFALD progresses from mild periportal inflammation and cholestasis eventually to liver fibrosis and cirrhosis [ 3 ]. Especially in patients with severe liver fibrosis, it is difficult to treat with isolated intestinal transplantation alone; liver transplantation might also be needed. Therefore, evaluation of liver fibrosis during follow-up before the development of IFALD is critical. Liver biopsy (LBx) is the standard evaluation for liver fibrosis, but it is an invasive test that might cause serious complications [ 4 ]. Thus, noninvasive biomarkers have been explored. Mac-2 binding protein glycosylation-modified isomer (M2BPGi) was recently established as a glycol biomarker of liver fibrosis in patients with chronic hepatitis C [ 5 ]. M2BPGi has been shown to be a useful predictor in many chronic liver diseases. [ 6 – 9 ]. The usefulness of M2BPGi as a biomarker was demonstrated in pediatric biliary atresia [ 10 ]. However, there have been no available data regarding the relationship between serum M2BPGi levels and histological findings of liver fibrosis during regular follow-up of patients with IF prior to the development of IFALD. Therefore, we focused on the serum liver fibrosis marker M2BPGi and compared it with the histopathological findings from percutaneous LBx. Thus, the aim of this study was to examine the relationship between serum M2BPGi levels and liver histological findings during regular follow-up of patients with IF before they develop IFALD. Methods Patients Patients diagnosed with persistent IF but not IFALD who were followed at our hospital between May 2016 and February 2022 were included in this study. Patients who underwent LBx per protocol as part of the evaluation for intestinal transplantation were included. They underwent follow-up LBx every 1–2 years as candidates for isolated intestinal transplantation. We examined the relationship between M2BPGi levels and histological findings of liver fibrosis and compared them with other laboratory markers of liver fibrosis, including aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio, AST to platelet ratio index (APRI), and FIB-4 index. The APRI score was calculated using Wai’s formula:[ (AST/upper limit of normal)/platelet count (× 10 9 /L)] × 100 [ 11 ]. The FIB-4 index was calculated using Sterling’s formula: [age (years) × AST (IU/L)] / [platelet count (× 10 9 /L) × √ALT (IU/ L)] [ 12 ]. Laboratory data were obtained within 3 months of LBx. Patients with C-reactive protein (CRP) over 1.00 mg/dL were excluded to avoid the effect of inflammation. Persistent IF was defined as IF patients required parental nutrition permanently. IFALD was defined as Total Bilirubin (TB) > 2.0 mg/dL. Patients with existing IFALD were excluded. This study examined whether liver fibrosis before reaching the IFALD stage could be detected. M2BPGi measurement Serum M2BPGi levels were measured using a two-site enzyme immunoassay. The assay reagent, which is commercially available in Japan, was purchased from Sysmex Corporation (Kobe, Japan). Quantification of M2BPGi was based on a lectin–antibody sandwich immunoassay using the fully automatic HISCL-800 immune analyzer (Sysmex Corporation). M2BPGi measurements were indexed with values obtained using the following equation: cutoff index (COI) = ([M2BPGi] sample [M2BPGi] NC)/([M2BPGi] PC + [M2BPGi] NC), in which [M2BPGi] sample is the M2BPGi concentration in the serum sample, NC is the negative control, and PC is the positive control. The PC was supplied as a calibration solution preliminarily standardized to yield a COI value of 1.0 [ 5 ]. Histological assessment LBx samples were assessed with hematoxylin–eosin and Masson’s trichrome stains. Percutaneous LBx was performed with a 16-gauge biopsy needle. All LBx were performed using an ultrasound-guided maneuver under either general anesthesia or intravenous sedation. The specimens were fixed in 4% phosphate-buffered formaldehyde and embedded in paraffin. After hematoxylin–eosin and Masson’s trichrome staining, LBx specimens were examined microscopically. Experienced pathologists in our hospital evaluated the samples. Fibrosis was staged as F0–F4: F0, no fibrosis; F1, portal fibrosis without septa; F2, portal fibrosis with rare septa; F3, numerous septa without cirrhosis; and F4, liver cirrhosis [ 13 ]. No serious procedure-related complications were observed. In this study, progressive fibrosis was defined as ≥ F2. The presence of fibrosis was defined as ≥ F1. Statistical analysis Receiver operating characteristic (ROC) curve analysis was performed to calculate the area under the curve (AUC) for serum M2BPGi level and select the optimal cutoff value that maximized the sum of sensitivity and specificity for the presence of liver fibrosis (≥ F1) and progressive fibrosis (≥ F2) on histological examination. For continuous variables, comparisons among groups were performed using Student’s t-test. Data are expressed as medians (range). P < 0.05 was considered statistically significant. Statistical analyses were performed with JMP 11 software (SAS Institute, Cary, NC, USA). This study was approved by our hospital institutional review board (approval number 21481). Results Demographic characteristics of the study patients The characteristics of the study patients (n = 8) are shown in Table 1 . There were 4 males and 4 females, with a median age of 11.5 years (range, 1.8–32 years). Laboratory data were from the time of the last LBx. Percutaneous LBx was performed 18 times; 18 specimens were obtained from 8 patients. A summary of LBx and laboratory values is presented in Table 2. Regarding the degree of liver fibrosis based on histological examination, F0 was observed in 3 specimens, F1 in 12, and F2 in 3. M2BPGi values in this study ranged from 0.48 to 1.62 COI (median, 0.74 COI). CRP ranged from 0.04 to 0.85 mg/dL. Total bilirubin ranged from 0.2 to 1.5 mg/dL. None of the patients had IFALD. M2BPGi and liver fibrosis By fibrosis stage (F0–F2), the mean M2BPGi value was 0.44 COI (SD, 0.06 COI) in patients with F0 fibrosis, 0.78 COI (SD, 0.39 COI) in patients with F1 fibrosis, and 1.63 COI (SD, 1.16 COI) in patients with F2 fibrosis. The mean M2BPGi value was significantly higher in patients with F2 versus F1 fibrosis ( P < 0.016) and in patients with F2 versus F0 fibrosis ( P < 0.028) (Fig. 1 (a)). Other fibrosis markers and liver fibrosis By fibrosis stage (F0–F2), the mean AST/ALT ratio was 1.36 (SD, 0.54) in patients with F0 fibrosis; 0.87 (SD, 0.27) in patients with F1 fibrosis, and 1.53 (SD, 0.62) in patients with F2 fibrosis. The mean AST/ALT ratio was significantly higher in patients with F2 versus F1 fibrosis ( P < 0.017) (Fig. 1 (b)). However, there was no statistically significant difference between patients with F2 and F0 fibrosis. By fibrosis stage (F0–F2), mean APRI was 0.44 (SD, 0.10) in patients with F0 fibrosis, 0.61 (SD, 0.37) in patients with F1 fibrosis, and 0.54 (SD, 0.15) in patients with F2 fibrosis. There was no statistically significant difference between the groups (Fig. 1 (c)). By fibrosis stage (F0–F2), mean FIB-4 index was 0.41 (SD, 0.04) in patients with F0 fibrosis, 0.39 (SD, 0.35) in patients with F1 fibrosis, and 0.90 (SD, 0.16) in patients with F2 fibrosis. Mean FIB-4 index was significantly higher in patients with F2 versus F1 fibrosis ( P < 0.022) (Fig. 1 b). However, there was no statistically significant difference between patients with F2 and F0 fibrosis (Fig. 1 (d)). M2BPGi and fibrosis stages over times M2BPGi and fibrosis stage at the first and latest liver biopsies of 6 patients who underwent liver biopsy more than once were plotted to figure out the progression of liver fibrosis in IFALD patients. (Fig. 2 ) The interval between the first and latest liver biopsy was median 14.2 months (11.0-50.1months). There was no change in fibrosis stage in 5 cases during this observation period, and 1 case changed from F1 to F2. M2BPGi increased in 3 cases and decreased in 3 cases. ROC curve analysis For predicting progressive liver fibrosis (F2), a M2BPGi level of 1.62 COI yielded a high AUC (0.73). For presence of liver fibrosis (≥ F1), an M2BPGi level of 0.44 COI yielded a high AUC (0.89) (Fig. 3 (a)–(b)). Discussion The prognosis of persistent IF depends on complications, including IFALD. The prognosis of IF with IFALD is poor [ 14 ]. The prognosis of IFALD depends greatly upon the extent of hepatic fibrosis. Patients with advanced liver fibrosis have higher morbidity due to complications from cirrhosis; they also have higher mortality [ 15 ]. In ultra-short bowel syndrome, IFALD occurs rapidly and cirrhosis is likely[ 16 ]. Patients with IF and IFALD might need combined liver and intestinal transplantation [ 17 ]. Early detection of liver fibrosis allows patient consultation at an intestinal rehabilitation and transplant center, pre-transplant evaluation, and transplant listing [ 18 ]. In Japan, it is necessary to perform isolated intestinal transplantation before IFALD and liver cirrhosis progression because combined transplantation of the liver and small intestines is difficult in Japan due to a shortage of donors. Therefore, early detection of IFALD in development is important. For this purpose, identifying liver fibrosis progression is essential. However, the development of fibrosis cannot be detected by blood tests until the late stage [ 19 ]. LBx is the standard for assessing the degree of liver fibrosis. However, it might cause complications such as organ injury, hemorrhage, and pain. In pediatric patients, general anesthesia is needed for LBx [ 20 ]. Serial LBx should be avoided, but it might be needed to follow the progression of fibrosis. Another problem is that the evaluation of fibrosis by LBx is uncertain due to sampling error and variation among observers [ 21 ]. LBx provides a classified grading system that allows comparing fibrosis stage among patients. However, LBx allows for the evaluation at a static point. In addition, there are only five classifications (F0–F4) in the METAVIR system. A marker that allows for the identification of patients with IFALD progression, in order to avoid repeating LBx procedures unnecessarily, is desirable. In recent years, several noninvasive tests have been developed. Noninvasive biomarkers for predicting fibrosis in patients with IFALD have been explored. APRI is one such biomarker of fibrosis. APRI has been used to detect fibrosis and cirrhosis in adult patients with hepatitis C [ 11 ]. In pediatric patients, APRI has been used to evaluate fibrosis progression during follow-up in biliary atresia [ 22 ]. APRI > 1.6 in patients with IFALD correlates with advanced fibrosis in the pediatric population [ 23 ]. FIB-4 index is another fibrosis marker that has been used in patients with IFALD. FIB-4 index and liver fibrosis stage are positively correlated. This evaluation of FIB-4 index versus LBx supports the use of the FIB-4 index in the detection of liver fibrosis in IF [ 24 ]. These methods detect high levels of liver fibrosis in IFALD that has already developed. They were inadequate for early detection of liver fibrosis before IFALD has developed. As a non-blood test–based methods, transient elastography measures the elasticity or stiffness of the liver to detect more severe hepatic fibrosis using ultrasound. Ultrasound-based transient elastography is another less invasive method for evaluating liver fibrosis that has recently been reported as highly useful [ 25 ]. Its use in children has been reported [ 26 , 27 ]. However, there have been no reports about early detection of liver fibrosis prior to the development of IFALD. These methods detect high levels of liver fibrosis and are inadequate for early detection. M2BPGi is a predictor of liver fibrosis that performed better than other markers such as FIB-4 index. M2BPGi might be the most reliable serum biomarker [ 5 ]. M2BPGi is a marker for assessing liver fibrosis in viral hepatitis [ 5 , 6 , 9 ]. In addition, M2BPGi is useful for assessing liver fibrosis in patients with Primary Biliary Cholangitis [ 28 ], autoimmune hepatitis [ 8 ], and non-alcoholic fatty liver disease [ 29 ]. Its usefulness has been demonstrated in pediatric biliary atresia [ 10 ]. M2BPGi might be useful for follow-up of fibrosis progression over time even if fibrosis stage remains constant [ 30 ]. ROC curve analysis demonstrated that serum M2BPGi levels in patients with IF have good diagnostic ability for detecting grade F2 fibrosis. We found that the degree of liver fibrosis differed by M2BPGi level. Our study suggests that M2BPGi is useful for predicting progressive fibrosis (≥ F2) with a cutoff of 1.62 COI and the presence of liver fibrosis (≥ F1) with a cutoff of 0.44 COI. LBx can be avoided until M2BPGi predicts the presence of liver fibrosis before IFALD in patients without jaundice. The primary strength of our study is the inclusion of a unique cohort of patients who underwent LBx before the development of IFALD. Once patients develop jaundice, IFALD can be easily detected. Utilizing the proposed cutoff values, sensitivity and specificity values are provided for future studies to include or exclude advanced liver fibrosis simply based on M2BPGi. We acknowledge several study limitations. The primary limitation of our study is the inclusion of only individuals preparing for intestinal transplantation. The study population does not cover all patients with IF. There were not enough patients to produce significant specificity and sensitivity in ROC curve analysis. Additionally, subgroup analysis about the correlation between the M2BPGi value and factors for liver damage could not be performed due to the small number of cases this time. Subgroups will be a primary disease, patients' age, duration, and composition of PN, length of residual intestine, presence of ileocecal valve, and so on. Further study is required after the accumulation of cases. The progression of liver fibrosis and the increase of M2BPGi were not evident in this study since there was not enough observation period. The relationship between the progress of liver fibrosis and the value of M2BPGi in IF patients are for further investigation. We did not perform elastography; thus, elastography findings could not be compared with M2BPGi data. Further analysis will be needed. Lastly, although M2BPGi is significantly correlated with fibrosis stage, the sensitivity of the M2BPGi index is insufficient. It should be used with other markers such as FIB-4 index before performing LBx to prove liver fibrosis. In conclusion, serum M2BPGi is a novel marker for liver fibrosis in patients with IF. It is especially useful for follow-up in patients with IF prior to IFALD. Serum M2BPGi levels can support the interpretation of liver status. Declarations Compliance with Ethical Standards Conflict of Interest : The authors declare that they have no conflict of interest. Ethical approval : All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study formal consent is not required References Duro D, Kamin D, Duggan C (2008) Overview of pediatric short bowel syndrome. J Pediatr Gastroenterol Nutr. 47 Suppl 1:S33-6. doi: 10.1097/MPG.0b013e3181819007. Nehra D, Fallon EM, Puder M (2011) The prevention and treatment of intestinal failure-associated liver disease in neonates and children. Surg Clin North Am 91(3):543-63. doi: 10.1016/j.suc.2011.02.003. 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Ueno T, Kodama T, Noguchi Y, Nomura M, Saka R, Takama Y, et al (2019) Serum Mac-2-binding protein (M2BPGi) as a marker of chronological liver fibrosis in biliary atresia patients with cirrhosis. Pediatr Surg Int 35(10):1065-70. doi: 10.1007/s00383-019-04535-9. Tables Table 1 Patient demographics: Data were expressed as median with ranges. Histological findings were described by METAVIR score. AST: aspartate aminotransferase; ALT: alanine aminotransferase ; M2BPGi:Mac-2 binding protein glycosylation-modified isomer ; APRI: aspartate aminotransferase to platelet ratio index; FIB-4:Fibrosis-4 index Variables n=8 Age, years 11.5(1.8-32) Gender, male/female 4/4 Original disease Short gut 5 Motility disorder 3 AST ,IU/L 47(31-110) ALT ,IU/L 71(21-124) Serum albumin, g/dL 4.1(3.1-4.4) Total bilirubin, mg/dL 0.5(0.2-1.5) Prothrombin time, INR 1.3(1.1-1.5) Platelets, 10 4 /mm3 18.8(12.0-31.1) M2BPGi 0.74(0.48-1.62) APRI 0.52(0.38-1.71) FIB-4 0.32(0.11-1.31) LBx performed, times 2(1-5) Interval, months 14.2(11.0-50.1) Histological findings F0 1 F1 5 F2 2 Table 2 Sampling demographics : Data were expressed as median with ranges. Histological findings were described by METAVIR score. AST: aspartate aminotransferase; ALT: alanine aminotransferase ; M2BPGi:Mac-2 binding protein glycosylation-modified isomer ; APRI: aspartate aminotransferase to platelet ratio index; FIB-4:Fibrosis-4 index Variables n=18 Age, years 11.0(1.8-31.4) AST ,IU/L 37(23-110) ALT ,IU/L 43(14-124) Serum albumin, g/dL 4.0(3.0-4.4) Total bilirubin, mg/dL 0.5(0.2-1.5) Prothrombin time, INR 1.2(1.1-1.5) Platelets, 10 4 /mm3 18.3(11.8-39.7) CRP 0.04(0.04-0.85) M2BPGi 0.58(0.4-2.79) APRI 0.50(0.35-1.71) FIB-4 0.41(0.09-1.11) AST/ALT ratio 0.91(0.49-2.24) Fibrosis stage F0 3 F1 12 F2 3 Additional Declarations No competing interests reported. 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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-2047447","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":135458144,"identity":"2bd4dd9e-20b6-43dc-ab21-e5c2a3997697","order_by":0,"name":"Takehisa Ueno","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABMUlEQVRIie2RsWrDMBCGTxjsxTSrhPE7OAhEDWmeJcLgLM4bdNCkLE2zulNewV1MxhRDs4jO7lQHQ+iQwV4KWZI6Ju1ip9CtUH/D8eukj0MSQEfHX6UAQOKc6/C9AtxuoPDXimZeVlpw1rOn/GY5sBfhJH9HwcAWxnRThrfAhZFk4C6binrx6ET5NErH7BrFPhWmoiR6rhTTd4CoppIGzJrIhEfY1x0UJ1zgAEimH7mAAIDIpvK2Y5Yrj3wR1kp1Eo/zfXaopvR27UpqMgvJFRepr2UorgIeMfIooR7XphAV0P5MeTRSWx147FFpKuY+3AOVeOusWu5ytVb9bL8c2ouprxVlPLTnxjR/vfsAe97zNjlpvljN+Rt0PDrVr+4pJET8qGhFc6e8oHR0dHT8Jz4BEmRwOybzkEsAAAAASUVORK5CYII=","orcid":"","institution":"Osaka University of Graduation School of Medicine","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Takehisa","middleName":"","lastName":"Ueno","suffix":""},{"id":135458145,"identity":"25f41fe4-6b62-413a-8f17-026eabd9d899","order_by":1,"name":"Koki Takase","email":"","orcid":"","institution":"Osaka University of Graduation School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Koki","middleName":"","lastName":"Takase","suffix":""},{"id":135458146,"identity":"a23971b7-f735-45d6-88f9-e72cc1350659","order_by":2,"name":"Koichi Deguchi","email":"","orcid":"","institution":"Osaka University of Graduation School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Koichi","middleName":"","lastName":"Deguchi","suffix":""},{"id":135458147,"identity":"ebecb6f8-ac5e-4285-8170-4032df496ef5","order_by":3,"name":"Kazunori Masahata","email":"","orcid":"","institution":"Osaka University of Graduation School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kazunori","middleName":"","lastName":"Masahata","suffix":""},{"id":135458148,"identity":"1dc1dd58-fe5f-4636-ac48-7849f8ccc744","order_by":4,"name":"Motonari Nomura","email":"","orcid":"","institution":"Osaka University of Graduation School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Motonari","middleName":"","lastName":"Nomura","suffix":""},{"id":135458149,"identity":"de62f113-e4dc-4bee-a7d9-65e7310f559f","order_by":5,"name":"Miho Watanabe","email":"","orcid":"","institution":"Osaka University of Graduation School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Miho","middleName":"","lastName":"Watanabe","suffix":""},{"id":135458150,"identity":"75d64635-a757-4944-865a-c2655a0919d3","order_by":6,"name":"Masafumi Kamiyama","email":"","orcid":"","institution":"Osaka University of Graduation School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Masafumi","middleName":"","lastName":"Kamiyama","suffix":""},{"id":135458151,"identity":"ec051888-a1e7-4257-92fd-851c9b346575","order_by":7,"name":"Yuko Tazuke","email":"","orcid":"","institution":"Osaka University of Graduation School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yuko","middleName":"","lastName":"Tazuke","suffix":""},{"id":135458152,"identity":"ecf70801-069b-4a57-aaba-10e97cfc8372","order_by":8,"name":"Kazuhiko Bessho","email":"","orcid":"","institution":"Osaka University of Graduation School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kazuhiko","middleName":"","lastName":"Bessho","suffix":""},{"id":135458153,"identity":"e66f09c3-b9be-4d3a-8cf5-c6ad3eac8314","order_by":9,"name":"Hiroomi Okuyama","email":"","orcid":"","institution":"Osaka University of Graduation School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hiroomi","middleName":"","lastName":"Okuyama","suffix":""}],"badges":[],"createdAt":"2022-09-09 05:14:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2047447/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2047447/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":26415231,"identity":"75fd6a19-2274-4790-9a62-01d2607eef2b","added_by":"auto","created_at":"2022-09-13 19:55:45","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":754781,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRelationship between fibrosis markers and the stage of fibrosis. \u003c/strong\u003eFibrosis stages were descried METVIR score. (a) M2BPGi, (b) AST/ALT, (c) APRI, (d) FIB-4 index. M2BPGi: Mac-2 binding protein glycosylation-modified isomer; APRI: aspartate aminotransferase to platelet ratio index; FIB-4:Fibrosis-4 index\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2047447/v1/306f8801a3dce1124b9e24cd.jpg"},{"id":26415094,"identity":"bd336cec-f49a-44d0-8ace-8c6a57992d59","added_by":"auto","created_at":"2022-09-13 19:50:45","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":187463,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eM2BPGi and fibrosis stages over time:\u003c/strong\u003e M2BPGi and fibrosis stage at first and latest biopsy were plotted. Fibrosis stages were F0：●, F1:▲ and F2:■ ; M2BPGi:Mac-2 binding protein glycosylation-modified\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2047447/v1/203f4dd26022dba438b07f3a.jpg"},{"id":26415092,"identity":"5bda7d5b-a63a-4195-8d05-34c0fe8a899b","added_by":"auto","created_at":"2022-09-13 19:50:45","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":528393,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eROC curve analysis of M2BPGi and the stages of fibrosis. \u003c/strong\u003eFibrosis stages were described METAVIR score (a) F≥2, (b) F≥1. M2BPGi: Mac-2 binding protein glycosylation-modified isomer\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2047447/v1/e9850e19499e218f0517469b.jpg"},{"id":26415260,"identity":"0b183be4-b4bb-465f-95c4-15a8b601c4ad","added_by":"auto","created_at":"2022-09-13 19:55:49","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":470847,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2047447/v1/e0b79734-2d72-4218-a61a-3e713240634a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Early detection of liver fibrosis with serum Mac-2 binding protein glycosylation-modified isomer (M2BPGi) during follow-up intestinal failure patients without intestinal failure–associated liver disease (IFALD)","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIntestinal failure (IF) is the inability of the gut to absorb nutrition, mostly due to short gut syndrome or motility disorder. Patients with IF are usually dependent on parenteral nutrition (PN). PN is a definitive therapy for these children. Home PN is the standard of care for children with IF [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The prognosis of persistent IF has improved due to the development of PN. However, prolonged PN causes numerous complications, including catheter-related sepsis and vital organ disorder.\u003c/p\u003e \u003cp\u003eSome patients might develop IF-associated liver disease (IFALD). IFALD is a potentially life-threatening complication [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. IFALD progresses from mild periportal inflammation and cholestasis eventually to liver fibrosis and cirrhosis [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Especially in patients with severe liver fibrosis, it is difficult to treat with isolated intestinal transplantation alone; liver transplantation might also be needed. Therefore, evaluation of liver fibrosis during follow-up before the development of IFALD is critical. Liver biopsy (LBx) is the standard evaluation for liver fibrosis, but it is an invasive test that might cause serious complications [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Thus, noninvasive biomarkers have been explored.\u003c/p\u003e \u003cp\u003eMac-2 binding protein glycosylation-modified isomer (M2BPGi) was recently established as a glycol biomarker of liver fibrosis in patients with chronic hepatitis C [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. M2BPGi has been shown to be a useful predictor in many chronic liver diseases. [\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The usefulness of M2BPGi as a biomarker was demonstrated in pediatric biliary atresia [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. However, there have been no available data regarding the relationship between serum M2BPGi levels and histological findings of liver fibrosis during regular follow-up of patients with IF prior to the development of IFALD.\u003c/p\u003e \u003cp\u003eTherefore, we focused on the serum liver fibrosis marker M2BPGi and compared it with the histopathological findings from percutaneous LBx. Thus, the aim of this study was to examine the relationship between serum M2BPGi levels and liver histological findings during regular follow-up of patients with IF before they develop IFALD.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003ePatients diagnosed with persistent IF but not IFALD who were followed at our hospital between May 2016 and February 2022 were included in this study. Patients who underwent LBx per protocol as part of the evaluation for intestinal transplantation were included. They underwent follow-up LBx every 1\u0026ndash;2 years as candidates for isolated intestinal transplantation. We examined the relationship between M2BPGi levels and histological findings of liver fibrosis and compared them with other laboratory markers of liver fibrosis, including aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio, AST to platelet ratio index (APRI), and FIB-4 index. The APRI score was calculated using Wai\u0026rsquo;s formula:[ (AST/upper limit of normal)/platelet count (\u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L)] \u0026times; 100 [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The FIB-4 index was calculated using Sterling\u0026rsquo;s formula: [age (years) \u0026times; AST (IU/L)] / [platelet count (\u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L) \u0026times; \u0026radic;ALT (IU/ L)] [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eLaboratory data were obtained within 3 months of LBx. Patients with C-reactive protein (CRP) over 1.00 mg/dL were excluded to avoid the effect of inflammation. Persistent IF was defined as IF patients required parental nutrition permanently. IFALD was defined as Total Bilirubin (TB)\u0026thinsp;\u0026gt;\u0026thinsp;2.0 mg/dL. Patients with existing IFALD were excluded. This study examined whether liver fibrosis before reaching the IFALD stage could be detected.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eM2BPGi measurement\u003c/h2\u003e \u003cp\u003eSerum M2BPGi levels were measured using a two-site enzyme immunoassay. The assay reagent, which is commercially available in Japan, was purchased from Sysmex Corporation (Kobe, Japan). Quantification of M2BPGi was based on a lectin\u0026ndash;antibody sandwich immunoassay using the fully automatic HISCL-800 immune analyzer (Sysmex Corporation). M2BPGi measurements were indexed with values obtained using the following equation: cutoff index (COI) = ([M2BPGi] sample [M2BPGi] NC)/([M2BPGi] PC + [M2BPGi] NC), in which [M2BPGi] sample is the M2BPGi concentration in the serum sample, NC is the negative control, and PC is the positive control. The PC was supplied as a calibration solution preliminarily standardized to yield a COI value of 1.0 [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eHistological assessment\u003c/h2\u003e \u003cp\u003eLBx samples were assessed with hematoxylin\u0026ndash;eosin and Masson\u0026rsquo;s trichrome stains. Percutaneous LBx was performed with a 16-gauge biopsy needle. All LBx were performed using an ultrasound-guided maneuver under either general anesthesia or intravenous sedation. The specimens were fixed in 4% phosphate-buffered formaldehyde and embedded in paraffin.\u003c/p\u003e \u003cp\u003eAfter hematoxylin\u0026ndash;eosin and Masson\u0026rsquo;s trichrome staining, LBx specimens were examined microscopically. Experienced pathologists in our hospital evaluated the samples. Fibrosis was staged as F0\u0026ndash;F4: F0, no fibrosis; F1, portal fibrosis without septa; F2, portal fibrosis with rare septa; F3, numerous septa without cirrhosis; and F4, liver cirrhosis [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNo serious procedure-related complications were observed. In this study, progressive fibrosis was defined as \u0026ge;\u0026thinsp;F2. The presence of fibrosis was defined as \u0026ge;\u0026thinsp;F1.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eReceiver operating characteristic (ROC) curve analysis was performed to calculate the area under the curve (AUC) for serum M2BPGi level and select the optimal cutoff value that maximized the sum of sensitivity and specificity for the presence of liver fibrosis (\u0026ge;\u0026thinsp;F1) and progressive fibrosis (\u0026ge;\u0026thinsp;F2) on histological examination. For continuous variables, comparisons among groups were performed using Student\u0026rsquo;s t-test. Data are expressed as medians (range). \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. Statistical analyses were performed with JMP 11 software (SAS Institute, Cary, NC, USA). This study was approved by our hospital institutional review board (approval number 21481).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eDemographic characteristics of the study patients\u003c/h2\u003e \u003cp\u003eThe characteristics of the study patients (n\u0026thinsp;=\u0026thinsp;8) are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. There were 4 males and 4 females, with a median age of 11.5 years (range, 1.8\u0026ndash;32 years). Laboratory data were from the time of the last LBx. Percutaneous LBx was performed 18 times; 18 specimens were obtained from 8 patients. A summary of LBx and laboratory values is presented in Table\u0026nbsp;2. Regarding the degree of liver fibrosis based on histological examination, F0 was observed in 3 specimens, F1 in 12, and F2 in 3. M2BPGi values in this study ranged from 0.48 to 1.62 COI (median, 0.74 COI). CRP ranged from 0.04 to 0.85 mg/dL. Total bilirubin ranged from 0.2 to 1.5 mg/dL. None of the patients had IFALD.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eM2BPGi and liver fibrosis\u003c/h2\u003e \u003cp\u003eBy fibrosis stage (F0\u0026ndash;F2), the mean M2BPGi value was 0.44 COI (SD, 0.06 COI) in patients with F0 fibrosis, 0.78 COI (SD, 0.39 COI) in patients with F1 fibrosis, and 1.63 COI (SD, 1.16 COI) in patients with F2 fibrosis. The mean M2BPGi value was significantly higher in patients with F2 versus F1 fibrosis (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.016) and in patients with F2 versus F0 fibrosis (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.028) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e(a)).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eOther fibrosis markers and liver fibrosis\u003c/h2\u003e \u003cp\u003eBy fibrosis stage (F0\u0026ndash;F2), the mean AST/ALT ratio was 1.36 (SD, 0.54) in patients with F0 fibrosis; 0.87 (SD, 0.27) in patients with F1 fibrosis, and 1.53 (SD, 0.62) in patients with F2 fibrosis. The mean AST/ALT ratio was significantly higher in patients with F2 versus F1 fibrosis (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.017) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e(b)). However, there was no statistically significant difference between patients with F2 and F0 fibrosis.\u003c/p\u003e \u003cp\u003eBy fibrosis stage (F0\u0026ndash;F2), mean APRI was 0.44 (SD, 0.10) in patients with F0 fibrosis, 0.61 (SD, 0.37) in patients with F1 fibrosis, and 0.54 (SD, 0.15) in patients with F2 fibrosis. There was no statistically significant difference between the groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e(c)).\u003c/p\u003e \u003cp\u003eBy fibrosis stage (F0\u0026ndash;F2), mean FIB-4 index was 0.41 (SD, 0.04) in patients with F0 fibrosis, 0.39 (SD, 0.35) in patients with F1 fibrosis, and 0.90 (SD, 0.16) in patients with F2 fibrosis. Mean FIB-4 index was significantly higher in patients with F2 versus F1 fibrosis (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.022) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb). However, there was no statistically significant difference between patients with F2 and F0 fibrosis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e(d)).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eM2BPGi and fibrosis stages over times\u003c/h2\u003e \u003cp\u003eM2BPGi and fibrosis stage at the first and latest liver biopsies of 6 patients who underwent liver biopsy more than once were plotted to figure out the progression of liver fibrosis in IFALD patients. (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) The interval between the first and latest liver biopsy was median 14.2 months (11.0-50.1months). There was no change in fibrosis stage in 5 cases during this observation period, and 1 case changed from F1 to F2. M2BPGi increased in 3 cases and decreased in 3 cases.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eROC curve analysis\u003c/h2\u003e \u003cp\u003eFor predicting progressive liver fibrosis (F2), a M2BPGi level of 1.62 COI yielded a high AUC (0.73). For presence of liver fibrosis (\u0026ge;\u0026thinsp;F1), an M2BPGi level of 0.44 COI yielded a high AUC (0.89) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e(a)\u0026ndash;(b)).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe prognosis of persistent IF depends on complications, including IFALD. The prognosis of IF with IFALD is poor [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The prognosis of IFALD depends greatly upon the extent of hepatic fibrosis. Patients with advanced liver fibrosis have higher morbidity due to complications from cirrhosis; they also have higher mortality [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In ultra-short bowel syndrome, IFALD occurs rapidly and cirrhosis is likely[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Patients with IF and IFALD might need combined liver and intestinal transplantation [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Early detection of liver fibrosis allows patient consultation at an intestinal rehabilitation and transplant center, pre-transplant evaluation, and transplant listing [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In Japan, it is necessary to perform isolated intestinal transplantation before IFALD and liver cirrhosis progression because combined transplantation of the liver and small intestines is difficult in Japan due to a shortage of donors.\u003c/p\u003e \u003cp\u003eTherefore, early detection of IFALD in development is important. For this purpose, identifying liver fibrosis progression is essential. However, the development of fibrosis cannot be detected by blood tests until the late stage [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. LBx is the standard for assessing the degree of liver fibrosis. However, it might cause complications such as organ injury, hemorrhage, and pain. In pediatric patients, general anesthesia is needed for LBx [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Serial LBx should be avoided, but it might be needed to follow the progression of fibrosis. Another problem is that the evaluation of fibrosis by LBx is uncertain due to sampling error and variation among observers [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. LBx provides a classified grading system that allows comparing fibrosis stage among patients. However, LBx allows for the evaluation at a static point. In addition, there are only five classifications (F0\u0026ndash;F4) in the METAVIR system. A marker that allows for the identification of patients with IFALD progression, in order to avoid repeating LBx procedures unnecessarily, is desirable.\u003c/p\u003e \u003cp\u003eIn recent years, several noninvasive tests have been developed. Noninvasive biomarkers for predicting fibrosis in patients with IFALD have been explored. APRI is one such biomarker of fibrosis. APRI has been used to detect fibrosis and cirrhosis in adult patients with hepatitis C [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In pediatric patients, APRI has been used to evaluate fibrosis progression during follow-up in biliary atresia [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. APRI\u0026thinsp;\u0026gt;\u0026thinsp;1.6 in patients with IFALD correlates with advanced fibrosis in the pediatric population [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. FIB-4 index is another fibrosis marker that has been used in patients with IFALD. FIB-4 index and liver fibrosis stage are positively correlated. This evaluation of FIB-4 index versus LBx supports the use of the FIB-4 index in the detection of liver fibrosis in IF [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. These methods detect high levels of liver fibrosis in IFALD that has already developed. They were inadequate for early detection of liver fibrosis before IFALD has developed. As a non-blood test\u0026ndash;based methods, transient elastography measures the elasticity or stiffness of the liver to detect more severe hepatic fibrosis using ultrasound. Ultrasound-based transient elastography is another less invasive method for evaluating liver fibrosis that has recently been reported as highly useful [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Its use in children has been reported [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. However, there have been no reports about early detection of liver fibrosis prior to the development of IFALD.\u003c/p\u003e \u003cp\u003eThese methods detect high levels of liver fibrosis and are inadequate for early detection. M2BPGi is a predictor of liver fibrosis that performed better than other markers such as FIB-4 index. M2BPGi might be the most reliable serum biomarker [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. M2BPGi is a marker for assessing liver fibrosis in viral hepatitis [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In addition, M2BPGi is useful for assessing liver fibrosis in patients with Primary Biliary Cholangitis [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], autoimmune hepatitis [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], and non-alcoholic fatty liver disease [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Its usefulness has been demonstrated in pediatric biliary atresia [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. M2BPGi might be useful for follow-up of fibrosis progression over time even if fibrosis stage remains constant [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eROC curve analysis demonstrated that serum M2BPGi levels in patients with IF have good diagnostic ability for detecting grade F2 fibrosis. We found that the degree of liver fibrosis differed by M2BPGi level. Our study suggests that M2BPGi is useful for predicting progressive fibrosis (\u0026ge;\u0026thinsp;F2) with a cutoff of 1.62 COI and the presence of liver fibrosis (\u0026ge;\u0026thinsp;F1) with a cutoff of 0.44 COI. LBx can be avoided until M2BPGi predicts the presence of liver fibrosis before IFALD in patients without jaundice. The primary strength of our study is the inclusion of a unique cohort of patients who underwent LBx before the development of IFALD. Once patients develop jaundice, IFALD can be easily detected. Utilizing the proposed cutoff values, sensitivity and specificity values are provided for future studies to include or exclude advanced liver fibrosis simply based on M2BPGi.\u003c/p\u003e \u003cp\u003eWe acknowledge several study limitations. The primary limitation of our study is the inclusion of only individuals preparing for intestinal transplantation. The study population does not cover all patients with IF. There were not enough patients to produce significant specificity and sensitivity in ROC curve analysis. Additionally, subgroup analysis about the correlation between the M2BPGi value and factors for liver damage could not be performed due to the small number of cases this time. Subgroups will be a primary disease, patients' age, duration, and composition of PN, length of residual intestine, presence of ileocecal valve, and so on. Further study is required after the accumulation of cases. The progression of liver fibrosis and the increase of M2BPGi were not evident in this study since there was not enough observation period. The relationship between the progress of liver fibrosis and the value of M2BPGi in IF patients are for further investigation. We did not perform elastography; thus, elastography findings could not be compared with M2BPGi data. Further analysis will be needed. Lastly, although M2BPGi is significantly correlated with fibrosis stage, the sensitivity of the M2BPGi index is insufficient. It should be used with other markers such as FIB-4 index before performing LBx to prove liver fibrosis.\u003c/p\u003e \u003cp\u003eIn conclusion, serum M2BPGi is a novel marker for liver fibrosis in patients with IF. It is especially useful for follow-up in patients with IF prior to IFALD. Serum M2BPGi levels can support the interpretation of liver status.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eCompliance with Ethical Standards\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e: The authors declare that they have no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study formal consent is not required\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eDuro D, Kamin D, Duggan C (2008) Overview of pediatric short bowel syndrome. 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Transplant Proc 50(9):2779-82. doi: 10.1016/j.transproceed.2018.03.067.\u003c/li\u003e\n \u003cli\u003eGanousse-Mazeron S, Lacaille F, Colomb-Jung V, Talbotec C, Ruemmele F, Sauvat F, et al (2015) Assessment and outcome of children with intestinal failure referred for intestinal transplantation. Clin Nutr34(3):428-35. doi: 10.1016/j.clnu.2014.04.015.\u003c/li\u003e\n \u003cli\u003eNoguchi Y, Ueno T, Matsuura R, Kodama T, Deguchi K, Umeda S, et al (2017) Liver Failure From Ultra-Short Bowel Syndrome on the Intestinal Transplant Waiting List: A Retrospective Study. Transplant Proc 49(1):135-8. doi: 10.1016/j.transproceed.2016.10.019.\u003c/li\u003e\n \u003cli\u003eTaha AM, Sharif K, Johnson T, Clarke S, Murphy MS, Gupte GL (2012) Long-term outcomes of isolated liver transplantation for short bowel syndrome and intestinal failure-associated liver disease. J Pediatr Gastroenterol Nutr54(4):547-51. doi: 10.1097/MPG.0b013e31823f42e7.\u003c/li\u003e\n \u003cli\u003eKaufman SS, Atkinson JB, Bianchi A, Goulet OJ, Grant D, Langnas AN, et al (2001) \u0026nbsp;Indications for pediatric intestinal transplantation: a position paper of the American Society of Transplantation. Pediatr Transplant 5(2):80-7. doi: 10.1034/j.1399-3046.2001.005002080.x.\u003c/li\u003e\n \u003cli\u003eFitzgibbons SC, Jones BA, Hull MA, Zurakowski D, Duro D, Duggan C, et al (2010) \u0026nbsp;Relationship between biopsy-proven parenteralnutrition-associated liver fibrosis and biochemical cholestasis in children with short bowel syndrome. J Pediatr Surg 45(1):95-9; discussion 9. doi: 10.1016/j.jpedsurg.2009.10.020.\u003c/li\u003e\n \u003cli\u003eFilingeri V, Sforza D, Tisone G (2015) Complications and risk factors of a large series of percutaneous liver biopsies in patients with liver transplantation or liver disease. Eur Rev Med Pharmacol Sci 19(9):1621-9.\u003c/li\u003e\n \u003cli\u003eBravo AA, Sheth SG, Chopra S \u0026nbsp;(2001) Liver biopsy. The New England journal of medicine 344(7):495-500. doi: 10.1056/NEJM200102153440706.\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(4):789-95. doi: 10.1016/j.jpedsurg.2012.10.010.\u003c/li\u003e\n \u003cli\u003eRumbo C, Martinez MI, Cabanne A, Trentadue J, Fern\u0026aacute;ndez A, Gondolesi G (2017) Utility of Aminotransferase/Platelet Ratio Index to Predict Liver Fibrosis in Intestinal Failure-Associated Liver Disease in Pediatric Patients. JPEN J Parenter Enteral Nutr 41(5):884-9. doi: 10.1177/0148607115625779.\u003c/li\u003e\n \u003cli\u003eMicic D, Huard G, Lee SM, Fiel MI, Moon J, Schiano TD, et al (2021) Evaluation of the fibrosis-4 index for detection of advanced fibrosis among individuals at risk for intestinal failure-associated liver disease. JPEN J Parenter Enteral Nutr doi: 10.1002/jpen.2135.\u003c/li\u003e\n \u003cli\u003eFoucher J, Chanteloup E, Vergniol J, Cast\u0026eacute;ra L, Le Bail B, Adhoute X, et al (2006) Diagnosis of cirrhosis by transient elastography (FibroScan): a prospective study. Gut 55(3):403-8. doi: 10.1136/gut.2005.069153.\u003c/li\u003e\n \u003cli\u003eWu JF, Lee CS, Lin WH, Jeng YM, Chen HL, Ni YH, et al (2018) Transient elastography is useful in diagnosing biliary atresia and predicting prognosis after hepatoportoenterostomy. Hepatology doi: 10.1002/hep.29856.\u003c/li\u003e\n \u003cli\u003eUchida H, Sakamoto S, Kobayashi M, Shigeta T, Matsunami M, Sasaki K, et al (2015) The degree of spleen stiffness measured on acoustic radiation force impulse elastography predicts the severity of portal hypertension in patients with biliary atresia after portoenterostomy. Journal of pediatric surgery 50(4):559-64. doi: 10.1016/j.jpedsurg.2014.12.026.\u003c/li\u003e\n \u003cli\u003eUmemura T, Joshita S, Sekiguchi T, Usami Y, Shibata S, Kimura T, et al (2015) Serum Wisteria floribunda Agglutinin-Positive Mac-2-Binding Protein Level Predicts Liver Fibrosis and Prognosis in Primary Biliary Cirrhosis. The American journal of gastroenterology 110(6):857-64. doi: 10.1038/ajg.2015.118.\u003c/li\u003e\n \u003cli\u003eAbe M, Miyake T, Kuno A, Imai Y, Sawai Y, Hino K, et al (2015) Association between Wisteria floribunda agglutinin-positive Mac-2 binding protein and the fibrosis stage of non-alcoholic fatty liver disease. Journal of gastroenterology 50(7):776-84. doi: 10.1007/s00535-014-1007-2.\u003c/li\u003e\n \u003cli\u003eUeno T, Kodama T, Noguchi Y, Nomura M, Saka R, Takama Y, et al (2019) Serum Mac-2-binding protein (M2BPGi) as a marker of chronological liver fibrosis in biliary atresia patients with cirrhosis. Pediatr Surg Int 35(10):1065-70. doi: 10.1007/s00383-019-04535-9.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1 Patient demographics:\u0026nbsp;\u003c/strong\u003eData were expressed as median with ranges. Histological findings were described by METAVIR score. AST: aspartate aminotransferase; ALT: alanine aminotransferase ; M2BPGi:Mac-2 binding protein glycosylation-modified isomer ; APRI: aspartate aminotransferase to platelet ratio index; FIB-4:Fibrosis-4 index\u003c/p\u003e\n\u003ctable border=\"0\" cellpadding=\"0\" cellspacing=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariables\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"52.74949083503055%\"\u003e\n \u003cp\u003e\u003cstrong\u003en=8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003eAge, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"52.74949083503055%\"\u003e\n \u003cp\u003e11.5(1.8-32)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003eGender, male/female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"52.74949083503055%\"\u003e\n \u003cp\u003e4/4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003eOriginal disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"52.74949083503055%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003eShort gut\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"52.74949083503055%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003eMotility disorder\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"52.74949083503055%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003eAST ,IU/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"52.74949083503055%\"\u003e\n \u003cp\u003e47(31-110)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003eALT ,IU/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"52.74949083503055%\"\u003e\n \u003cp\u003e71(21-124)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003eSerum albumin, g/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"52.74949083503055%\"\u003e\n \u003cp\u003e4.1(3.1-4.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003eTotal bilirubin, mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"52.74949083503055%\"\u003e\n \u003cp\u003e0.5(0.2-1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003eProthrombin time, INR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"52.74949083503055%\"\u003e\n \u003cp\u003e1.3(1.1-1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003ePlatelets, 10\u003csup\u003e4\u003c/sup\u003e/mm3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"52.74949083503055%\"\u003e\n \u003cp\u003e18.8(12.0-31.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003eM2BPGi\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"52.74949083503055%\"\u003e\n \u003cp\u003e0.74(0.48-1.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003eAPRI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"52.74949083503055%\"\u003e\n \u003cp\u003e0.52(0.38-1.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003eFIB-4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"52.74949083503055%\"\u003e\n \u003cp\u003e0.32(0.11-1.31)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003eLBx\u0026nbsp;performed, times\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"52.74949083503055%\"\u003e\n \u003cp\u003e2(1-5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003eInterval, months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"52.74949083503055%\"\u003e\n \u003cp\u003e14.2(11.0-50.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003eHistological findings\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"52.74949083503055%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003eF0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"52.74949083503055%\"\u003e\n \u003cp\u003e1\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003eF1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"52.74949083503055%\"\u003e\n \u003cp\u003e5\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003eF2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"52.74949083503055%\"\u003e\n \u003cp\u003e2\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\u003cbr/\u003e\n\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e2 Sampling demographics\u003c/strong\u003e\u003cstrong\u003e:\u0026nbsp;\u003c/strong\u003eData were expressed as median with ranges. Histological findings were described by METAVIR score. AST: aspartate aminotransferase; ALT: alanine aminotransferase ; M2BPGi:Mac-2 binding protein glycosylation-modified isomer ; APRI: aspartate aminotransferase to platelet ratio index; FIB-4:Fibrosis-4 index\u003c/p\u003e\n\u003ctable border=\"0\" cellpadding=\"0\" cellspacing=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariables\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"52.74949083503055%\"\u003e\n \u003cp\u003e\u003cstrong\u003en=18\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003eAge, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"52.74949083503055%\"\u003e\n \u003cp\u003e11.0(1.8-31.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003eAST ,IU/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"52.74949083503055%\"\u003e\n \u003cp\u003e37(23-110)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003eALT ,IU/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"52.74949083503055%\"\u003e\n \u003cp\u003e43(14-124)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003eSerum albumin, g/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"52.74949083503055%\"\u003e\n \u003cp\u003e4.0(3.0-4.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003eTotal bilirubin, mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"52.74949083503055%\"\u003e\n \u003cp\u003e0.5(0.2-1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003eProthrombin time, INR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"52.74949083503055%\"\u003e\n \u003cp\u003e1.2(1.1-1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003ePlatelets, 10\u003csup\u003e4\u003c/sup\u003e/mm3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"52.74949083503055%\"\u003e\n \u003cp\u003e18.3(11.8-39.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003eCRP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"52.74949083503055%\"\u003e\n \u003cp\u003e0.04(0.04-0.85)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003eM2BPGi\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"52.74949083503055%\"\u003e\n \u003cp\u003e0.58(0.4-2.79)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003eAPRI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"52.74949083503055%\"\u003e\n \u003cp\u003e0.50(0.35-1.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003eFIB-4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"52.74949083503055%\"\u003e\n \u003cp\u003e0.41(0.09-1.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003eAST/ALT ratio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"52.74949083503055%\"\u003e\n \u003cp\u003e0.91(0.49-2.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003eFibrosis stage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"52.74949083503055%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003eF0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"52.74949083503055%\"\u003e\n \u003cp\u003e3\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003eF1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"52.74949083503055%\"\u003e\n \u003cp\u003e12\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.25050916496945%\"\u003e\n \u003cp\u003eF2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"52.74949083503055%\"\u003e\n \u003cp\u003e3\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\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":"Mac-2 binding protein glycosylation-modified isomer (M2BPGi), Liver Fibrosis, Intestinal failure–associated liver disease (IFALD), Intestinal failure, Liver biopsy ","lastPublishedDoi":"10.21203/rs.3.rs-2047447/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2047447/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eMac-2 binding protein glycosylation-modified isomer (M2BPGi) is a new marker for hepatic fibrosis progression. We examined the relationship between serum M2BPGi levels and liver histological findings in intestinal failure (IF) patients without IF-associated liver disease (IFALD).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis study included IF patients without IFALD followed at our hospital. All patients underwent routine liver biopsies per protocol every 1\u0026ndash;2 years. We examined M2BPGi levels and histological findings in relation to aspartate aminotransferase (AST) to platelet ratio index, fibrosis-4 index, and AST/ALT ratio. Liver fibrosis was evaluated based on the METAVIR score.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eTotal 18 liver biopsies out of 8 patients were included. The median age was 11.5 years. Mean M2BPGi was 0.44 cutoff index (COI) in patients with F0 fibrosis; 0.78 COI in patients with F1 fibrosis; and 1.63 COI in patients with F2 fibrosis. Mean M2BPGi was significantly higher in patients with F2 versus F1 or F0 fibrosis (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.016 and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.028, respectively). M2BPGi levels were more strongly correlated with fibrosis stage than with other conventional fibrosis markers.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eSerum M2BPGi is a novel marker of liver fibrosis in patients with IF. It is useful for follow-up prior to IFALD. Serum M2BPGi levels can support the interpretation of liver status.\u003c/p\u003e","manuscriptTitle":"Early detection of liver fibrosis with serum Mac-2 binding protein glycosylation-modified isomer (M2BPGi) during follow-up intestinal failure patients without intestinal failure–associated liver disease (IFALD)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-09-13 19:50:43","doi":"10.21203/rs.3.rs-2047447/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2022-09-09T14:28:53+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"214417cc-123c-4578-bbd2-bb9abc982b4f","date":"2022-09-09T14:26:56+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2022-09-09T14:26:12+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2022-09-09T14:23:29+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2022-09-09T13:42:54+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pediatric Surgery International","date":"2022-09-09T05:07:21+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":"6df5efb7-7cea-4ae0-98c5-d92267b3a15e","owner":[],"postedDate":"September 13th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2022-09-13T19:50:43+00:00","versionOfRecord":[],"versionCreatedAt":"2022-09-13 19:50:43","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2047447","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2047447","identity":"rs-2047447","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}