Topical Collection "Biliary Atresia: Aetiology, Diagnosis and Treatment"

Editor

Prof. Dr. Claus Petersen
E-Mail Website
Guest Editor
Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany
Interests: neonatal cholestasis; biliary atresia; choledochal cyst

Topical Collection Information

Dear Colleagues,

Despite extensive clinical and basic research, we know very little about the aetiology and pathomechanism of biliary atresia (BA). Today, it is a matter of common sense that early diagnosis (screening programs), sequential surgical treatment (the Kasai procedure and optional liver transplantation), and thorough follow-up in paediatric liver units improve survival rates among BA patients with native livers. However, BA still remains the most frequent indication of paediatric liver transplantation in patients with an unfavourable outcome after the Kasai procedure because the survival with native liver drops below 30% over the long term. Therefore, the following aspects should be considered alongside individual health issues: first, early organ replacement is a multifactorial burden for the growing organism, and second, every patient who survives with their native liver relieves the limited availability of donor organs and benefits national health expenditures with economic savings.

From that point of view, international and interdisciplinary strategies are mandatory, in as much as BA is a rare disease. Over the last several years, national and international initiatives have been established in order to improve screening, centralization, diagnosis, as well as surgical and adjuvant treatment protocols. One such initiative is the recently launched European rare diseases network “rare-liver”.

Prof. Dr. Claus Petersen
Guest Editor

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Keywords

  • neonatal cholestasis
  • biliary atresia
  • registry
  • clinical research
  • basic research
  • rare diseases
  • transition
  • pediatric liver transplantation

Published Papers (13 papers)

2022

Jump to: 2021

Article
Primary Liver Transplantation vs. Transplant after Kasai Portoenterostomy for Infants with Biliary Atresia
J. Clin. Med. 2022, 11(11), 3012; https://doi.org/10.3390/jcm11113012 - 26 May 2022
Viewed by 407
Abstract
Introduction: Primary liver transplants (pLT) in patients with biliary atresia (BA) are infrequent, since most babies with BA undergo a prior Kasai portoenterostomy (KPE). This study compared transplant outcomes in children with BA with or without a prior KPE. We hypothesized that pLT [...] Read more.
Introduction: Primary liver transplants (pLT) in patients with biliary atresia (BA) are infrequent, since most babies with BA undergo a prior Kasai portoenterostomy (KPE). This study compared transplant outcomes in children with BA with or without a prior KPE. We hypothesized that pLT have less morbidity and better outcomes compared to those done after a failed KPE. Methods: A retrospective review of patients with BA transplanted at our institution was performed. Patients were included if they received a pLT or if they were transplanted less than 2 years from KPE. Outcomes were compared between those groups. Comparisons were also made based on era (early: 1997–2008 vs. modern: 2009–2020). p < 0.05 was considered significant. Results: Patients who received a pLT were older at diagnosis (141.5 ± 46.0 vs. KPE 67.1 ± 25.5 days, p < 0.001). The time between diagnosis and listing for transplant was shorter in the pLT group (44.5 ± 44.7 vs. KPE 140.8 ± 102.8 days, p < 0.001). In the modern era, the calculated PELD score for the pLT was significantly higher (23 ± 8 vs. KPE 16 ± 8, p = 0.022). Two waitlist deaths occurred in the KPE group (none in pLT, p = 0.14). Both the duration of transplant surgery and transfusion requirements were similar in both groups. There was a significant improvement in graft survival in transplants after KPE between eras (early era 84.3% vs. modern era 97.8%, p = 0.025). The 1-year patient and graft survival after pLT was 100%. Conclusions: Patient and graft survival after pLT are comparable to transplants after a failed KPE but pLT avoids a prior intervention. There was no significant difference in pre- or peri-transplant morbidity between groups other than wait list mortality. A multicenter collaboration with more patients may help demonstrate the potential benefits of pLT in patients predicted to have early failure of KPE. Full article
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Article
Variability of Care and Access to Transplantation for Children with Biliary Atresia Who Need a Liver Replacement
J. Clin. Med. 2022, 11(8), 2142; https://doi.org/10.3390/jcm11082142 - 12 Apr 2022
Cited by 1 | Viewed by 544
Abstract
Background & Aims: Biliary atresia (BA) is the commonest single etiology indication for liver replacement in children. As timely access to liver transplantation (LT) remains challenging for small BA children (with prolonged waiting time being associated with clinical deterioration leading to both preventable [...] Read more.
Background & Aims: Biliary atresia (BA) is the commonest single etiology indication for liver replacement in children. As timely access to liver transplantation (LT) remains challenging for small BA children (with prolonged waiting time being associated with clinical deterioration leading to both preventable pre- and post-transplant morbidity and mortality), the care pathway of BA children in need of LT was analyzed—from diagnosis to LT—with particular attention to referral patterns, timing of referral, waiting list dynamics and need for medical assistance before LT. Methods: International multicentric retrospective study. Intent-to-transplant study analyzing BA children who had indication for LT early in life (aged < 3 years at the time of assessment), over the last 5 years (2016–2020). Clinical and laboratory data of 219 BA children were collected from 8 transplant centers (6 in Europe and 2 in USA). Results: 39 patients underwent primary transplants. Children who underwent Kasai in a specialist -but not transplant- center were older at time of referral and at transplant. At assessment for LT, the vast majority of children already were experiencing complication of cirrhosis, and the majority of children needed medical assistance (nutritional support, hospitalization, transfusion of albumin or blood) while waiting for transplantation. Severe worsening of the clinical condition led to the need for requesting a priority status (i.e., Peld Score exception or similar) for timely graft allocation for 76 children, overall (35%). Conclusions: As LT currently results in BA patient survival exceeding 95% in many expert LT centers, the paradigm for BA management optimization and survival have currently shifted to the pre-LT management. The creation of networks dedicated to the timely referral to a pediatric transplant center and possibly centralization of care should be considered, in combination with implementing all different graft type surgeries in specialist centers (including split and living donor LTs) to achieve timely LT in this vulnerable population. Full article
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Article
Features of Nodules in Explants of Children Undergoing Liver Transplantation for Biliary Atresia
J. Clin. Med. 2022, 11(6), 1578; https://doi.org/10.3390/jcm11061578 - 13 Mar 2022
Viewed by 546
Abstract
(1) Background: In patients with biliary atresia (BA) liver nodules can be identified either by pre-transplant imaging or on the explant. This study aimed to (i) analyze the histopathology of liver nodules, and (ii) to correlate histopathology with pretransplant radiological features. (2) Methods: [...] Read more.
(1) Background: In patients with biliary atresia (BA) liver nodules can be identified either by pre-transplant imaging or on the explant. This study aimed to (i) analyze the histopathology of liver nodules, and (ii) to correlate histopathology with pretransplant radiological features. (2) Methods: Retrospective analysis of liver nodules in explants of BA patients transplanted in our center (2000–2021). Correlations with pretransplant radiological characteristics, patient age at liver transplantation (LT), time from Kasai hepatoportoenterostomy (KPE) to LT, age at KPE and draining KPE. (3) Results: Of the 63 BA-patients included in the analysis, 27/63 (43%) had nodules on explants. A majority were benign macroregenerative nodules. Premalignant (low-grade and high-grade dysplastic) and malignant (hepatocellular carcinoma) nodules were identified in 6/63 and 2/63 patients, respectively. On pretransplant imaging, only 13/63 (21%) patients had liver nodules, none meeting radiological criteria for malignancy. The occurrence of liver nodules correlated with patient age at LT (p < 0.001), time KPE-LT (p < 0.001) and draining KPE (p = 0.006). (4) Conclusion: In BA patients, pretransplant imaging did not correlate with the presence of liver nodules in explants. Liver nodules were frequent in explanted livers, whereby 25% of explants harboured malignant/pre-malignant nodules, emphasizing the need for careful surveillance in BA children whose clinical course may require LT. Full article
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Article
Controversies in Choledochal Malformation in Children: An International Survey among Pediatric Hepatobiliary Surgeons and Gastroenterologists
J. Clin. Med. 2022, 11(4), 1148; https://doi.org/10.3390/jcm11041148 - 21 Feb 2022
Viewed by 585
Abstract
Background: While congenital choledochal malformation (CCM) is relatively well known within the pediatric surgical and pediatric gastroenterological communities, many controversies and questions remain. Methods: In this paper, we will discuss the results of an international Delphi survey among members of the European Reference [...] Read more.
Background: While congenital choledochal malformation (CCM) is relatively well known within the pediatric surgical and pediatric gastroenterological communities, many controversies and questions remain. Methods: In this paper, we will discuss the results of an international Delphi survey among members of the European Reference Network RARE-LIVER and of the faculty of the Biliary Atresia and Related Diseases (BARD) network to identify the most common practices as well as controversies regarding diagnosis, treatment and follow-up of this still enigmatic disease. Results: Twenty-two individual respondents completed the survey. While there seems to be agreement on the definitions of CCM, preoperative workup, surgical approach and follow-up still vary considerably. The mainstay of treatment remains the removal of the entire extrahepatic biliary tract, clearance of debris both proximally and distally, followed by reconstruction with (according to 86% of respondents) a Roux-en-Y hepaticojejunostomy. Nonetheless, both laparoscopic and robotic-assisted resections are gaining ground with the suggestion that this might be facilitated by concentration of care and resources in specialized centers. However, long-term outcomes are still lacking. Conclusions: As even post-surgical CCM has to be considered as having premalignant potential, follow-up should be well-organized and continued into adulthood. This seems to be lacking in many centers. International cooperation for both benchmarking and research is paramount to improving care for this rare disease. Full article
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Article
Biliary Atresia in 2021: Epidemiology, Screening and Public Policy
J. Clin. Med. 2022, 11(4), 999; https://doi.org/10.3390/jcm11040999 - 14 Feb 2022
Cited by 3 | Viewed by 647
Abstract
Biliary atresia (BA) is a rare newborn liver disease with significant morbidity and mortality, especially if not recognized and treated early in life. It is the most common cause of liver-related death in children and the leading indication for liver transplantation in the [...] Read more.
Biliary atresia (BA) is a rare newborn liver disease with significant morbidity and mortality, especially if not recognized and treated early in life. It is the most common cause of liver-related death in children and the leading indication for liver transplantation in the pediatric population. Timely intervention with a Kasai portoenterostomy (KPE) can significantly improve prognosis. Delayed disease recognition, late patient referral, and untimely surgery remains a worldwide problem. This article will focus on biliary atresia from a global public health perspective, including disease epidemiology, current national screening programs, and their impact on outcome, as well as new and novel BA screening initiatives. Policy challenges for the implementation of BA screening programs will also be discussed, highlighting examples from the North American, European, and Asian experience. Full article
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Article
Incidence, Impact and Treatment of Ongoing CMV Infection in Patients with Biliary Atresia in Four European Centres
J. Clin. Med. 2022, 11(4), 945; https://doi.org/10.3390/jcm11040945 - 11 Feb 2022
Cited by 1 | Viewed by 489
Abstract
Cytomegalovirus (CMV) infection has been suggested to be of importance for the development and outcome of biliary atresia (BA). However, most data are only available from single centre studies. We retrospectively collected data on rates, outcomes, and treatments for ongoing CMV infection at [...] Read more.
Cytomegalovirus (CMV) infection has been suggested to be of importance for the development and outcome of biliary atresia (BA). However, most data are only available from single centre studies. We retrospectively collected data on rates, outcomes, and treatments for ongoing CMV infection at the time of Kasai portoenterostomy (KPE) from four different tertiary centres in Europe. The rate of ongoing CMV infection varied between 10–32% in the four centres. CMV positive patients were significantly older and had higher levels of several liver biochemistries at the time of KPE (p < 0.05 for all comparisons). In the largest centre, CMV infection was more common in non-Caucasians, and CMV infected patients had poorer long-term survival with native liver than CMV negative patients (p = 0.0001). In contrast, survival with native liver in the subgroup of CMV infected patients who had received antiviral treatment was similar to the CMV negative group. We conclude that ongoing CMV infection at the time of KPE occurs in a significant proportion of BA patients and that these patients seem to differ from CMV negative patients regarding age and biochemistry at the time of KPE as well as long-term survival with native liver. The latter difference may be reduced by antiviral treatment, but randomized, controlled trials are needed before such treatment can be recommended routinely. Full article
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Article
Cholangitis Definition and Treatment after Kasai Hepatoportoenterostomy for Biliary Atresia: A Delphi Process and International Expert Panel
J. Clin. Med. 2022, 11(3), 494; https://doi.org/10.3390/jcm11030494 - 19 Jan 2022
Viewed by 640
Abstract
(1) Background: Acute cholangitis during the first year after Kasai hepatoportoenterostomy (HPE) has a negative impact on patient and native liver survival. There are no consistent guidelines for the definition, treatment, and prophylaxis of cholangitis after HPE. The aim of this study was [...] Read more.
(1) Background: Acute cholangitis during the first year after Kasai hepatoportoenterostomy (HPE) has a negative impact on patient and native liver survival. There are no consistent guidelines for the definition, treatment, and prophylaxis of cholangitis after HPE. The aim of this study was to develop definition, treatment, and prophylaxis guidelines to allow for expeditious management and for standardization in reporting. (2) Methods: the Delphi method, an extensive literature review, iterative rounds of surveys, and expert panel discussions were used to establish definition, treatment, and prophylaxis guidelines for cholangitis in the first year after HPE. (3) Results: Eight elements (pooled into two groups: clinical and laboratory/imaging) were identified to define cholangitis after HPE. The final proposed definitions for suspected and confirmed cholangitis are a combination of one element, respectively, two elements from each group; furthermore, the finding of a positive blood culture was added to the definition of confirmed cholangitis. The durations for prophylaxis and treatment of suspected and confirmed cholangitis were uniformly agreed upon by the experts. (4) Conclusions: for the first time, an international consensus was found for guidelines for definition, treatment, and prophylaxis for cholangitis during the first year after Kasai HPE. Applicability will need further prospective multicentered studies. Full article
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2021

Jump to: 2022

Article
Adjuvant Therapy with Budesonide Post-Kasai Reduces the Need for Liver Transplantation in Biliary Atresia
J. Clin. Med. 2021, 10(24), 5758; https://doi.org/10.3390/jcm10245758 - 09 Dec 2021
Viewed by 805
Abstract
Based on the hypothesis that autoimmunological factors coregulate the pathomechanism in biliary atresia (BA), adjuvant therapy with steroids has become routine, although its efficacy has never been proven. In 2010, a study on the advantages of budesonide compared to prednisolone in autoimmune hepatitis [...] Read more.
Based on the hypothesis that autoimmunological factors coregulate the pathomechanism in biliary atresia (BA), adjuvant therapy with steroids has become routine, although its efficacy has never been proven. In 2010, a study on the advantages of budesonide compared to prednisolone in autoimmune hepatitis gave rise to experimental therapy using budesonide as an adjuvant BA treatment. Ninety-five BA patients prospectively received a budesonide 2 mg/dose rectal foam daily for three months (SG). A case-matched control group (CG: 81) was retrospectively recruited. The outcome measures were survival with native liver (SNL), determined at six months and two years after the Kasai procedure. The follow-up rate was 100%. At six months, SNL was statistically not different but became so after two years (SG: 54%; CG: 32%; p < 0.001). No steroid-related side effects were observed, except for eight patients with finally caught-up growth retardation. This study demonstrates for the first time a significantly longer survival with native liver in patients with BA after adjuvant therapy. However, indication, dosage, and duration of any budesonide application is not given in neonates with BA. Hence, we suggest extending the postoperative use of budesonide in a multicenter observational study with a clearly defined follow-up protocol, particularly in terms of potentially underestimated side effects. Full article
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Review
Biliary Atresia: Clinical Phenotypes and Aetiological Heterogeneity
J. Clin. Med. 2021, 10(23), 5675; https://doi.org/10.3390/jcm10235675 - 01 Dec 2021
Cited by 3 | Viewed by 1085
Abstract
Biliary atresia (BA) is an obliterative condition of the biliary tract that presents with persistent jaundice and pale stools typically in the first few weeks of life. While this phenotypic signature may be broadly similar by the time of presentation, it is likely [...] Read more.
Biliary atresia (BA) is an obliterative condition of the biliary tract that presents with persistent jaundice and pale stools typically in the first few weeks of life. While this phenotypic signature may be broadly similar by the time of presentation, it is likely that this is only the final common pathway with a number of possible preceding causative factors and disparate pathogenic mechanisms—i.e., aetiological heterogeneity. Certainly, there are distinguishable variants which suggest a higher degree of aetiological homogeneity such as the syndromic variants of biliary atresia splenic malformation or cat-eye syndrome, which implicate an early developmental mechanism. In others, the presence of synchronous viral infection also make this plausible as an aetiological agent though it is likely that disease onset is from the perinatal period. In the majority of cases, currently termed isolated BA, there are still too few clues as to aetiology or indeed pathogenesis. Full article
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Brief Report
Prepregnancy Assessment of Liver Function to Predict Perinatal and Postpregnancy Outcomes in Biliary Atresia Patients with Native Liver
J. Clin. Med. 2021, 10(17), 3956; https://doi.org/10.3390/jcm10173956 - 31 Aug 2021
Cited by 1 | Viewed by 1017
Abstract
Considering that some biliary atresia (BA) survivors with native liver have reached reproductive age and face long-lasting complications, specific attention needs to be paid to pregnant cases. This study aimed to investigate the relationship between liver function, perinatal outcomes, and prognosis. A database [...] Read more.
Considering that some biliary atresia (BA) survivors with native liver have reached reproductive age and face long-lasting complications, specific attention needs to be paid to pregnant cases. This study aimed to investigate the relationship between liver function, perinatal outcomes, and prognosis. A database review was conducted to identify pregnant BA cases with native liver and perinatal data, and clinical information on BA-related complications was analyzed. Perinatal serum cholinesterase (ChE) levels, model for end-stage liver-disease (MELD) score, and platelet trends were analyzed, and the association between these indicators and perinatal outcomes was investigated. Patients were categorized into three groups according to the perinatal clinical outcomes: favorable (term babies with or without several episodes of cholangitis; n = 3), borderline (term baby and following liver dysfunction; n = 1), and unfavorable (premature delivery with subsequent liver failure; n = 1). Lower serum ChE levels, lower platelet counts, and higher MELD scores were observed in the unfavorable category. Borderline and unfavorable patients displayed a continuous increase in MELD score, with one eventually needing a liver transplantation. Pregnancy in patients with BA requires special attention. Serum ChE levels, platelet counts, and MELD scores are all important markers for predicting perinatal prognosis. Full article
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Article
Increased Serum Levels of Activated Caspases in Murine and Human Biliary Atresia
J. Clin. Med. 2021, 10(12), 2718; https://doi.org/10.3390/jcm10122718 - 19 Jun 2021
Viewed by 718
Abstract
In biliary atresia (BA), apoptosis is part of the pathomechanism, which results in progressive liver fibrosis. There is increasing evidence suggesting that apoptotic liver injury can be non-invasively detected by measuring the caspase activity in the serum. The purpose of this study was [...] Read more.
In biliary atresia (BA), apoptosis is part of the pathomechanism, which results in progressive liver fibrosis. There is increasing evidence suggesting that apoptotic liver injury can be non-invasively detected by measuring the caspase activity in the serum. The purpose of this study was to investigate whether serological detection of caspase activation mirrors apoptotic liver injury in the infective murine BA-model and represents a suitable biomarker for BA in humans. Analysis showed increased caspase-3 activity and apoptosis in the livers of cholestatic BALB/c mice, which correlated significantly with caspase activation in the serum. We then investigated caspase activation and apoptosis in liver tissues and sera from 26 BA patients, 23 age-matched healthy and 11 cholestatic newborns, due to other hepatopathies. Compared to healthy individuals, increased caspase activation in the liver samples of BA patients was present. Moreover, caspase-3 activity was significantly higher in sera from BA infants compared to patients with other cholestatic diseases (sensitivity 85%, specificity 91%). In conclusion, caspase activation and hepatocyte apoptosis play an important role in experimental and human BA. We demonstrated that serological detection of caspase activation represents a reliable non-invasive biomarker for monitoring disease activity in neonatal cholestatic liver diseases including BA. Full article
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Article
Prognostic and Pathophysiologic Significance of IL-8 (CXCL8) in Biliary Atresia
J. Clin. Med. 2021, 10(12), 2705; https://doi.org/10.3390/jcm10122705 - 18 Jun 2021
Cited by 2 | Viewed by 716
Abstract
Interleukin (IL)-8 (CXCL8), a chemokine involved in neutrophil recruitment, has been implicated in ductular reaction and liver fibrogenesis. We studied liver and serum IL-8 expression in a large biliary atresia (BA) cohort and explored its prognostic and pathophysiological potential. IL-8 expression was assessed [...] Read more.
Interleukin (IL)-8 (CXCL8), a chemokine involved in neutrophil recruitment, has been implicated in ductular reaction and liver fibrogenesis. We studied liver and serum IL-8 expression in a large biliary atresia (BA) cohort and explored its prognostic and pathophysiological potential. IL-8 expression was assessed in liver utilizing quantitative polymerase chain reaction (qPCR), immunohistochemistry and in situ hybridization and in serum using an enzyme-linked immunosorbent assay, among 115 BA patients, 10 disease controls and 68 normal controls. Results were correlated to portoenterostomy (PE) outcomes, biochemical and histological liver injury, transcriptional markers of fibrosis and cholangiocytes, and expression of other related cytokines. IL-8 was markedly overexpressed in liver and serum of BA patients at PE (n = 88) and in serum samples obtained during postoperative follow-up (n = 40). IL-8 expression in the liver was predominantly in cholangiocytes within areas of ductular reaction. Liver IL-8 mRNA expression correlated positively with its serum concentration, bile ductular proliferation, Metavir fibrosis stage, and transcriptional markers of activated myofibroblasts (ACTA2) and cholangiocytes (KRT19). Taken together, IL-8 may mediate liver injury in BA by promoting ductular reaction and associated liver fibrogenesis. Prognostic value of serum IL-8 to predict native liver survival was limited and confined to the postoperative period after PE. Full article
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Article
Growth Factors Assessed during Kasai Procedure in Liver and Serum Are Not Predictive for the Postoperative Liver Deterioration in Infants with Biliary Atresia
J. Clin. Med. 2021, 10(9), 1978; https://doi.org/10.3390/jcm10091978 - 05 May 2021
Cited by 1 | Viewed by 746
Abstract
Background: Biliary atresia (BA) is a neonatal cholangiopathy characterized by progressive destruction of the biliary system resulting in liver cirrhosis. Residual bile drainage can temporarily be achieved through Kasai portoenterostomy (KPE) and some children show long-term survival with their native liver. However, most [...] Read more.
Background: Biliary atresia (BA) is a neonatal cholangiopathy characterized by progressive destruction of the biliary system resulting in liver cirrhosis. Residual bile drainage can temporarily be achieved through Kasai portoenterostomy (KPE) and some children show long-term survival with their native liver. However, most children eventually require liver transplantation (LTX). As several growth factors (GF) and chemokines have been shown to promote fibrogenesis in the liver, we assessed whether GF are predictive for the course of disease. Material and Methods: Liver and sera samples were collected from 49 infants with BA during KPE. Levels of 13 different GF were measured by multiplex immunoassay. Patient outcomes were stratified into favorable (bilirubin < 20 µmol/L at 2-year follow-up) and unfavorable (LTX). GF levels were compared between groups by a t-test, correlation coefficients were calculated, and principal component analyses performed. Results: Twenty-two patients showed a favorable and 27 an unfavorable disease course. No relation of GF and outcome could be established. In both groups, high levels of SDF-1alpha/CXCL12 (1473.0 ± 497.5 pg/mL), FGF2 (301.2 ± 207.8 pg/mL), and VEGF-a (209.0 ± 146.4 pg/mL) levels were measured within the liver, followed (in descending order) by PDGF-bb, LIF, GM-CSF, BDNF, VEGF-d, beta-NGF, IL-7, SCF, PIGF-1, and EGF. Serum marker levels showed much higher mean variation compared to hepatic values and no correlation to the protein microenvironment in the liver. Conclusions: Our study demonstrates high amounts of GF in livers from infants with BA at KPE, but no correlation to the outcome or serum values could be established. Our data suggest that local or systemic GF levels are unsuitable for prediction of the disease course. Collectively, we conclude that in BA the degree of proliferative activity caused by GF is a dismissible factor for the further course of disease. Full article
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