Molecular signature of active fibrogenesis prevails in biliary atresia after successful portoenterostomy

Kerola, Anna; Lampela, Hanna; Heikkilä, Päivi; Mutanen, Annika; Jalanko, Hannu; Pakarinen, Mikko P.

doi:10.1016/j.surg.2017.04.013

Cited by 22 publications

(14 citation statements)

References 39 publications

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“…20,24,25 In our earlier study, a molecular signature of active fibrogenesis persisted after a successful PE, whereas the RNA expression of various Th1 and Th2 proinflammatory cytokines was low, suggesting that inflammation may have a less central role in the progression of fibrosis after the clearance of jaundice. 32 In the present study, the coupling of TGF superfamily cytokines with the expression of α-SMA, a marker of extracellular matrix-producing myofibroblast, strengthens their role as active regulators of native liver fibrogenesis after the clearance of jaundice in BA.…”

Section: Discussionsupporting

confidence: 66%

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Divergent expression of liver transforming growth factor superfamily cytokines after successful portoenterostomy in biliary atresia

Kerola

Heikkilä

Mutanen

et al. 2019

Surgery

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Background: Pathogenesis of progressive liver fibrosis in biliary atresia after successful portoenterostomy remains unclear. We related hepatic expression of transforming growth factor beta (TGF-β) superfamily cytokines to histologic liver injury after successful portoenterostomy. Methods: Enrolled in our study were 28 patients with biliary atresia who had liver biopsies obtained during and after successful portoenterostomy, which normalized serum bilirubin (< 20 μmol/l). Biopsies were evaluated for cholestasis, inflammation, ductal reaction, and fibrosis and were stained immunohistochemically for transforming growth factor beta 1, transforming growth factor beta 2, connective tissue growth factor, and decorin. Respective gene expression (TGFB1, TGFB2, TGFB3, CTGF, DCN) was analyzed at follow-up using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Results were compared with fibrotic and healthy control livers. Results: After median follow-up of 3.0 years, histologic cholestasis resolved, whereas fibrosis had progressed only in isolated biliary atresia. Liver protein expression of transforming growth factor beta 1 and connective tissue growth factor (P < .001 for both), but not that of transforming growth factor beta 2 or decorin, decreased after successful portoenterostomy, although expression of all four cytokines remained elevated. In accordance with postportoenterostomy changes in protein expression, follow-up ribonucleic acid expression of TGFB2 and DCN, but not that of TGFB1 and CTGF, was upregulated when compared with the controls. Both protein and gene expression of transforming growth factor beta 1 and protein expression of transforming growth factor beta 2, connective tissue growth factor and decorin correlated with METAVIR fibrosis stage. Syndromic patients (n = 12) showed milder fibrosis and lower transforming growth factor beta 1 expression than patients with isolated biliary atresia. Conclusion: These findings support a central role of transforming growth factor beta superfamily in mediating continuing liver fibrogenesis after successful portoenterostomy. Transforming growth factor beta pathway cytokines responded divergently to clearance of jaundice, which was reflected by differential progression of fibrosis between syndromic and isolated patients.

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Section: Discussionsupporting

confidence: 66%

“…Immunostaining for α-SMA, a marker of activated myofibroblasts, was performed as described in detail elsewhere. 32 The proportion of the antibody-positive area to the entire biopsy surface area (area fraction) was calculated for CK-7 and α-…”

Section: Liver Biopsies and Immunohistochemistrymentioning

confidence: 99%

Divergent expression of liver transforming growth factor superfamily cytokines after successful portoenterostomy in biliary atresia

Kerola

Heikkilä

Mutanen

et al. 2019

Surgery

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“…Resident macrophages also play a role in fibrogenesis with a transition from M1 to M2 profiles. The combination of these cells with the secretion of soluble mediators like IL‐8, transforming growth factor‐beta, platelet‐derived growth factor, chemokine (C‐X‐C motif) ligand 1, and toll‐like receptor 4 are likely to create an ecosystem conducive to excessive fibrosis in BA …”

Section: Basic Researchmentioning

confidence: 99%

“…The combination of these cells with the secretion of soluble mediators like IL-8, transforming growth factor-beta, platelet-derived growth factor, chemokine (C-X-C motif ) ligand 1, and toll-like receptor 4 are likely to create an ecosystem conducive to excessive fibrosis in BA. (33) Several nonimmune factors have been implicated in triggering and amplifying fibrogenic signals in human cholangiopathies, but few have been systematically studied in BA. Tissue analyses from patients with BA and other cholangiopathies identify "reactive ductular cells," a population of cholangiocyte-like cells that are thought to participate in tissue repair and join portal myofibroblasts and stellate cells in the regulation of biliary cirrhosis.…”

Section: Fibrosismentioning

confidence: 99%

Biliary Atresia: Clinical and Research Challenges for the Twenty‐First Century

et al. 2018

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Biliary atresia (BA) is a fibroinflammatory disease of the intra- and extrahepatic biliary tree. Without medical treatment, surgical hepatic portoenterosmy (HPE) may restore bile drainage, but progression of the intrahepatic disease results in complications of portal hypertension and advanced cirrhosis in most children. Recognizing that further progress in the field is unlikely without a better understanding of the underlying cause(s) and pathogenesis of the disease, the National Institutes of Diabetes and Digestive and Kidney Diseases sponsored a research workshop focused on innovative and promising approaches and on identifying future areas of research. Investigators discussed recent advances using gestational ultrasound and results of newborn BA screening with serum direct (conjugated) bilirubin that support a pre-natal onset of biliary injury. Experimental and human studies implicate the toxic properties of environmental toxins (e.g. biliatresone) and of viruses (e.g. CMV) to the biliary system. Among host factors, sequence variants in genes related to biliary development and ciliopathies, a notable lack of a cholangiocyte glycocalyx and of submucosal collagen bundles in the neonatal extrahepatic bile ducts, and an innate pro-inflammatory bias of the neonatal immune system contribute to an increased susceptibility to damage and obstruction following an epithelial injury. These advances form the foundation for a future research agenda focused on identifying the environmental and host factor(s) that cause BA, the potential use of population screening, studies of the mechanisms of prominent fibrosis in young infants, determinations of clinical surrogates of disease progression, and the design of clinical trials that target subgroups of patients with initial drainage following HPE. This article is protected by copyright. All rights reserved.

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“…1 , 23-26 Indeed, the minority of patients who demonstrate less progressive fibrosis after successful PEostomy also express less pronounced ductular reaction than others. 24,27 Retention of hydrophobic bile acids has been shown to promote ductular reaction-driven fibrosis in other congenital cholangiopathies. 28 Accordingly, by reflecting efficient bile flow and hepatic clearance of bile acids, very low postoperative serum bilirubin levels may indicate less active ductular reaction and, therefore, slower fibrosis progression in BA.…”

Section: Discussionmentioning

confidence: 99%

Very low bilirubin after portoenterostomy improves survival of the native liver in patients with biliary atresia by deferring liver fibrogenesis

Hukkinen

Kerola

Jahnukainen

et al. 2019

Surgery

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Background: Progression of fibrosis and ensuing complications determine the postoperative course of patients operated on for biliary atresia. We evaluated predictors of the progression of fibrosis in the native liver after operative treatment. Methods: Among patients whose bilirubin decreased to < 34 μmol/L after portoenterostomy (n = 41), predictors of follow-up cirrhosis and the progression of fibrosis were analyzed with logistic regression and survival of their native liver was evaluated with the Kaplan-Meier method. Areas under receiving operating characteristic were used to define optimal cutoffs. Results: After median follow-up of 5.2 years (interquartile range 1.6-10.2) after portoenterostomy, liver biopsies showed cirrhosis in 53% of patients, and the Metavir stage remained stable or decreased in 38%. The development of cirrhosis was predicted by total or conjugated bilirubin ≥170/120 μmol/L at the time of portoenterostomy (P ≤ .009); normalization of bilirubin within 1.9 months (P = .002); total or conjugated bilirubin ≥ 12.5/7.5 μmol/L (P = .002) and aspartate aminotransferase-to-platelet ratio ≥ 0.55 at 3 months postoperatively (P = .001); and total or conjugated bilirubin ≥ 7.5/2.5 μmol/L (P ≤ .001), aspartate aminotransferase-to-platelet ratio ≥ 0.63 (P = .004), and gamma glutamyl transferase ≥ 266 U/L (P = .007) at 6 months postoperatively. In multiple regression analysis, conjugated bilirubin ≥ 2.5 μmol/L at 6 months increased the risk of cirrhosis 35-fold (P = .020), and other predictors were not predictive. Total or conjugated bilirubin < 12.5/7.5 μmol/L (P ≤ .014), aspartate aminotransferase-to-platelet ratio < 0.55 at 3 months (P = .006), and total or conjugated bilirubin < 7.5/2.5 μmol/L at 6 months postoperatively (P ≤ .014) were the strongest predictors of a stable, nonprogressive fibrosis. Decreases in total or conjugated bilirubin to < 12.5/7.5 μmol/L by 3 months and to < 7.5/2.5 μmol/L by 6 months improved survival of the native liver (log-rank P ≤ .025). Age at follow-up or at portoenterostomy, anatomic type of biliary atresia, use of postoperative steroids, and episodes of cholangitis were unrelated to the progression of fibrosis or the development of cirrhosis (P = not significant). Conclusion: Among patients whose serum bilirubin normalizes after portoenterostomy, its rapid decrease to very low levels prolongs the survival of their native liver by delaying the progression of fibrosis.

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Molecular signature of active fibrogenesis prevails in biliary atresia after successful portoenterostomy

Cited by 22 publications

References 39 publications

Divergent expression of liver transforming growth factor superfamily cytokines after successful portoenterostomy in biliary atresia

Divergent expression of liver transforming growth factor superfamily cytokines after successful portoenterostomy in biliary atresia

Biliary Atresia: Clinical and Research Challenges for the Twenty‐First Century

Very low bilirubin after portoenterostomy improves survival of the native liver in patients with biliary atresia by deferring liver fibrogenesis

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