The histological quantification of alpha-smooth muscle actin predicts future graft fibrosis in pediatric liver transplant recipients
Sharat Varma
Service de Gastroentérologie et Hépatologie Pédiatrique, Université Catholique de Louvain, Cliniques Universitaires St Luc, Brussels, Belgium
Pediatric Research Unit, Université Catholique de Louvain, Cliniques Universitaires St Luc, Brussels, Belgium
Search for more papers by this authorXavier Stéphenne
Service de Gastroentérologie et Hépatologie Pédiatrique, Université Catholique de Louvain, Cliniques Universitaires St Luc, Brussels, Belgium
Pediatric Research Unit, Université Catholique de Louvain, Cliniques Universitaires St Luc, Brussels, Belgium
Search for more papers by this authorMina Komuta
Service de Anatomopathologie, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Cliniques Universitaires St Luc, Brussels, Belgium
Search for more papers by this authorCaroline Bouzin
Imaging Platform (2IP), Université Catholique de Louvain, Cliniques Universitaires St Luc, Brussels, Belgium
Search for more papers by this authorJerome Ambroise
Centre for Applied Molecular Technologies (CTMA), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Cliniques Universitaires St Luc, Brussels, Belgium
Search for more papers by this authorFrançoise Smets
Service de Gastroentérologie et Hépatologie Pédiatrique, Université Catholique de Louvain, Cliniques Universitaires St Luc, Brussels, Belgium
Pediatric Research Unit, Université Catholique de Louvain, Cliniques Universitaires St Luc, Brussels, Belgium
Search for more papers by this authorRaymond Reding
Unités de Chirurgie Pédiatrique, Université Catholique de Louvain, Cliniques Universitaires St Luc, Brussels, Belgium
Search for more papers by this authorCorresponding Author
Etienne M. Sokal
Service de Gastroentérologie et Hépatologie Pédiatrique, Université Catholique de Louvain, Cliniques Universitaires St Luc, Brussels, Belgium
Pediatric Research Unit, Université Catholique de Louvain, Cliniques Universitaires St Luc, Brussels, Belgium
Correspondence
Prof. Etienne M. Sokal, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
Email: [email protected]
Search for more papers by this authorSharat Varma
Service de Gastroentérologie et Hépatologie Pédiatrique, Université Catholique de Louvain, Cliniques Universitaires St Luc, Brussels, Belgium
Pediatric Research Unit, Université Catholique de Louvain, Cliniques Universitaires St Luc, Brussels, Belgium
Search for more papers by this authorXavier Stéphenne
Service de Gastroentérologie et Hépatologie Pédiatrique, Université Catholique de Louvain, Cliniques Universitaires St Luc, Brussels, Belgium
Pediatric Research Unit, Université Catholique de Louvain, Cliniques Universitaires St Luc, Brussels, Belgium
Search for more papers by this authorMina Komuta
Service de Anatomopathologie, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Cliniques Universitaires St Luc, Brussels, Belgium
Search for more papers by this authorCaroline Bouzin
Imaging Platform (2IP), Université Catholique de Louvain, Cliniques Universitaires St Luc, Brussels, Belgium
Search for more papers by this authorJerome Ambroise
Centre for Applied Molecular Technologies (CTMA), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Cliniques Universitaires St Luc, Brussels, Belgium
Search for more papers by this authorFrançoise Smets
Service de Gastroentérologie et Hépatologie Pédiatrique, Université Catholique de Louvain, Cliniques Universitaires St Luc, Brussels, Belgium
Pediatric Research Unit, Université Catholique de Louvain, Cliniques Universitaires St Luc, Brussels, Belgium
Search for more papers by this authorRaymond Reding
Unités de Chirurgie Pédiatrique, Université Catholique de Louvain, Cliniques Universitaires St Luc, Brussels, Belgium
Search for more papers by this authorCorresponding Author
Etienne M. Sokal
Service de Gastroentérologie et Hépatologie Pédiatrique, Université Catholique de Louvain, Cliniques Universitaires St Luc, Brussels, Belgium
Pediatric Research Unit, Université Catholique de Louvain, Cliniques Universitaires St Luc, Brussels, Belgium
Correspondence
Prof. Etienne M. Sokal, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
Email: [email protected]
Search for more papers by this authorAbstract
Activated hepatic stellate cells express cytoplasmic ASMA prior to secreting collagen and consequent liver fibrosis. We hypothesized that quantifying ASMA could predict severity of future fibrosis after LT. For this, 32 pairs of protocol biopsies, that is, “baseline” and “follow-up” biopsies taken at 1- to 2-year intervals from 18 stable pediatric LT recipients, transplanted between 2006 and 2012 were selected. Morphometric quantification of “ASMA-positive area percentage” was performed on the baseline biopsy. Histological and fibrosis assessment using Metavir and LAFSc was performed on all biopsies. The difference of fibrosis severity between the “baseline” and “follow-up” was termed “prospective change in fibrosis.” Significant association was seen between extent of ASMA positivity on baseline biopsy and “prospective change in fibrosis” using Metavir (P=.02), cumulative LAFSc (P=.02), and portal LAFSc (P=.01) values. ASMA-positive area percentage >1.05 predicted increased fibrosis on next biopsy with 90.0% specificity. Additionally, an association was observed between extent of ASMA positivity and concomitant ductular reaction (P=.06), but not with histological inflammation in the portal tract or lobular area. Hence, ASMA quantification can predict the future course of fibrosis.
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References
- 1Bourdeaux C, Brunati A, Janssen M, et al. Liver retransplantation in children. A 21-year single-center experience. Transpl Int. 2009; 22: 416–422.
- 2Andries S, Casamayou L, Sempoux C, et al. Posttransplant immune hepatitis in pediatric liver transplant recipients: incidence and maintenance therapy with azathioprine. Transplantation. 2001; 72: 267–272.
- 3Venturi C, Sempoux C, Quinones JA, et al. Dynamics of allograft fibrosis in pediatric liver transplantation. Am J Transplant. 2014; 14: 1648–1656.
- 4Scheenstra R, Peeters PM, Verkade HJ, Gouw AS. Graft fibrosis after pediatric liver transplantation: ten years of follow-up. Hepatology. 2009; 49: 880–886.
- 5Evans HM, Kelly DA, McKiernan PJ, Hubscher S. Progressive histological damage in liver allografts following pediatric liver transplantation. Hepatology. 2006; 43: 1109–1117.
- 6Trautwein C, Friedman SL, Schuppan D, Pinzani M. Hepatic fibrosis: concept to treatment. J Hepatol. 2015; 62(1 Suppl): S15–S24.
- 7Varma S, Ambroise J, Komuta M, et al. Progressive fibrosis is driven by genetic predisposition, allo-immunity, and inflammation in pediatric liver transplant recipients. EBioMedicine. 2016; 9: 346–355.
- 8Lee YA, Wallace MC, Friedman SL. Pathobiology of liver fibrosis: a translational success story. Gut. 2015; 64: 830–841.
- 9Lee UE, Friedman SL. Mechanisms of hepatic fibrogenesis. Best Pract Res Clin Gastroenterol. 2011; 25: 195–206.
- 10Kisseleva T, Cong M, Paik Y, et al. Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis. Proc Natl Acad Sci USA. 2012; 109: 9448–9453.
- 11Troeger JS, Mederacke I, Gwak GY, et al. Deactivation of hepatic stellate cells during liver fibrosis resolution in mice. Gastroenterology. 2012; 143: 1073–1083.
- 12Venturi C, Sempoux C, Bueno J, et al. Novel histologic scoring system for long-term allograft fibrosis after liver transplantation in children. Am J Transplant. 2012; 12: 2986–2996.
- 13Rappa F, Greco A, Podrini C, et al. Immunopositivity for histone macroH2A1 isoforms marks steatosis-associated hepatocellular carcinoma. PLoS One. 2013; 8: e54458.
- 14Gawrieh S, Papouchado BG, Burgart LJ, Kobayashi S, Charlton MR, Gores GJ. Early hepatic stellate cell activation predicts severe hepatitis C recurrence after liver transplantation. Liver Transpl. 2005; 11: 1207–1213.
- 15Russo MW, Firpi RJ, Nelson DR, Schoonhoven R, Shrestha R, Fried MW. Early hepatic stellate cell activation is associated with advanced fibrosis after liver transplantation in recipients with hepatitis C. Liver Transpl. 2005; 11: 1235–1241.
- 16Carpino G, Morini S, Ginanni CS, et al. Alpha-SMA expression in hepatic stellate cells and quantitative analysis of hepatic fibrosis in cirrhosis and in recurrent chronic hepatitis after liver transplantation. Dig Liver Dis. 2005; 37: 349–356.
- 17Carpino G, Franchitto A, Morini S, Corradini SG, Merli M, Gaudio E. Activated hepatic stellate cells in liver cirrhosis. A morphologic and morphometrical study. Ital J Anat Embryol. 2004; 109: 225–238.
- 18Akpolat N, Yahsi S, Godekmerdan A, Yalniz M, Demirbag K. The value of alpha-SMA in the evaluation of hepatic fibrosis severity in hepatitis B infection and cirrhosis development: a histopathological and immunohistochemical study. Histopathology. 2005; 47: 276–280.
- 19Cisneros L, Londono MC, Blasco C, et al. Hepatic stellate cell activation in liver transplant patients with hepatitis C recurrence and in non-transplanted patients with chronic hepatitis C. Liver Transpl. 2007; 13: 1017–1027.
- 20Mallat A, Lotersztajn S. Reversion of hepatic stellate cell to a quiescent phenotype: from myth to reality? J Hepatol. 2013; 59: 383–386.
- 21Hirabaru M, Mochizuki K, Takatsuki M, et al. Expression of alpha smooth muscle actin in living donor liver transplant recipients. World J Gastroenterol. 2014; 20: 7067–7074.
- 22Maia JM, Maranhao HS, Sena LV, Rocha LR, Medeiros IA, Ramos AM. Hepatic stellate cell activation and hepatic fibrosis in children with type 1 autoimmune hepatitis: an immunohistochemical study of paired liver biopsies before treatment and after clinical remission. Eur J Gastroenterol Hepatol. 2010; 22: 264–269.
- 23Bilezikci B, Demirhan B, Sar A, Arat Z, Karakayali H, Haberal M. Hepatic stellate cells in biopsies from liver allografts with acute rejection. Transplant Proc. 2006; 38: 589–593.
- 24Clouston AD, Powell EE, Walsh MJ, Richardson MM, Demetris AJ, Jonsson JR. Fibrosis correlates with a ductular reaction in hepatitis C: roles of impaired replication, progenitor cells and steatosis. Hepatology. 2005; 41: 809–818.
- 25Richardson MM, Jonsson JR, Powell EE, et al. Progressive fibrosis in nonalcoholic steatohepatitis: association with altered regeneration and a ductular reaction. Gastroenterology. 2007; 133: 80–90.
- 26Wood MJ, Gadd VL, Powell LW, Ramm GA, Clouston AD. Ductular reaction in hereditary hemochromatosis: the link between hepatocyte senescence and fibrosis progression. Hepatology. 2014; 59: 848–857.
- 27Lee SJ, Park JB, Kim KH, et al. Immunohistochemical study for the origin of ductular reaction in chronic liver disease. Int J Clin Exp Pathol. 2014; 7: 4076–4085.
- 28Lotersztajn S, Julien B, Teixeira-Clerc F, Grenard P, Mallat A. Hepatic fibrosis: molecular mechanisms and drug targets. Annu Rev Pharmacol Toxicol. 2005; 45: 605–628.
- 29Olsen AL, Bloomer SA, Chan EP, et al. Hepatic stellate cells require a stiff environment for myofibroblastic differentiation. Am J Physiol Gastrointest Liver Physiol. 2011; 301: G110–G118.
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