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1
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Rabindranath M, Zaya R, Prayitno K, Orchanian-Cheff A, Patel K, Jaeckel E, Bhat M. A Comprehensive Review of Liver Allograft Fibrosis and Steatosis: From Cause to Diagnosis. Transplant Direct 2023; 9:e1547. [PMID: 37854023 PMCID: PMC10581596 DOI: 10.1097/txd.0000000000001547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 09/11/2023] [Accepted: 09/14/2023] [Indexed: 10/20/2023] Open
Abstract
Despite advances in posttransplant care, long-term outcomes for liver transplant recipients remain unchanged. Approximately 25% of recipients will advance to graft cirrhosis and require retransplantation. Graft fibrosis progresses in the context of de novo or recurrent disease. Recurrent hepatitis C virus infection was previously the most important cause of graft failure but is now curable in the majority of patients. However, with an increasing prevalence of obesity and diabetes and nonalcoholic fatty liver disease as the most rapidly increasing indication for liver transplantation, metabolic dysfunction-associated liver injury is anticipated to become an important cause of graft fibrosis alongside alloimmune hepatitis and alcoholic liver disease. To better understand the landscape of the graft fibrosis literature, we summarize the associated epidemiology, cause, potential mechanisms, diagnosis, and complications. We additionally highlight the need for better noninvasive methods to ameliorate the management of graft fibrosis. Some examples include leveraging the microbiome, genetic, and machine learning methods to address these limitations. Overall, graft fibrosis is routinely seen by transplant clinicians, but it requires a better understanding of its underlying biology and contributors that can help inform diagnostic and therapeutic practices.
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Affiliation(s)
- Madhumitha Rabindranath
- Ajmera Transplant Program, University Health Network, Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
| | - Rita Zaya
- Ajmera Transplant Program, University Health Network, Toronto, ON, Canada
| | - Khairunnadiya Prayitno
- Ajmera Transplant Program, University Health Network, Toronto, ON, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
| | - Ani Orchanian-Cheff
- Library and Information Services, University Health Network, Toronto, ON, Canada
| | - Keyur Patel
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Elmar Jaeckel
- Ajmera Transplant Program, University Health Network, Toronto, ON, Canada
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Mamatha Bhat
- Ajmera Transplant Program, University Health Network, Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Toronto, Toronto, ON, Canada
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2
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Abou-Beih S, Masson S, Saunders R, Haugk B, Oakley F, Tiniakos D. Sinusoidal and pericellular fibrosis in adult post-transplant liver biopsies: association with hepatic stellate cell activation and patient outcome. Virchows Arch 2019; 475:233-243. [PMID: 31201503 PMCID: PMC6647882 DOI: 10.1007/s00428-019-02585-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2018] [Revised: 04/17/2019] [Accepted: 05/07/2019] [Indexed: 12/18/2022]
Abstract
Post-transplant sinusoidal fibrosis (SF) and pericellular fibrosis (PCF) have not been extensively investigated in adults. Fifty-two post-transplant liver biopsies from 28 consented patients (12 men, mean age 49, range 33–67 years) were studied. Tissue morphology, including an arbitrary summative fibrosis score was assessed in detail. Collagen proportionate area (CPA) and alpha-smooth muscle actin (α-SMA) immunostain were evaluated by digital image analysis (DIA). Anti-keratin 7, anti-C4d and anti-sonic hedgehog (Shh) immunostains were scored semi-quantitatively. SF was observed in 36/52 (69.2%) biopsies and most of these (20/36, 55.6%) had centrilobular fibrosis (CLF). PCF was seen in 7/52 (13.5%) biopsies exclusively in cases with CLF. CPA was significantly correlated with time since liver transplantation (p = 0.043), summative fibrosis score and its main components but not with α-SMA. α-SMA-positive area significantly correlated with the Banff rejection score (p = 0.022) and centrilobular inflammatory changes were more severe in cases with CLF (p = 0.003). Hepatocyte ballooning of cholestatic type was associated with PCF (p = 0.016) and Shh expression (p < 0.001). Sinusoidal fibrosis is a frequent occurrence in post-transplant adult livers, with predilection toward centrilobular areas. Graft age and oxidative stress may contribute to SF development, while hepatocyte ballooning may be implicated in PCF development. Hepatic stellate cell (HSC) activation is likely affected by centrilobular inflammation.
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Affiliation(s)
- Sameh Abou-Beih
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, W. Leech Building, M4.143, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.,Department of Pathology, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | - Steven Masson
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, W. Leech Building, M4.143, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.,Liver Transplant Unit, Freeman Hospital, Newcastle upon Tyne, UK
| | - Rachael Saunders
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, W. Leech Building, M4.143, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK
| | - Beate Haugk
- Department of Cellular Pathology, Royal Victoria Infirmary, NUTH NHS Trust, Newcastle upon Tyne, UK
| | - Fiona Oakley
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, W. Leech Building, M4.143, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK
| | - Dina Tiniakos
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, W. Leech Building, M4.143, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK. .,Department of Pathology, Aretaieion Hospital, Medical School, National & Kapodistrian University of Athens, Athens, Greece.
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3
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The Mexican consensus on the treatment of hepatitis C. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2018. [DOI: 10.1016/j.rgmxen.2017.11.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022] Open
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4
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Aiza-Haddad I, Ballesteros-Amozurrutia A, Borjas-Almaguer OD, Castillo-Barradas M, Castro-Narro G, Chávez-Tapia N, Chirino-Sprung RA, Cisneros-Garza L, Dehesa-Violante M, Flores-Calderón J, Flores-Gaxiola A, García-Juárez I, González-Huezo MS, González-Moreno EI, Higuera-de la Tijera F, Kershenobich-Stalnikowitz D, López-Méndez E, Malé-Velázquez R, Marín-López E, Mata-Marín JA, Méndez-Sánchez N, Monreal-Robles R, Moreno-Alcántar R, Muñoz-Espinosa L, Navarro-Alvarez S, Pavia-Ruz N, Pérez-Ríos AM, Poo-Ramírez JL, Rizo-Robles MT, Sánchez-Ávila JF, Sandoval-Salas R, Torre A, Torres-Ibarra R, Trejo-Estrada R, Velarde-Ruiz Velasco JA, Wolpert-Barraza E, Bosques-Padilla F. The Mexican consensus on the treatment of hepatitis C. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2018; 83:275-324. [PMID: 29803325 DOI: 10.1016/j.rgmx.2017.11.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Revised: 10/17/2017] [Accepted: 11/02/2017] [Indexed: 12/12/2022]
Abstract
The aim of the Mexican Consensus on the Treatment of HepatitisC was to develop clinical practice guidelines applicable to Mexico. The expert opinion of specialists in the following areas was taken into account: gastroenterology, infectious diseases, and hepatology. A search of the medical literature was carried out on the MEDLINE, EMBASE, and CENTRAL databases through keywords related to hepatitisC treatment. The quality of evidence was subsequently evaluated using the GRADE system and the consensus statements were formulated. The statements were then voted upon, using the modified Delphi system, and reviewed and corrected by a panel of 34 voting participants. Finally, the level of agreement was classified for each statement. The present guidelines provide recommendations with an emphasis on the new direct-acting antivirals, to facilitate their use in clinical practice. Each case must be individualized according to the comorbidities involved and patient management must always be multidisciplinary.
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Affiliation(s)
| | | | - O D Borjas-Almaguer
- Hospital Universitario «Dr. José Eleuterio González», Monterrey, Nuevo León, México
| | | | - G Castro-Narro
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México
| | | | | | - L Cisneros-Garza
- Centro de Enfermedades Hepáticas del Hospital San José, Monterrey, Nuevo León, México
| | | | - J Flores-Calderón
- Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Ciudad de México, México
| | | | - I García-Juárez
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México
| | | | - E I González-Moreno
- Hospital Universitario «Dr. José Eleuterio González», Monterrey, Nuevo León, México
| | | | | | - E López-Méndez
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México
| | - R Malé-Velázquez
- Instituto de Salud Digestiva y Hepática, Guadalajara, Jalisco, México
| | | | - J A Mata-Marín
- Hospital de Infectología del Centro Médico Nacional «La Raza», Ciudad de México, México
| | | | - R Monreal-Robles
- Hospital Universitario «Dr. José Eleuterio González», Monterrey, Nuevo León, México
| | | | - L Muñoz-Espinosa
- Hospital Universitario «Dr. José Eleuterio González», Monterrey, Nuevo León, México
| | | | - N Pavia-Ruz
- Hospital Infantil de México «Federico Gómez», Ciudad de México, México
| | - A M Pérez-Ríos
- Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, México
| | - J L Poo-Ramírez
- Clínica San Jerónimo de Salud Hepática y Digestiva, Ciudad de México, México
| | | | - J F Sánchez-Ávila
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México
| | | | - A Torre
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México
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Dai E, Zhang L, Ye L, Wan S, Feng L, Qi Q, Yao F, Li Z. Hepatic expression of cannabinoid receptors CB1 and CB2 correlate with fibrogenesis in patients with chronic hepatitis B. Int J Infect Dis 2017; 59:124-130. [PMID: 28315398 DOI: 10.1016/j.ijid.2017.03.008] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 02/13/2017] [Accepted: 03/08/2017] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND The endocannabinoid system is involved in the pathogenesis of liver fibrosis. However, most of the findings in this area have come from experimental studies in animal models or clinical trials on chronic hepatitis C. The roles of cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) in hepatofibrosis in patients with chronic hepatitis B (CHB) have not been studied fully. This study aimed to explore the relationship between liver fibrosis and the expression of CB1 and CB2 in patients with CHB. METHODS Eighty liver biopsy specimens from patients with CHB (52 male, 28 female) were analyzed in this study. Fibrosis was staged on a scale of 1 to 4 (F1 to F4, with F4 defining cirrhosis). There were 20 samples for each fibrosis stage. The expression of hepatic alpha-smooth muscle actin (α-SMA), CB1, and CB2 was detected by immunohistochemistry. RESULTS Hepatic CB1 and CB2 were expressed in all patients with CHB. The degree of fibrosis was significantly associated with the increased expression of CB1 and CB2 in CHB. Furthermore a significant increase in cells positive for both CB1 and CB2 was detected in stage 3 and stage 4 disease compared to stage 1 and stage 2 disease. There was a strong positive association between CB1 expression and α-SMA expression. Moreover, double immunofluorescence staining for CB1 and α-SMA demonstrated that activated hepatic stellate cells (HSCs) express CB1. CONCLUSIONS The hepatic expression of CB1 and CB2 plays an important role during the progression of fibrosis induced by CHB. Endogenous activation of CB1 receptors in patients with CHB enhances fibrogenesis by direct effect on activated HSCs.
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Affiliation(s)
- Erhei Dai
- Division of Liver Diseases, The Fifth Hospital of Shijiazhuang, Hebei Medical University, Shijiazhuang, China
| | - Lianshan Zhang
- Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China.
| | - Lihong Ye
- Division of Liver Diseases, The Fifth Hospital of Shijiazhuang, Hebei Medical University, Shijiazhuang, China
| | - Shiqing Wan
- Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China
| | - Lulu Feng
- Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China
| | - Qi Qi
- Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China
| | - Fang Yao
- Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China
| | - Zhen Li
- Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China
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6
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Varma S, Stéphenne X, Komuta M, Bouzin C, Ambroise J, Smets F, Reding R, Sokal EM. The histological quantification of alpha-smooth muscle actin predicts future graft fibrosis in pediatric liver transplant recipients. Pediatr Transplant 2017; 21. [PMID: 27774712 DOI: 10.1111/petr.12834] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/21/2016] [Indexed: 12/11/2022]
Abstract
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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Affiliation(s)
- 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
| | - Xavier 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
| | - Mina Komuta
- Service de Anatomopathologie, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Cliniques Universitaires St Luc, Brussels, Belgium
| | - Caroline Bouzin
- Imaging Platform (2IP), Université Catholique de Louvain, Cliniques Universitaires St Luc, Brussels, Belgium
| | - Jerome Ambroise
- Centre for Applied Molecular Technologies (CTMA), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Cliniques Universitaires St Luc, Brussels, Belgium
| | - Françoise 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
| | - Raymond Reding
- Unités de Chirurgie Pédiatrique, Université Catholique de Louvain, Cliniques Universitaires St Luc, Brussels, Belgium
| | - 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
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7
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Venturi C, Reding R, Quinones JA, Sokal E, Rahier J, Bueno J, Sempoux C. Relevance of activated hepatic stellate cells in predicting the development of pediatric liver allograft fibrosis. Liver Transpl 2016; 22:822-9. [PMID: 26851053 DOI: 10.1002/lt.24412] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Revised: 01/09/2016] [Accepted: 01/19/2016] [Indexed: 01/12/2023]
Abstract
Activated hepatic stellate cells (HSCs) are the main collagen-producing cells in liver fibrogenesis. With the purpose of analyzing their presence and relevance in predicting liver allograft fibrosis development, 162 liver biopsies of 54 pediatric liver transplantation (LT) recipients were assessed at 6 months, 3 years, and 7 years after LT. The proportion of activated HSCs, identified by α-smooth muscle actin (ASMA) immunostaining, and the amount of fibrosis, identified by picrosirius red (PSR%) staining, were determined by computer-based morphometric analysis. Fibrosis was also staged by using the semiquantitative liver allograft fibrosis score (LAFSc), specifically designed to score fibrosis in the pediatric LT population. Liver allograft fibrosis displayed progression over time by PSR% (P < 0.001) and by LAFSc (P < 0.001). The ASMA expression decreased in the long term, with inverse evolution with respect to fibrosis (P < 0.01). Patients with ASMA-positive HSCs area ≥ 8% at 6 months (n = 20) developed a higher fibrosis proportion compared to those with ASMA-positive HSCs area ≤ 8% (n = 34) at the same period of time and in the long term (P = 0.03 and P < 0.01, respectively), but not at 3 years (P = 0.8). ASMA expression ≥ 8% at 6 months was found to be an independent risk factor for 7-year fibrosis development by PSR% (r(2) = 0.5; P < 0.01) and by LAFSc (r(2) = 0.3; P = 0.03). Furthermore, ASMA expression ≥ 8% at 3 years showed an association with the development of fibrosis at 7 years (P = 0.02). In conclusion, there is a high proportion of activated HSCs in pediatric LT recipients. ASMA ≥ 8% at 6 months seems to be a risk factor for early and longterm fibrosis development. In addition, activated HSCs showed inverse evolution with respect to fibrosis in the long term. Liver Transplantation 22 822-829 2016 AASLD.
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Affiliation(s)
- Carla Venturi
- Pediatric Surgery and Transplant Unit, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Raymond Reding
- Pediatric Surgery and Transplant Unit, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | | | - Etienne Sokal
- Service de Gastroentérologie and Hépatologie Pédiatrique, Cliniques Universitaires Saint-Luc, Brussels, Belgium.,Pediatric Hepatology and Cell Therapy, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
| | - Jacques Rahier
- Department of Pathology, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Javier Bueno
- Pediatric Surgery Department, Virgen del Rocio and Virgen de la Macarena, University Hospitals, Seville, Spain
| | - Christine Sempoux
- Department of Pathology, Cliniques Universitaires Saint-Luc, Brussels, Belgium
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Li T, Niu L, Li M, Liu Y, Xu Z, Gao X, Liu D. Effects of small interfering RNA-mediated downregulation of the Krüppel-like factor 4 gene on collagen metabolism in human hepatic stellate cells. Mol Med Rep 2015; 12:3972-3978. [PMID: 26018498 DOI: 10.3892/mmr.2015.3848] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Accepted: 05/01/2015] [Indexed: 11/06/2022] Open
Abstract
The nuclear transcription factor Krüppel-like factor 4 (KLF4) has an important role in cellular biological processes. However, the influence of KLF4 on collagen metabolism remains to be elucidated. In the present study, the effects and underlying mechanism of action of KLF4 on collagen metabolism was investigated in human hepatic stellate cells (HSC), by downregulating KLF4 expression using small interfering RNA (siRNA). The effects of KLF4 silencing by three predesigned siRNAs (siRNA1‑3) were evaluated using both reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blotting in the human LX2 HSC line. The mRNA expression levels of KLF4 were decreased by ~34, 40, and 69% in the siRNA1, siRNA2, and siRNA3 groups, respectively, as compared with the control group. These results were concordant with the protein expression levels of KLF4, as determined by western blot analysis. In the siRNA3 group, the quantity of type Ⅰ and type III collagen, and the expression levels of collagen metabolism proteins including matrix metalloproteinase‑1 (MMP‑1) and tissue inhibitors of metalloproteinases‑1 (TIMP‑1), were determined using both RT‑qPCR and western blotting. Both the mRNA and protein expression levels of type I and type III collagen were significantly decreased in the siRNA3 group, as compared with the control group. The mRNA and protein expression levels of TIMP‑1 were also significantly reduced in the siRNA3‑treated cells, whereas the mRNA and protein expression levels of MMP‑1 were significantly upregulated. Furthermore, KLF4 gene silencing significantly decreased the expression levels of numerous cytokines, including transforming grow factor‑β1, tumor necrosis factor‑α, and interleukin‑1β. The results of the present study provide evidence of siRNA‑mediated silencing of KLF4 expression, which may promote extracellular matrix (ECM) degradation, and inhibition of ECM synthesis. Therefore, KLF4 may be a promising target for the development of novel antifibrotic therapies.
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Affiliation(s)
- Tao Li
- Department of Epidemiology and Health Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Lijuan Niu
- Department of Oncology, The Third Hospital of Shijiazhuang, Shijiazhuang, Hebei 050000, P.R. China
| | - Man Li
- Department of Epidemiology and Health Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Ying Liu
- Department of Epidemiology and Health Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Zhengrong Xu
- Department of Epidemiology and Health Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Xia Gao
- Department of Epidemiology and Health Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Dianwu Liu
- Department of Epidemiology and Health Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
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Abstract
Chronic HCV infection is the leading indication for liver transplantation. However, as a result of HCV recurrence, patient and graft survival after liver transplantation are inferior compared with other indications for transplantation. HCV recurrence after liver transplantation is associated with considerable mortality and morbidity. The development of HCV-related fibrosis is accelerated after liver transplantation, which is influenced by a combination of factors related to the virus, donor, recipient, surgery and immunosuppression. Successful antiviral therapy is the only treatment that can attenuate fibrosis. The advent of direct-acting antiviral agents (DAAs) has changed the therapeutic landscape for the treatment of patients with HCV. DAAs have improved tolerability, and can potentially be used without PEG-IFN for a shorter time than previous therapies, which should result in better outcomes. In this Review, we describe the important risk factors that influence HCV recurrence after liver transplantation, highlighting the mechanisms of fibrosis and the integral role of hepatic stellate cells. Indirect and direct assessment of fibrosis, in addition to new antiviral therapies, are also discussed.
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10
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Hirabaru M, Mochizuki K, Takatsuki M, Soyama A, Kosaka T, Kuroki T, Shimokawa I, Eguchi S. Expression of alpha smooth muscle actin in living donor liver transplant recipients. World J Gastroenterol 2014; 20:7067-7074. [PMID: 24966580 PMCID: PMC4051953 DOI: 10.3748/wjg.v20.i22.7067] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Revised: 12/31/2013] [Accepted: 02/27/2014] [Indexed: 02/06/2023] Open
Abstract
Recently, there have been reports from liver biopsies that showed the progression of liver fibrosis in liver transplant patients after the cessation of immunosuppression. Herein, we focused on activated hepatic stellate cells expressing alpha smooth muscle actin (α-SMA) to understand the correlation between immunosuppressant medication and liver fibrosis. The study enrolled two pediatric patients who underwent living donor liver transplantation and ceased immunosuppressant therapy. The number of α-SMA-positive cells in the specimens obtained by liver biopsy from these two patients showed a three-fold increase compared with the number from four transplanted pediatric patients who were continuing immunosuppressant therapy. In addition, the α-SMA-positive area evaluated using the WinRooF image processing software program continued to increase over time in three adult transplanted patients with liver fibrosis, and the α-SMA-positive area was increasing even during the pre-fibrotic stage in these adult cases, according to a retrospective review. Therefore, α-SMA could be a useful marker for the detection of early stage fibrosis.
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11
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Urahashi T, Mizuta K, Ihara Y, Sanada Y, Wakiya T, Yamada N, Okada N. Impact of post-transplant flow cytometric panel-reactive antibodies on late-onset hepatic venous outflow obstruction following pediatric living donor liver transplantation. Transpl Int 2014; 27:322-9. [DOI: 10.1111/tri.12255] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2013] [Revised: 04/30/2013] [Accepted: 11/28/2013] [Indexed: 12/22/2022]
Affiliation(s)
- Taizen Urahashi
- Department of Transplant Surgery; Jichi Medical University; Shimotsuke-shi Japan
| | - Koichi Mizuta
- Department of Transplant Surgery; Jichi Medical University; Shimotsuke-shi Japan
| | - Yoshiyuki Ihara
- Department of Transplant Surgery; Jichi Medical University; Shimotsuke-shi Japan
| | - Yukihiro Sanada
- Department of Transplant Surgery; Jichi Medical University; Shimotsuke-shi Japan
| | - Taiichi Wakiya
- Department of Transplant Surgery; Jichi Medical University; Shimotsuke-shi Japan
| | - Naoya Yamada
- Department of Transplant Surgery; Jichi Medical University; Shimotsuke-shi Japan
| | - Noriki Okada
- Department of Transplant Surgery; Jichi Medical University; Shimotsuke-shi Japan
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Duvoux C, Firpi R, Grazi GL, Levy G, Renner E, Villamil F. Recurrent hepatitis C virus infection post liver transplantation: impact of choice of calcineurin inhibitor. Transpl Int 2013; 26:358-72. [PMID: 23413991 DOI: 10.1111/tri.12065] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2012] [Revised: 03/23/2012] [Accepted: 12/23/2012] [Indexed: 02/06/2023]
Abstract
Recurrence of hepatitis C virus infection following liver transplantation (LT) for hepatitis C is universal. After LT, hepatitis C is associated with accelerated fibrosis progression and reduced graft and patient survival. Furthermore, responses to antiviral therapy in patients with recurrent hepatitis C virus post-transplant are consistently sub-optimal. Calcineurin inhibitors (CNIs) like cyclosporine A (CsA) and tacrolimus continue to dominate immunosuppressive regimens in this population; however, there is still uncertainty as to whether either offers an advantage in terms of patient outcomes. Although tacrolimus demonstrates improved efficacy in the general LT population, differences have begun to emerge between these agents regarding diabetogenic potential, antiviral activity, and fibrosis progression in patients with hepatitis C. This review critically evaluates the existing literature, providing an overview of the reported differences, concluding that despite conflicting evidence, a potential benefit of CsA in patients with hepatitis C is supported by the data and warrants further investigation. Future studies examining the role of CNIs in hepatitis C virus-positive LT recipients are required to accurately examine the effects of CNIs on outcomes such as fibrosis progression, survival, and effects on response to antiviral therapy, to provide robust information that allows clinicians to make an informed choice concerning which CNI is best for their patients.
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Pissaia A, Aoudjehane L, Ben Othman S, Scatton O, Soubrane O, Housset C, Calmus Y, Conti F. Cyclosporine inhibits profibrotic effects of interleukin-4 and transforming growth factor β on human intrahepatic fibroblasts cultured in vitro. Transplant Proc 2011; 42:4343-6. [PMID: 21168695 DOI: 10.1016/j.transproceed.2010.09.124] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND Hepatic fibrosis, an outcome of chronic liver diseases, is characterized by an accumulation of collagen, which is produced by activated human intrahepatic fibroblasts (HIF). Transforming growth factor (TGF) β is an important inducer of fibrogenesis, in collaboration with other cytokines, such as interleukin (IL) 4. IL-4 is overexpressed in severe recurrent hepatitis C after liver transplantation, exerting profibrotic effects. In contrast, cyclosporine (CsA) had been shown to decrease fibroblast activation and collagen production. We therefore investigated the effects of CsA on TGF-β and IL-4 profibrotic activities on HIF in vitro. METHODS Isolated HIF were cultured without or with human TGF-β, human IL-4, CsA, or combined TGF- β+CsA or IL-4+CsA. We performed real-time polymerase chain reaction for collagen types I, III, and IV and alpha-SMA, a marker of fibroblast activation we also measured total collagen in supernates. TGF-β and IL-4 increased the expressions of alpha smooth muscle action (SMA) collagen I, III, and IV mRNAs (P < .05 vs untreated cells) as well as the overall collagen level in the supernates (P < .01). CsA decreased the expression of mRNAs encoding alpha-SMA and collagens (P < .01). Expressions of alpha-SMA and collagens I, III, and IV mRNAs were significantly lower under combined treatments (TGF-β vs TGF-β+CsA [P < .01] and IL-4 vs IL-4+CsA [P < .01]). Collagen level was decreased by combined treatments (TGF-β vs TGF-β+CsA [P < .05] and IL-4 vs IL-4+CsA [P = .05]). CONCLUSION CsA inhibited the profibrotic effects of TGF-β and IL-4 by decreasing the activation and production of collagen by HIF. CsA may decrease fibroblast activation and collagen accumulation, exerting beneficial effects on fibrosis progression, particularly among patients with recurrent hepatitis C.
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Affiliation(s)
- A Pissaia
- Inserm UMR 938, IFR 65, Université Paris 6, Paris, France
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14
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Eurich D, Bahra M, Boas-Knoop S, Lock JF, Golembus J, Neuhaus R, Neuhaus P, Neumann UP. Transforming growth factor β1 polymorphisms and progression of graft fibrosis after liver transplantation for hepatitis C virus--induced liver disease. Liver Transpl 2011; 17:279-88. [PMID: 21384510 DOI: 10.1002/lt.22190] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Re-infection with the hepatitis C virus (HCV) is an important development after liver transplantation (LT); it can lead to graft fibrosis. The aim of this study was to assess the role of transforming growth factor β1 (TGF-β1) polymorphisms in the development of HCV-related graft disease by evaluating protocol liver biopsies. A total of 192 patients with a recurrence of HCV infection after LT were genotyped for TGF-β1 codon 10 (C→T) and codon 25 (G→C) using the polymerase chain reaction. Histological evaluation of 614 protocol liver biopsies obtained from these patients was undertaken using the classification of Desmet and Scheuer to stage the degree of fibrosis. Mild stages of fibrosis (0-2) were compared to advanced stages of fibrosis (3-4) that developed during the period of infection with the virus. Correlations between the prevalence of TGF-β1 genotypes and the different degrees of fibrosis that developed were determined. No statistically significant differences were found for genotype distributions (codons 10 and 25) with respect to recipient age, donor sex, occurrence of acute cellular rejection, and response to antiviral therapy. However, the C allele at codon 25 was significantly less frequent in the group with advanced fibrosis (P = 0.001). Furthermore, a positive association was found between progression of fibrosis and male recipient sex (P = 0.024), donor age (P = 0.041), and viral genotype 1b (P = 0.002). In conclusion, this study, in which the evolution of hepatic fibrosis was assessed histologically in a large cohort of patients with HCV re-infection after LT, has demonstrated that the C allele at codon 25 of the TGF-β1 gene is a marker for the development of graft fibrosis.
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Affiliation(s)
- Dennis Eurich
- Department of General, Visceral and Transplant Surgery, Charité Campus Virchow, Berlin, Germany.
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15
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van der Laan LJW, Hudson M, McPherson S, Zondervan PE, Thomas RC, Kwekkeboom J, Lindsay AS, Burt AD, Kazemier G, Tilanus HW, Bassendine MF, Metselaar HJ. Results of a two-center study comparing hepatic fibrosis progression in HCV-positive liver transplant patients receiving cyclosporine or tacrolimus. Transplant Proc 2010; 42:4573-7. [PMID: 21168740 DOI: 10.1016/j.transproceed.2010.10.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2010] [Accepted: 10/11/2010] [Indexed: 01/22/2023]
Abstract
A 2-center retrospective analysis was performed in 60 patients undergoing liver transplantation for hepatitis C virus (HCV)-related disease (cyclosporine in 20, tacrolimus in 40). Mean (±SEM) follow-up was 23.6 ± 22.5 and 22.3 ± 13.7 months in patients receiving cyclosporine or tacrolimus, respectively. Clinically indicated biopsies were performed in 15/20 cyclosporine patients (75%) and 22/40 tacrolimus patients (55%; P = .17). The Ishak fibrosis score was significantly lower in cyclosporine-treated patients versus tacrolimus-treated patients (mean 1.7 ± 0.4 vs 3.1 ± 0.4; P = .023), as was percentage of fibrosis grade Ishak ≥4 (7% vs 41%; P = .028). The mean time to moderate fibrosis (Ishak score ≥3) was 38.2 ± 15.1 months in cyclosporine patients (4/15) and 23.5 ± 12.6 months in tacrolimus patients (14/22); the difference was not statistically significant (P = .09). This retrospective study suggests that cyclosporine-based immunosuppression is associated with less severe hepatic fibrosis in HCV-positive liver transplant recipients compared with tacrolimus-based regimens, but a larger prospective comparative trial is necessary to confirm these findings.
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Affiliation(s)
- L J W van der Laan
- Department of Surgery, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
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16
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Carrión JA, Fernández-Varo G, Bruguera M, García-Pagán JC, García-Valdecasas JC, Pérez-Del-Pulgar S, Forns X, Jiménez W, Navasa M. Serum fibrosis markers identify patients with mild and progressive hepatitis C recurrence after liver transplantation. Gastroenterology 2010; 138:147-58.e1. [PMID: 19786026 DOI: 10.1053/j.gastro.2009.09.047] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2009] [Revised: 08/25/2009] [Accepted: 09/16/2009] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS Significant fibrosis (fibrosis stage [F] >or= 2) and portal hypertension (hepatic venous pressure gradient [HVPG] >or= 6 mm Hg) in patients 1 year after liver transplantation indicate progressive hepatitis C recurrence. This study evaluated whether serum fibrosis markers can predict hepatitis C recurrence during the first year after liver transplantation. METHODS Hyaluronic acid, amino-terminal propeptide of type-III-procollagen, tissue inhibitor of matrix metalloproteinase type-1 concentrations were measured in serum samples from 133 patients infected with hepatitis C virus (HCV) at 3, 6, and 12 months after liver transplantation; routine laboratory tests were also performed. Liver biopsy samples (n = 133) and HVPGs (n = 94) were analyzed 1 year after transplantation. Sixteen patients who were not infected with HCV served as controls. RESULTS An algorithm, including the 3 markers (3-M-ALG) and 3 published scores (aspartate aminotransferase [AST]-to-alanine aminotransferase ratio, AST-to-platelet ratio index, and Benlloch) were analyzed. One year after liver transplantation, 50 patients (38%) had significant fibrosis (F >or= 2) and 31 (32%) had an HVPG >or= 6 mm Hg. The area under the receiver operator characteristic curve of the 3-M-ALG used to identify F >or= 2 at 3, 6, and 12 months after transplantation (0.67, 0.77, and 0.78) and of those with HVPG >or= 6 at the same time points (0.75, 0.87, and 0.90) were significantly higher than values obtained with the 3 published scores. At 12 months, a 3-M-ALG >or= 2 identified most patients at risk of decompensation/death. CONCLUSIONS Serum markers can accurately discriminate between patients with mild and progressive hepatitis C recurrence after liver transplantation.
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Affiliation(s)
- José A Carrión
- Liver Unit, Institut de Malalties Digestives, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, CIBERehd, Barcelona, Spain
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17
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Abstract
Fibrosis, the excess deposition of extracellular matrix in the liver is a form of anatomical damage to the liver parenchyma, so that liver biopsy is the only approach for its direct assessment. Although liver biopsy has its limitations, appropriate precautions can reduce the flaws inherent in this method. The level of accuracy obtained with biopsy is particularly important for obtaining a starting point in patients with chronic liver disease who are to be followed-up over a number of years. Therefore, liver biopsy has been used as the gold standard to establish algorithm combinations of biological tests. As well as an accurate assessment of the extent of liver fibrosis, the biopsy can reveal other informations and associated features relevant to evaluation of the fibrotic process.
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Affiliation(s)
- P Bedossa
- Department of Pathology, Beaujon Hospital, Clichy, University Denis Diderot - Paris 7, France.
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Popov Y, Schuppan D. Targeting liver fibrosis: strategies for development and validation of antifibrotic therapies. Hepatology 2009; 50:1294-306. [PMID: 19711424 DOI: 10.1002/hep.23123] [Citation(s) in RCA: 254] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
We have made striking progress in our understanding of the biochemistry and cell biology that underlies liver fibrosis and cirrhosis, including the development of strategies and agents to prevent and reverse fibrosis. However, translation of this knowledge into clinical practice has been hampered by (1) the limitation of many in vitro and in vivo models to confirm mechanisms and to test antifibrotic agents, and (2) the lack of sensitive methodologies to quantify the degree of liver fibrosis and the dynamics of fibrosis progression or reversal in patients. Furthermore, whereas cirrhosis and subsequent decompensation are accepted hard clinical endpoints, fibrosis and fibrosis progression alone are merely plausible surrogates for future clinical deterioration. In this review we focus on an optimized strategy for preclinical antifibrotic drug development and highlight the current and future techniques that permit noninvasive assessment and quantification of liver fibrosis and fibrogenesis. The availability of such noninvasive methodologies will serve as the pacemaker for the clinical development and validation of potent antifibrotic agents.
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Affiliation(s)
- Yury Popov
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
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Abstract
PURPOSE OF REVIEW Hepatitis C virus infection is the leading indication for liver transplantation, with recurrent hepatitis C almost universal. Although posttransplant treatment of hepatitis C virus infection remains suboptimal, active investigation continues to inform patient selection and risk-benefit analysis. RECENT FINDINGS Several key studies have identified components in the immunological response that are associated with the necroinflammatory and fibrotic response. Hepatitis C virus infection is associated with a higher rate of diabetes mellitus after transplant. Patients with diabetes and metabolic syndrome have poorer outcomes, and aggressive management is necessary. Differentiation of acute rejection from recurrent hepatitis C is difficult; however, the use of hepatitis C virus RNA tissue levels, immunohistochemistry and Councilman body/portal tract ratio may help with this diagnostic dilemma. The use of a specific calcineurin inhibitor appears not to influence recurrent hepatitis C, but rapid steroid taper is detrimental and, if steroids are used, long slow taper should be used. Use of rapid and early virological responses is very helpful in the management of hepatitis C after transplantation. In the patients with sustained virological response, histological and survival benefits are noted. SUMMARY The present review highlights advances in our understanding of the pathophysiology and treatment of hepatitis C virus infection after liver transplantation in the last few years.
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Pungpapong S, Nunes DP, Krishna M, Nakhleh R, Chambers K, Ghabril M, Dickson RC, Hughes CB, Steers J, Nguyen JH, Keaveny AP. Serum fibrosis markers can predict rapid fibrosis progression after liver transplantation for hepatitis C. Liver Transpl 2008; 14:1294-302. [PMID: 18756457 DOI: 10.1002/lt.21508] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Although recurrent hepatitis C virus (HCV) after liver transplantation (LT) is universal, a minority of patients will develop cirrhosis within 5 years of surgery, which places them at risk for allograft failure. This retrospective study investigated whether 2 serum fibrosis markers, serum hyaluronic acid (HA) and YKL-40, could be used to predict rapid fibrosis progression (RFP) post-LT. These markers were compared with conventional laboratory tests, histological assessment, and hepatic stellate cell activity (HSCA), a key step in fibrogenesis, as assessed by immunohistochemical staining for alpha-smooth muscle actin. Serum and protocol liver biopsy samples were obtained from 46 LT recipients at means of 5 +/- 2 (biopsy 1) and 39 +/- 6 (biopsy 2) months post-LT, respectively. RFP was defined as an increase in the fibrosis score >or= 2 from biopsy 1 to biopsy 2 (a mean interval of 33 +/- 6 months). The ability of parameters at biopsy 1 to predict RFP was compared with the areas under receiver operating characteristic curves (AUROCs). Of the 46 subjects, 15 developed RFP. Serum HA and YKL-40 performed significantly better than conventional parameters and HSCA in predicting RFP post-LT for HCV at biopsy 1, with AUROCs of 0.89 and 0.92, respectively. The accuracy of serum HA >or= 90 microg/L and YKL-40 >or= 200 microg/L in predicting RFP at biopsy 1 was 80% and 96%, respectively. In conclusion, we found that elevated levels of serum HA and YKL-40 within the first 6 months after LT accurately predicted RFP. Larger studies evaluating the role of serum HA and YKL-40 in post-LT management are warranted.
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Affiliation(s)
- Surakit Pungpapong
- Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL 32224, USA
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Yerian L. Identifying activated hepatic stellate cells in chronic and posttransplant recurrent hepatitis C. Liver Transpl 2008; 14:756-8. [PMID: 18508367 DOI: 10.1002/lt.21469] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
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