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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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Rodart IF, Pares MM, Mendes A, Accardo CM, Martins JRM, Silva CB, Carvalho FO, Barreto JA, Reis MG, Tersariol ILS, Nader HB. Diagnostic Accuracy of Serum Hyaluronan for Detecting HCV Infection and Liver Fibrosis in Asymptomatic Blood Donors. Molecules 2021; 26:molecules26133892. [PMID: 34202190 PMCID: PMC8270308 DOI: 10.3390/molecules26133892] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 06/18/2021] [Accepted: 06/22/2021] [Indexed: 01/04/2023] Open
Abstract
Background: The disease caused by hepatitis C virus (HCV) is asymptomatic, silent, and progressive liver disease. In HCV-infected patients the increase in serum HA is associated with the development of hepatic fibrosis and disease progression. Methods: HCV-RNA detection was performed in all serological samples of blood donors that tested positive using HCV Ultra ELISA. Determination of hyaluronan (HA) was performed in positive HCV samples using ELISA-like fluorometric method. The HA content was compared to HCV viral load, genotype of the virus, liver fibrosis as well as ALT and GGT liver biomarkers. Results: Persistently normal ALT (<40 U/L) and GGT (<50 U/L) serum levels were detected in 75% and 69% of the HCV-Infected blood donors, respectively. Based on ROC analysis, the HA value < 34.2 ng/mL is an optimal cut-off point to exclude HCV viremia (specificity = 91%, NPV = 99%). Applying HA value ≥34.2 ng/mL significant liver fibrosis (≥F2) can be estimated in 46% of the HCV-infected blood donors. HA serum level (≥34.2 ng/mL) associated with a high ALT level (>40 U/mL) can correctly identify HCV infection and probable liver fibrosis (sensitivity = 96% and specificity = 90%) in asymptomatic blood donors. Conclusions: A high level of HA (≥34.2 ng/mL) in association with ALT (≥40 U/L) in serum can provide a good clinical opportunity to detect HCV-infected asymptomatic persons that potentially require a liver biopsy confirmation and antiviral treatment to prevent the development of advanced liver fibrosis or cirrhosis.
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Affiliation(s)
- Itatiana F. Rodart
- Departamento de Bioquímica, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo 04021-001, Brazil; (I.F.R.); (A.M.); (C.M.A.); (J.R.M.M.)
| | - Madalena M. Pares
- Associação Beneficente de Coleta de Sangue (COLSAN), São Paulo 04038-000, Brazil; (M.M.P.); (C.B.S.); (F.O.C.); (J.A.B.)
| | - Aline Mendes
- Departamento de Bioquímica, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo 04021-001, Brazil; (I.F.R.); (A.M.); (C.M.A.); (J.R.M.M.)
| | - Camila M. Accardo
- Departamento de Bioquímica, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo 04021-001, Brazil; (I.F.R.); (A.M.); (C.M.A.); (J.R.M.M.)
| | - João R. M. Martins
- Departamento de Bioquímica, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo 04021-001, Brazil; (I.F.R.); (A.M.); (C.M.A.); (J.R.M.M.)
| | - Cleidenice B. Silva
- Associação Beneficente de Coleta de Sangue (COLSAN), São Paulo 04038-000, Brazil; (M.M.P.); (C.B.S.); (F.O.C.); (J.A.B.)
| | - Fabrício O. Carvalho
- Associação Beneficente de Coleta de Sangue (COLSAN), São Paulo 04038-000, Brazil; (M.M.P.); (C.B.S.); (F.O.C.); (J.A.B.)
| | - José A. Barreto
- Associação Beneficente de Coleta de Sangue (COLSAN), São Paulo 04038-000, Brazil; (M.M.P.); (C.B.S.); (F.O.C.); (J.A.B.)
| | - Mitermayer G. Reis
- Laboratório de Hepatites Virais, Centro de Pesquisas Gonçalo Muniz, Fundação Oswaldo Cruz, Salvador 40296-710, Brazil;
| | - Ivarne L. S. Tersariol
- Departamento de Bioquímica, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo 04021-001, Brazil; (I.F.R.); (A.M.); (C.M.A.); (J.R.M.M.)
- Correspondence: (I.L.S.T.); (H.B.N.); Tel.: +55-11-5579-3175 (I.L.S.T.); +55-11-5549-4629 (H.B.N.)
| | - Helena B. Nader
- Departamento de Bioquímica, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo 04021-001, Brazil; (I.F.R.); (A.M.); (C.M.A.); (J.R.M.M.)
- Correspondence: (I.L.S.T.); (H.B.N.); Tel.: +55-11-5579-3175 (I.L.S.T.); +55-11-5549-4629 (H.B.N.)
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3
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Babiker A, Hassan M, Muhammed S, Taylor G, Poonia B, Shah A, Bagchi S. Inflammatory and cardiovascular diseases biomarkers in chronic hepatitis C virus infection: A review. Clin Cardiol 2019; 43:222-234. [PMID: 31785111 PMCID: PMC7068107 DOI: 10.1002/clc.23299] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 11/09/2019] [Accepted: 11/12/2019] [Indexed: 12/12/2022] Open
Abstract
Hepatitis C virus (HCV) infects 180 million people worldwide and over 4 million people in the United States. HCV infection is a major cause of chronic liver disease and is recognized as a risk factor for clinical cardiovascular disease (CVD). Many studies have shown increased prevalence of cardiac and inflammatory biomarkers in patients with chronic HCV infection (CHC), and though these markers may be used to risk stratify people for cardiac disease in the general population their role in the HCV population is unknown. Patients with CHC have elevated cardiac and inflammatory biomarkers compared to noninfected controls which may play a role in CVD risk stratification. We undertook a systematic review of inflammatory and cardiac biomarkers in people with HCV infection with a focus on the effect of CHC on serum levels of these markers and their utility as predictors of CVD in this population. Medline, EMBASE, and Cochrane databases were searched for relevant articles until June 2019. A total of 2430 results were reviewed with 115 studies included. Our review revealed that HCV infection significantly alters serum levels of markers of inflammation, endothelial function, and cardiac dysfunction prior to HCV treatment, and some of which may change in response to HCV therapy. Current risk stratification tools for development of CVD in the general population may not account for the increased inflammatory markers that appear to be elevated among HCV‐infected patients contributing to increased CVD risk.
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Affiliation(s)
- Ahmed Babiker
- Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Mohamed Hassan
- Division of General Internal Medicine, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Safwan Muhammed
- Department of Medicine, University of Maryland Medical Center, Baltimore, Maryland.,Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Gregory Taylor
- Department of Family Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - Bhawna Poonia
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Anoop Shah
- Division of Cardiology, University of Edinburgh, Little France, Edinburgh
| | - Shashwatee Bagchi
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland.,Division of Infectious Diseases, University of Maryland School of Medicine, Baltimore, Maryland
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Rostved AA, Ostrowski SR, Peters L, Lundgren JD, Hillingsø J, Johansson PI, Rasmussen A. Hyaluronic Acid Is a Biomarker for Allograft Dysfunction and Predicts 1-Year Graft Loss After Liver Transplantation. Transplant Proc 2018; 50:3635-3643. [PMID: 30577249 DOI: 10.1016/j.transproceed.2018.09.018] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2018] [Revised: 08/28/2018] [Accepted: 09/05/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Allograft dysfunction after liver transplantation has a profound impact on the risks of death and retransplantation within the first year. We tested whether elevated hyaluronic acid (HA; a glycosaminoglycan cleared by hepatic sinusoidal endothelium) levels may predict excess risk of graft loss. METHODS This was a retrospective single-center prognostic cohort study. Patients with either a plasma sample before transplantation, an early post-transplantation sample nearest day 30 (range 10-89 d, 80% within days 15-60), or both were included. Plasma HA was measured with the use of enzyme-linked immunosorbent assays. The primary end point was 1-year graft loss (all-cause mortality and retransplantation). A secondary end point was biliary stricture. RESULTS In this study, 169 of 196 patients who received a liver transplant in the study period were included. Pre-transplantation HA (n = 152) did not predict graft loss. Post-transplantation HA (n = 124) was higher among patients with graft loss (median, 177 μg/L [interquartile range (IQR), 89-465] vs 54 μg/L [IQR 37-93]) and was a strong predictor of this outcome (hazard ratio per 50 μg/L, 1.24 [95% confidence interval [CI], 1.14-1.34]). The discriminatory ability of HA was high (area under the receiver operating characteristic curve, 0.86 [95% CI, 0.77-0.94]) and noninferior to other liver function tests. When adjusted for known risk factors of graft loss, HA remained an independent predictor of graft loss. CONCLUSIONS High post-transplantation plasma HA level was a strong predictor of 1-year all-cause mortality and retransplantation, whereas pre-transplantation levels were not, despite variety in the time span of blood sampling. Prospective studies are warranted to assess the utility of HA in liver transplantation.
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Affiliation(s)
- A A Rostved
- Department of Surgical Gastroenterology and Transplantation, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
| | - S R Ostrowski
- Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - L Peters
- Section 2100, CHIP, Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - J D Lundgren
- Section 2100, CHIP, Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - J Hillingsø
- Department of Surgical Gastroenterology and Transplantation, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - P I Johansson
- Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - A Rasmussen
- Department of Surgical Gastroenterology and Transplantation, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
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5
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Abstract
Modern multianalyte "omics" technologies allow for the identification of molecular signatures that confer significantly more information than measurement of a single parameter as typically used in current medical diagnostics. Proteomics and metabolomics bioanalytical assays capture a large set of proteins and metabolites in body fluids, cells, or tissues and, complementing genomics, assess the phenome. Proteomics and metabolomics contribute to the development of novel predictive clinical biomarkers in transplantation in 2 ways: they can be used to generate a diagnostic fingerprint or they can be used to discover individual proteins and metabolites of diagnostic potential. Much fewer metabolomics than proteomics biomarker studies in transplant patients have been reported, and, in contrast to proteomics discovery studies, new lead metabolite markers have yet to emerge. Most clinical proteomics studies have been discovery studies. Several of these studies have assessed diagnostic sensitivity and specificity. Nevertheless, none of these newly discovered protein biomarkers have yet been implemented in clinical decision making in transplantation. The currently most advanced markers discovered in proteomics studies in transplant patients are the chemokines CXCL-9 and CXCL-10, which have successfully been validated in larger multicenter trials in kidney transplant patients. These chemokines can be measured using standard immunoassay platforms, which should facilitate clinical implementation. Based on the published evidence, it is reasonable to expect that these chemokine markers can help guiding and individualizing immunosuppressive regimens, may be able to predict acute and chronic T-cell-mediated and antibody-mediated rejection, and may be useful tools for risk stratification of kidney transplant patients.
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6
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Crespo G, Gambato M, Millán O, Casals G, Ruiz P, Londoño MC, Mira A, Forns X, Brunet M, Jiménez W, Navasa M. Early non-invasive selection of patients at high risk of severe hepatitis C recurrence after liver transplantation. Transpl Infect Dis 2016; 18:471-9. [PMID: 26992003 DOI: 10.1111/tid.12526] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Revised: 12/04/2015] [Accepted: 01/20/2016] [Indexed: 01/10/2023]
Abstract
BACKGROUND The early identification of patients at high risk of severe post liver transplant hepatitis C recurrence is relevant, as these patients may be treated using interferon (IFN)-free regimens. METHODS In a retrospective study with prospectively collected data, we investigated whether the use of several non-invasive methods (fibrosis 4 index [FIB-4], AST-to-platelets ratio index [APRI], enhanced liver fibrosis test [ELF], IFN-γ-inducible protein 10 [IP-10], and transient elastography by Fibroscan) and their combinations 6 months after transplantation could identify those recipients at higher risk of severe recurrence, defined by the presence of significant fibrosis (F ≥2) and/or portal hypertension (hepatic venous pressure gradient ≥6 mmHg) 12 months after transplant. Seventy-two hepatitis C virus (HCV)-infected liver transplant patients and 10 recipients in whom HCV was eradicated before transplantation were included in the study. RESULTS The levels of all biomarkers were significantly higher in HCV-infected recipients than in controls. Among HCV recipients, levels of biomarkers were significantly higher in patients with severe recurrence. Although there were no statistically significant differences between biomarkers, APRI, ELF, and FIB-4 obtained the highest area under the ROC curve values. The combination of serum biomarkers with Fibroscan increased the negative and positive predictive values, although diagnostic accuracy of individual tests was not significantly improved. CONCLUSIONS Patients at higher risk of severe HCV recurrence can be identified early, 6 months after transplantation, using readily available non-invasive methods.
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Affiliation(s)
- G Crespo
- Liver Unit, Hospital Clinic, IDIBAPS and CIBERehd, University of Barcelona, Barcelona, Spain
| | - M Gambato
- Liver Unit, Hospital Clinic, IDIBAPS and CIBERehd, University of Barcelona, Barcelona, Spain
| | - O Millán
- Department of Biochemistry and Molecular Genetics, Hospital Clinic, IDIBAPS and CIBERehd, University of Barcelona, Barcelona, Spain
| | - G Casals
- Department of Biochemistry and Molecular Genetics, Hospital Clinic, IDIBAPS and CIBERehd, University of Barcelona, Barcelona, Spain
| | - P Ruiz
- Liver Unit, Hospital Clinic, IDIBAPS and CIBERehd, University of Barcelona, Barcelona, Spain
| | - M C Londoño
- Liver Unit, Hospital Clinic, IDIBAPS and CIBERehd, University of Barcelona, Barcelona, Spain
| | - A Mira
- Department of Biochemistry and Molecular Genetics, Hospital Clinic, IDIBAPS and CIBERehd, University of Barcelona, Barcelona, Spain
| | - X Forns
- Liver Unit, Hospital Clinic, IDIBAPS and CIBERehd, University of Barcelona, Barcelona, Spain
| | - M Brunet
- Department of Biochemistry and Molecular Genetics, Hospital Clinic, IDIBAPS and CIBERehd, University of Barcelona, Barcelona, Spain
| | - W Jiménez
- Department of Biochemistry and Molecular Genetics, Hospital Clinic, IDIBAPS and CIBERehd, University of Barcelona, Barcelona, Spain
| | - M Navasa
- Liver Unit, Hospital Clinic, IDIBAPS and CIBERehd, University of Barcelona, Barcelona, Spain
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7
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Crescioli C. Chemokines and transplant outcome. Clin Biochem 2016; 49:355-62. [DOI: 10.1016/j.clinbiochem.2015.07.026] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Revised: 07/10/2015] [Accepted: 07/20/2015] [Indexed: 12/26/2022]
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Cytokine Response Associated with Hepatitis C Virus Clearance in HIV Coinfected Patients Initiating Peg Interferon-α Based Therapy. Mediterr J Hematol Infect Dis 2016; 8:e2016003. [PMID: 26740864 PMCID: PMC4696469 DOI: 10.4084/mjhid.2016.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Accepted: 11/09/2015] [Indexed: 12/28/2022] Open
Abstract
Background Treatment of hepatitis C virus (HCV) infection based on peginterferon-α (pegIFNα) and ribavirin induces important changes in cytokine release and T cell activation. Objective Immune response to pegIFNα-ribavirin therapy was explored in patients coinfected by HCV and HIV. Methods Concentrations of 25 cytokines and CD8+ T cell activation were monitored in HCV/HIV coinfected patients classified as sustained virological responders (SVR, n=19) and non-responders (NR, n=11). Results High pretreatment concentrations of IP-10 (CXCL-10) and MCP-1 (CCL-2) were associated with a poor anti-HCV response. PegIFNα-ribavirin therapy increased CD8+ T cell activation and induced significant changes in levels of eleven cytokines related to both Th1 and Th2 responses in SVR (IL-1β, IL-1RA, IL-4, IL-5, IL-6, IL-7, IL-12p40/70, IL-13, IP-10, eotaxin, MCP-1) but of only six cytokines in NR (IL-1β, IL-2, IL-5, IL-12p40/70, IL-13, eotaxin). The highest rise in MIP-1β and MCP-1 levels was observed four weeks after anti-HCV treatment initiation in SVR compared to NR (p=0.002 and p=0.03, respectively), whereas a decrease in IL-8 concentration was associated with treatment failure (p= 0.052). Conclusions Higher and broader cytokine responses to pegIFNα-ribavirin therapy were observed in SVR patients compared to NR. Changes in IL-8, MIP-1β, and MCP-1 serum concentrations may be associated with efficacy of pegIFNα- and ribavirin-based therapies in patients coinfected by HCV and HIV.
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9
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Ansari AWW, Schmidt RE, Shankar EM, Kamarulzaman A. Immuno-pathomechanism of liver fibrosis: targeting chemokine CCL2-mediated HIV:HCV nexus. J Transl Med 2014; 12:341. [PMID: 25528160 PMCID: PMC4272802 DOI: 10.1186/s12967-014-0341-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2014] [Accepted: 11/24/2014] [Indexed: 12/19/2022] Open
Abstract
Even in the era of successful combination antiretroviral therapy (cART), co-infection of Hepatitis C virus (HCV) remains one of the leading causes of non-AIDS-related mortality and morbidity among HIV-positive individuals as a consequence of accelerated liver fibrosis and end-stage liver disease (ESLD). The perturbed liver microenvironment and induction of host pro-inflammatory mediators in response to HIV and HCV infections, play a pivotal role in orchestrating the disease pathogenesis and clinical outcomes. How these viruses communicate each other via chemokine CCL2 and exploit the liver specific cellular environment to exacerbate liver fibrosis in HIV/HCV co-infection setting is a topic of intense discussion. Herein, we provide recent views and insights on potential mechanisms of CCL2 mediated immuno-pathogenesis, and HIV-HCV cross-talk in driving liver inflammation. We believe CCL2 may potentially serve an attractive target of anti-fibrotic intervention against HIV/HCV co-infection associated co-morbidities.
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Affiliation(s)
- A W Wahid Ansari
- Centre of Excellence for Research in AIDS, Faculty of Medicine, University of Malaya, Lambah Pantai 50603, Kuala Lumpur, Malaysia.
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10
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Fernández-Yunquera A, Ripoll C, Bañares R, Puerto M, Rincón D, Yepes I, Catalina V, Salcedo M. Everolimus immunosuppression reduces the serum expression of fibrosis markers in liver transplant recipients. World J Transplant 2014; 4:133-140. [PMID: 25032102 PMCID: PMC4094948 DOI: 10.5500/wjt.v4.i2.133] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2013] [Revised: 01/29/2014] [Accepted: 02/19/2014] [Indexed: 02/05/2023] Open
Abstract
AIM: To evaluate the expression of serum fibrosis markers in liver transplantation (LT) recipients on everolimus monotherapy compared to patients on an anti-calcineurin regimen.
METHODS: This cross-sectional case-control study included LT patients on everolimus monotherapy (cases) (E) (n = 30) and matched controls on an anti-calcineurin regimen (calcineurin inhibitors, CNI), paired by etiology of liver disease and time since LT (n = 30). Clinical characteristics, blood tests and elastography were collected. Serum levels of transforming growth factor-β (TGF-β), angiopoietin-1, tumor necrosis factor (TNF), platelet derived growth factor, amino-terminal propeptide of type III procollagen (PIIINP), hyaluronic acid (HA), VCM-1 (ng/mL), interleukin (IL)-10, interferon-inducible protein 10 (IP-10), vascular endothelial growth factor and hepatocyte growth factor (HGF) (pg/mL) were determined by enzyme-linked immunosorbent assay. Expression of these markers between E and CNI was compared. Stratified analysis was done according to factors that may influence liver fibrosis. Variables are described with medians (interquartillic range) or percentages.
RESULTS: A total of 60 patients [age: 59 (49-64), hepatitis C virus (HCV): n = 21 (35%), time from LT: 73 mo (16-105)] were included. Patients had been on everolimus for a median of 15 mo. No differences in inflammatory activity, APRI test or liver elastography were found between the groups. No significant differences were observed between the groups in serum levels of PIIINP, metalloproteinase type = 1, angiopoietin, HGF, IP-10, TNF-α, IL-10 and vascular cell adhesion molecule. Patients on E had a lower expression of TGF-β [E: 12.7 (3.7-133.6), CNI: 152.5 (14.4-333.2), P = 0.009] and HA [E: 702.89 (329.4-838.2), CNI: 1513.6 (691.9-1951.4), P = 0.001] than those on CNI. This difference was maintained in the stratified analysis when recipient age is more than 50 years (TFG-β1: P = 0.06; HA: P = 0.005), in patients without active neoplasia (TFG-β1, P = 0.009; HA: P = 0.01), according to time since LT (> than 5 years, TFG-β1: P = 0.001; HA: P = 0.002), related to previous history of biliary complications (HA: P = 0.01) and HCV recurrence (HA: P = 0.004). Liver transplant recipients with everolimus monotherapy had less serum expression of TGF-β y HA than matched patients with anti-calcineurins. This difference remains when classifying patients according to donor age and time since LT. Due to the small sample size, when examining patients with a prior history of biliary complications or recurrent HCV, the difference was non-significant but trends towards the lower expression of TFG-β1 in the everolimus group. Mammalian target of rapamycin (mTOR) plays a role in the transformation of quiescent hepatocellular stellate cell to their active profibrotic state, and experimental models have demonstrated the potential activity of mTOR inhibition in attenuating fibrogenesis.
CONCLUSION: This study supports a possible role of everolimus in liver fibrosis modulation after LT in a clinical setting and suggests that tailoring immunosuppression could avoid fibrosis progression in the allograft.
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11
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Howell J, Angus P, Gow P. Hepatitis C recurrence: the Achilles heel of liver transplantation. Transpl Infect Dis 2013; 16:1-16. [PMID: 24372756 DOI: 10.1111/tid.12173] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2013] [Revised: 06/12/2013] [Accepted: 08/03/2013] [Indexed: 12/18/2022]
Abstract
Hepatitis C virus (HCV) infection is the most common indication for liver transplantation worldwide; however, recurrence post transplant is almost universal and follows an accelerated course. Around 30% of patients develop aggressive HCV recurrence, leading to rapid fibrosis progression (RFP) and culminating in liver failure and either death or retransplantation. Despite many advances in our knowledge of clinical risks for HCV RFP, we are still unable to accurately predict those most at risk of adverse outcomes, and no clear consensus exists on the best approach to management. This review presents a critical overview of clinical factors shown to influence the course of HCV recurrence post transplant, with particular focus on recent data identifying the important role of metabolic factors, such as insulin resistance, in HCV recurrence. Emerging data for genetic markers of HCV recurrence and their usefulness for predicting adverse outcomes will also be explored.
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Affiliation(s)
- J Howell
- Liver Transplant Unit, Austin Hospital, Melbourne, Australia; Department of Medicine, University of Melbourne, Melbourne, Australia
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12
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Berenguer M, Schuppan D. Progression of liver fibrosis in post-transplant hepatitis C: mechanisms, assessment and treatment. J Hepatol 2013; 58:1028-41. [PMID: 23262248 DOI: 10.1016/j.jhep.2012.12.014] [Citation(s) in RCA: 117] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2012] [Revised: 12/10/2012] [Accepted: 12/10/2012] [Indexed: 12/12/2022]
Abstract
Liver fibrosis results from an excessive wound healing response in most chronic liver diseases, such as hepatitis C. Despite great advances in antiviral therapy in recent years, progressive liver fibrosis remains a major problem for patients with recurrent hepatitis C after liver transplantation. Liver biopsy remains a central tool in the management of HCV-positive liver transplant recipients, but reliable non-invasive methods for the assessment of liver fibrosis, such as ultrasound elastography, are increasingly being incorporated in the management of post-transplant patients, helping predict prognosis, guide treatment decisions, and stratify patients for emerging antifibrotic therapies. In this manuscript, we will review the natural history as well as tools to monitor fibrosis progression in the HCV-positive liver transplant recipient, the mechanisms underlying rapid fibrosis progression in up to 30% of these patients, the effect of antiviral therapies and highlight promising antifibrotic approaches.
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Affiliation(s)
- Marina Berenguer
- University Valencia, Dept. of Medicine, Hepatology & Liver Transplantation Unit, La Fe Hospital and CIBEREHD, National Network Center for Hepatology and Gastroenterology Research, Instituto de Salud Carlos III, Spain.
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13
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Bowen DG, Shackel NA. Hepatitis C pathogenesis and outcomes after liver transplantation: probing microRNA expression for new insights. Liver Transpl 2013; 19:355-7. [PMID: 23447337 DOI: 10.1002/lt.23625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2013] [Accepted: 02/12/2013] [Indexed: 01/12/2023]
Affiliation(s)
| | - Nicholas A. Shackel
- A. W. Morrow Gastroenterology and Liver Centre; Centenary Institute; Sydney; Australia
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14
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Sigdel TK, Gao X, Sarwal MM. Protein and peptide biomarkers in organ transplantation. Biomark Med 2012; 6:259-71. [PMID: 22731899 DOI: 10.2217/bmm.12.29] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Organ transplantation is the optimal treatment choice for end-stage organ failure in pediatric patients. The ideal maintenance of a transplanted organ requires efficient monitoring tools and an effective individualized post-transplant treatment plan. Currently available post-transplant monitoring options are not ideal because of their invasiveness or their lack of sensitivity and specificity when providing an accurate assessment of transplant injury. Current research on proteins and peptides, including mass spectrometry-based proteomics, can identify novel surrogate protein and peptide biomarkers that can assist in monitoring the graft in order to correctly assess the status of the transplanted organ. In this article, we have critically reviewed current relevant literature to highlight the importance of protein and peptide biomarkers in the field of pediatric organ transplantation, the status of research findings in the field of protein and peptide biomarkers in different organ transplantation and factors that impact and inhibit the progression of protein biomarker discovery in the field of solid-organ transplantation in pediatrics.
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Affiliation(s)
- Tara K Sigdel
- California Pacific Medical Center - Research Institute, San Francisco, USA.
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do O NT, Eurich D, Schmitz P, Schmeding M, Heidenhain C, Bahra M, Trautwein C, Neuhaus P, Neumann UP, Wasmuth HE. A 7-gene signature of the recipient predicts the progression of fibrosis after liver transplantation for hepatitis C virus infection. Liver Transpl 2012; 18:298-304. [PMID: 22139994 DOI: 10.1002/lt.22475] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Fibrosis recurrence after liver transplantation (LT) for hepatitis C virus (HCV) is a universal event and strongly determines a patient's prognosis. The recipient risk factors for fibrosis recurrence are still poorly defined. Here we assess a genetic risk score as a predictor of fibrosis after LT. The cirrhosis risk score (CRS), which comprises allele variants in 7 genes (adaptor-related protein complex 3 S2, aquaporin 2, antizyme inhibitor 1, degenerative spermatocyte homolog 1 lipid desaturase, syntaxin binding protein 5-like, toll-like receptor 4, and transient receptor potential cation channel M5), was calculated for 137 patients who underwent LT for HCV infection and experienced HCV reinfection of the graft. The patients were stratified into 3 CRS categories: <0.5, 0.5 to 0.7, and >0.7. All patients underwent protocol biopsy after LT (median follow-up = 5 years), and liver fibrosis was assessed according to the Desmet and Scheuer score. The data were analyzed with univariate and multivariate analyses. The results showed that the highest CRS category was strongly associated with the presence of F2 or F3 fibrosis in protocol biopsy samples 1, 3, and 5 years after LT (P = 0.006, P = 0.001, and P = 0.02, respectively). Overall, 75.0% of the patients with a CRS > 0.7 developed at least F2 fibrosis, whereas 51.5% developed F3 fibrosis during follow-up. The predictive value of the CRS for fibrosis progression was independent of known clinical risk factors, including the age of the donor, the sex of the recipient, and the occurrence of acute rejection. A Kaplan-Meier analysis confirmed the prognostic value of the CRS with respect to the recurrence of severe liver fibrosis in HCV-infected patients after LT (log rank = 6.23, P = 0.03). In conclusion, the genetic signature of the recipient predicts the likelihood of severe liver fibrosis in the graft after HCV recurrence. The CRS might help with early clinical decision making (eg, the selection of patients for antiviral therapy after LT).
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Affiliation(s)
- Nicole T do O
- Medical Department III, Charité University Hospital, Berlin, Germany
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17
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Lladó L, Ramos E. [Use of biological markers in the differential diagnosis of sepsis after liver transplant]. Cir Esp 2011; 90:85-90. [PMID: 21530952 DOI: 10.1016/j.ciresp.2011.01.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2010] [Accepted: 01/28/2011] [Indexed: 11/17/2022]
Abstract
The use of biological markers is developing in the field of liver transplant. Biomarkers are being studied in different contexts: 1) detection of tolerant patient; 2) recurrence of hepatitis C virus; 3) diagnosis and prognosis of liver cancers, and 4) diagnosis of infection. The immunological changes occurring in the transplant patient given their previous cirrhotic condition, the immunosuppression received, and possible intercurrent diagnoses (rejection, recurrence of hepatitis C virus…) highlight the importance of finding useful biomarkers in clinical practice to diagnose infection. After a review of the usefulness of biomarkers, we should perhaps add the serial determination of C-reactive protein in the immediate post-operative period, and later on procalcitonin, in the infection diagnosis algorithm. Although the determination of procalcitonin appears to be the most reliable biomarker in the differential diagnosis of sepsis and rejection, the studies carried out make it difficult to establish conclusions on its real clinical usefulness.
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Affiliation(s)
- Laura Lladó
- Unidad de Trasplante Hepático, Servicio de Cirugía General y Digestiva, Hospital Universitari de Bellvitge, Barcelona, España.
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Berres ML, Trautwein C, Schmeding M, Eurich D, Tacke F, Bahra M, Neuhaus P, Neumann UP, Wasmuth HE. Serum chemokine CXC ligand 10 (CXCL10) predicts fibrosis progression after liver transplantation for hepatitis C infection. Hepatology 2011; 53:596-603. [PMID: 21274880 DOI: 10.1002/hep.24098] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2010] [Accepted: 10/14/2010] [Indexed: 12/14/2022]
Abstract
UNLABELLED The recurrence of liver fibrosis after liver transplantation (LT) for hepatitis C virus (HCV) infection is responsible for graft loss and patient mortality. Although the contribution of the immune system to fibrosis recurrence is anticipated, systematic studies evaluating immune parameters as predictive markers of allograft fibrosis are lacking. The infiltration of immune cells into the graft is governed by chemokines. Here we assessed the predictive value of serum levels of chemokines [chemokine (C-X-C motif) ligand 9 (CXCL9), CXCL10, CXCL11, and chemokine (C-C motif) ligand 2 (CCL2)] with respect to fibrosis recurrence after LT in 90 HCV-infected organ recipients. Chemokines were determined within the first and third years after LT and were correlated with histological fibrosis progression in protocol biopsy samples at 1, 3, 5, and 7 years (median follow-up = 3 years). The association of chemokines with fibrosis progression was assessed by univariate and multivariate analyses and by Cox regression analysis. The results for the analyzed chemokines showed that CXCL10 levels in the first year after LT were strongly associated with early fibrosis recurrence (P = 0.005) independently of risk confounders (including the donor age, HCV viral load, HCV genotype, acute rejection, and inflammatory activity). As assessed by Cox regression analysis, a CXCL10 serum level ≤ 140 pg/mL was significantly predictive of the absence of F2 fibrosis (P = 0.001), whereas a level ≤ 220 pg/mL early after LT predicted the absence of F3 fibrosis during follow-up (P = 0.035). CONCLUSION CXCL10 is an independent biomarker of the recurrence of significant fibrosis after LT for HCV infection. These results might guide patients' care after transplantation and help us to select optimal candidates for antiviral therapy post-LT.
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Manousou P, Dhillon AP, Isgro G, Calvaruso V, Luong TV, Tsochatzis E, Xirouchakis E, Kalambokis G, Cross TJ, Rolando N, O'Beirne J, Patch D, Thornburn D, Burroughs AK. Digital image analysis of liver collagen predicts clinical outcome of recurrent hepatitis C virus 1 year after liver transplantation. Liver Transpl 2011; 17:178-88. [PMID: 21280191 DOI: 10.1002/lt.22209] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Clinical outcomes of recurrent hepatitis C virus after liver transplantation are difficult to predict. We evaluated collagen proportionate area (CPA), a quantitative histological index, at 1 year with respect to the first episode of clinical decompensation. Patients with biopsies at 1 year after liver transplantation were evaluated by Ishak stage/grade, and biopsy samples stained with Sirius red for digital image analysis were evaluated for CPA. Cox regression was used to evaluate variables associated with first appearance of clinical decompensation. Receiver operating characteristic (ROC) curves were also used. A total of 135 patients with median follow-up of 76 months were evaluated. At 1 year, median CPA was 4.6% (0.2%-36%) and Ishak stage was 0-2 in 101 patients, 3-4 in 23 patients, and 5-6 in 11 patients. Decompensation occurred in 26 (19.3%) at a median of 61 months (15-138). Univariately, CPA, tacrolimus monotherapy, and Ishak stage/grade at 1 year were associated with decompensation; upon multivariate analysis, only CPA was associated with decompensation (P = 0.010; Exp(B) = 1.169; 95%CI, 1.037-1.317). Area under the ROC curve was 0.97 (95%CI, 0.94-0.99). A cutoff value of 6% of CPA had 82% sensitivity and 95% specificity for decompensation. In the 89 patients with hepatic venous pressure gradient (HVPG) measurement, similar results were obtained. When both cutoffs of CPA > 6% and HVPG ≥ 6 mm Hg were used, all patients decompensated. Thus, CPA at 1-year biopsy after liver transplantation was highly predictive of clinical outcome in patients infected with hepatitis C virus who underwent transplantation, better than Ishak stage or HVPG.
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Affiliation(s)
- Pinelopi Manousou
- The Royal Free Sheila Sherlock Liver Centre and Division of Surgery and Interventional Sciences, University College London, London, UK
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Cholongitas E, Tsochatzis E, Goulis J, Burroughs AK. Noninvasive tests for evaluation of fibrosis in HCV recurrence after liver transplantation: a systematic review. Transpl Int 2010; 23:861-70. [PMID: 20704691 DOI: 10.1111/j.1432-2277.2010.01142.x] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Noninvasive tests (NIT) for evaluation of hepatic fibrosis have not been evaluated extensively in liver transplantation. We systematically reviewed the literature regarding NIT after liver transplantation. We identified 14 studies evaluating NIT based on serum markers and/or liver imaging techniques: 10 studies assessed NIT in recipients with recurrent HCV infection for fibrosis and four studies evaluated predictors of progression of fibrosis in recurrent HCV. Transient Elastography (TE) had good discrimination for significant fibrosis (median AUROC: 0.88). Among the serum NIT, APRI had good performance (median AUROC: 0.75). TE performed better than serum (direct and indirect) NIT for significant fibrosis with median AUROC 0.88 (vs. 0.66, P < 0.001), median sensitivity 0.86 (vs. 0.56, P = 0.002), median NPV 0.90 (vs. 0.74, P = 0.05) and median PPV 0.80 (vs. 0.63, P = 0.02). TE compared to indirect serum NIT, had better performance, but was not superior to APRI score. Finally, direct, compared to indirect NIT, were not significantly different except for specificity: median: 0.83 vs. 0.69, respectively, P = 0.04. In conclusion, NIT could become an important tool in clinical management of liver transplant recipients, but whether they can improve clinical practice needs further evidence. Their optimal combination with liver biopsy and assessment of collagen content requires investigation.
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Affiliation(s)
- Evangelos Cholongitas
- The 4th Department of Internal Medicine, Medical School of Aristotle University, Greece. Royal Free Hospital, London, UK
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Aytaman A, Kaufman M, Terrault NA. Management of posttransplant hepatitis C infection. Curr Opin Organ Transplant 2010; 15:301-9. [PMID: 20445452 DOI: 10.1097/mot.0b013e3283398237] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
PURPOSE OF REVIEW Chronic hepatitis C virus (HCV) infection is the leading cause of liver transplantation. Outcome of HCV-associated liver transplantation has been worse than transplantation from other causes. This is mostly related to universal recurrence of HCV in the allograft leading to graft and patient loss or retransplantation. Current antiviral therapies (AVTs) are inadequate and ineffective in the vast majority of the patients with intolerable side effects in most. However, a sustained virologic response (SVR) is associated with improved graft and patient survival. New specifically targeted AVTs for HCV (STAT-C) agents in development will significantly improve the success of AVT. This review focuses on recent data in peritransplant management of HCV with special emphasis on predictors of outcome, diagnosis, prevention and control of reinfection with newer treatments on the horizon. RECENT FINDINGS In the immediate pretransplant setting, AVT should be considered in select patients to eradicate the virus. Careful donor selection, immunosuppression (IMS) modulation with steroid and calcineurin inhibitor (CNI) minimization, avoidance of T-cell-depleting treatments and acute rejection episodes, and control of metabolic syndrome can improve allograft outcomes and improve the response to AVT. AVT prior to significant damage to the allograft is strongly recommended. SUMMARY With modified novel IMS protocols, careful donor selection, and AVT prior to significant damage to the allograft we can improve the outcome of posttransplant hepatitis C infection. Albeit there are no available data on new antiviral agents, STAT-Cs will have a significant impact in this setting in the near future.
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Affiliation(s)
- Ayse Aytaman
- VA New York Harbor HCS Brooklyn, Brooklyn, New York 11209, USA.
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Maluf DG, Archer KJ, Villamil F, Stravitz RT, Mas V. Hepatitis C virus recurrence after liver transplantation: biomarkers of disease and fibrosis progression. Expert Rev Gastroenterol Hepatol 2010; 4:445-58. [PMID: 20678018 DOI: 10.1586/egh.10.39] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
End-stage liver disease due to hepatitis C virus infection (HCV) is the principal indication for liver transplantation. In the USA, over a third of available liver allografts are transplanted into recipients with chronic HCV infection. Reinfection of the graft is universal, but the impact of reinfection on short- and long-term liver function is highly variable. HCV infection in liver transplantation recipients is characterized by an accelerated fibrogenesis, with approximately a third of patients developing cirrhosis within 5 years of follow-up. HCV is associated with decreased patient and graft survival when compared with other indications of orthotopic liver transplantation. The mechanisms responsible for the accelerated liver damage in HCV-infected orthotopic liver transplantation recipients remain largely unknown.
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Affiliation(s)
- Daniel G Maluf
- Transplant Division, Virginia Commonwealth University Medical Center, Medical College of Virginia Hospitals, 1200 East Broad Street, West Hospital, 9th Fl, South Wing, PO Box 980254, Richmond, VA 23298, USA.
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