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Lee DU, Ponder R, Lee K, Menegas S, Fan GH, Chou H, Jung D, Lee K, Hastie DJ, Urrunaga NH. The differences in post-liver transplant outcomes of patients with autoimmune hepatitis who present with overlapping autoimmune liver diseases. Hepatol Int 2023; 17:720-734. [PMID: 36575337 PMCID: PMC10225314 DOI: 10.1007/s12072-022-10468-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 12/03/2022] [Indexed: 12/28/2022]
Abstract
BACKGROUND Patients with autoimmune hepatitis (AIH) may co-present with features of primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC). Using a national transplant registry, the outcomes of patients with these autoimmune liver conditions were compared. METHODS The UNOS-STAR registry was used to select a study population of AIH, PSC, and PBC liver transplant (LT) patients. Living and multi-organ transplant cases were excluded. Using the UNOS-registered diagnoses, the study population was subdivided into those with nonoverlapping autoimmune liver diseases and those with overlapping forms (e.g., AIH-PBC). Outcomes were compared, using endpoints such as all-cause mortality, graft failure, and organ-system specific causes of death. RESULTS The main analysis featured 2048 entries, with 1927 entries having nonoverlapping AIH, 52 entries having PSC overlap, and 69 entries having PBC overlap. Patients with PBC overlap were more likely to have graft failure (adjusted hazard ratio [aHR] 3.46 95% CI 1.70-7.05), mortality secondary to respiratory causes (aHR 3.57 95% CI 1.23-10.43), and mortality secondary to recurrent disease (aHR 9.53 95% CI 1.85-49.09). Case incidence rates reflected these findings, expressed in events per 1000 person-years. For patients with PBC overlap and nonoverlapping AIH cases, respectively. Graft failure: 28.87 events vs. 9.42 events, mortality secondary to respiratory causes: 12.83 deaths vs. 3.77 deaths, mortality secondary to recurrent disease: 6.42 deaths vs. 1.26 deaths. Those with AIH-PSC overlap experienced a higher risk of death from graft infection (aHR 10.43 95% CI 1.08-100.37; case-incidence rate: 3.89 vs. 0.31 mortalities per 1000 person-years). Supplementary analysis showed similar findings, in which overlapping autoimmune conditions were associated with higher adverse outcome rates. CONCLUSION Patients with AIH-PBC overlap have higher risk of mortality due to recurrent liver disease and respiratory causes, and patients with AIH-PSC overlap have higher risk of mortality due to graft infection. While further prospective studies are needed to clarify the underlying mechanisms related to these findings, our study characterizes the prognostic implications of AIH overlap on post-LT mortality and graft failure risks.
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Affiliation(s)
- David Uihwan Lee
- Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, 22 S. Greene St N3W50, Baltimore, MD, 21201, USA.
| | - Reid Ponder
- Department of Medicine, Tufts University School of Medicine, Washington St, Boston, MA, 02111, USA
| | - Kijung Lee
- Department of Medicine, Tufts University School of Medicine, Washington St, Boston, MA, 02111, USA
| | - Samantha Menegas
- Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, 22 S. Greene St N3W50, Baltimore, MD, 21201, USA
| | - Gregory Hongyuan Fan
- Department of Medicine, Tufts University School of Medicine, Washington St, Boston, MA, 02111, USA
| | - Harrison Chou
- Department of Medicine, Tufts University School of Medicine, Washington St, Boston, MA, 02111, USA
| | - Daniel Jung
- Department of Medicine, University of Missouri-Kansas City School of Medicine, Boston, MA, USA
| | - Keeseok Lee
- Department of Medicine, Tufts University School of Medicine, Washington St, Boston, MA, 02111, USA
| | - David Jeffrey Hastie
- Department of Medicine, Tufts University School of Medicine, Washington St, Boston, MA, 02111, USA
| | - Nathalie Helen Urrunaga
- Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, 22 S. Greene St N3W50, Baltimore, MD, 21201, USA
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Toshida K, Toshima T, Harada N, Nakayama Y, Tomiyama T, Morinaga A, Kosai-Fujimoto Y, Tomino T, Kurihara T, Nagao Y, Morita K, Itoh S, Yoshizumi T. Autoimmune Hepatitis in an Immunosuppression-Free Patient Who Underwent Living Donor Liver Transplantation From an Identical Twin: A Case Report. Transplant Proc 2022; 54:2791-2793. [DOI: 10.1016/j.transproceed.2022.09.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/24/2022] [Accepted: 09/13/2022] [Indexed: 11/16/2022]
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Drenth J, Barten T, Hartog H, Nevens F, Taubert R, Torra Balcells R, Vilgrain V, Böttler T. EASL Clinical Practice Guidelines on the management of cystic liver diseases. J Hepatol 2022; 77:1083-1108. [PMID: 35728731 DOI: 10.1016/j.jhep.2022.06.002] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 06/01/2022] [Indexed: 02/07/2023]
Abstract
The advent of enhanced radiological imaging techniques has facilitated the diagnosis of cystic liver lesions. Concomitantly, the evidence base supporting the management of these diseases has matured over the last decades. As a result, comprehensive clinical guidance on the subject matter is warranted. These Clinical Practice Guidelines cover the diagnosis and management of hepatic cysts, mucinous cystic neoplasms of the liver, biliary hamartomas, polycystic liver disease, Caroli disease, Caroli syndrome, biliary hamartomas and peribiliary cysts. On the basis of in-depth review of the relevant literature we provide recommendations to navigate clinical dilemmas followed by supporting text. The recommendations are graded according to the Oxford Centre for Evidence-Based Medicine system and categorised as 'weak' or 'strong'. We aim to provide the best available evidence to aid the clinical decision-making process in the management of patients with cystic liver disease.
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Duizendstra AA, De Knegt RJ, Nagtzaam NMA, Betjes MGH, Dik WA, Litjens NHR, Kwekkeboom J. Minimal Development of Liver Fibrosis in Adult Tolerant Liver Transplant Recipients Late After Immunosuppressive Drug Weaning and Transplantation. Transplant Proc 2022; 54:1874-1880. [PMID: 36100485 DOI: 10.1016/j.transproceed.2022.04.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 04/13/2022] [Indexed: 10/14/2022]
Abstract
BACKGROUND Operationally tolerant liver transplant (LTx)-recipients can be weaned off immunosuppressive (IS) drugs without development of graft rejection. However, it is feared that liver fibrosis might develop after complete IS weaning. The purpose of this small single-center study was to assess liver fibrosis in adult tolerant LTx recipients long after LTx and IS weaning. METHODS Liver fibrosis was assessed in adult tolerant LTx-recipients (n = 9) using noninvasive transient elastography and measurements of multiple pro- and antifibrotic serum markers associated with liver fibrosis. The data was collected for 2 subsequent years; 8 and 9 years after IS weaning and 19 and 20 years after transplantation. Healthy individuals (n = 9) matched for age and sex were included as a reference for fibrosis-related serum markers. This study was conducted in accordance with the Declaration of Helsinki and approved by the medical ethics committee of our institution. RESULTS Transient elastography indicated that 7 of 9 tolerant LTx recipients had no or minimal liver fibrosis (F0-F1), whereas 2 recipients had moderate or severe liver fibrosis (F2-F3). Most fibrosis-related serum markers in tolerant LTx recipients were within or close to the range obtained for healthy individuals. CONCLUSIONS The results from this small, single-center study indicated that most adult tolerant LTx recipients have no or minimal liver graft fibrosis long after transplantation and IS weaning, and their fibrosis-related serum marker profile indicates an absence of a profibrotic status.
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Affiliation(s)
- Aafke A Duizendstra
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Robert J De Knegt
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Nicole M A Nagtzaam
- Laboratory of Medical Immunology, Department of Immunology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Michiel G H Betjes
- Erasmus MC Transplant Institute, Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Willem A Dik
- Laboratory of Medical Immunology, Department of Immunology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Nicolle H R Litjens
- Erasmus MC Transplant Institute, Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Jaap Kwekkeboom
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
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Tejedor-Tejada J, Valenzuela EF, Muñoz RN, Gómez LH, García-Pajares F, Álvarez CA, Sánchez-Martín F, Alonso-Martín C, Sánchez-Antolín G. De-novo nonalcoholic fatty liver disease at 5 years after liver transplantation: prevalence and predictive factors. Eur J Gastroenterol Hepatol 2021; 33:399-406. [PMID: 32317584 DOI: 10.1097/meg.0000000000001736] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS Nonalcoholic fatty liver disease (NAFLD) is a long-term complication after liver transplantation. Our aims were to determine de-novo-NAFLD at 5-year post-liver transplantation and identify predictive risk factors. METHODS This was a retrospective analysis of de-novo-NAFLD at 5-year post-liver transplantation. NAFLD was defined as the radiological evidence of steatosis. Data from transplanted patients between November 2001 and May 2014 were collected. Noninvasive fibrosis scores were calculated. Predictors of de-novo NAFLD and survival were assessed by multivariate analyses and Kaplan-Meier method. RESULTS A total of 252 liver transplantations were evaluated after applying exclusion criteria, (78.6% men) with 54.9 years old (SD ± 9.5). Prevalence of de-novo NAFLD at 5-year post-liver transplantation was 36.1%. Cardiovascular events were presented in 19.88% and 23.08% of non-NAFLD and NAFLD patients, (P = 0.58). On multivariate analysis, male sex (OR, 5.40; P = 0.001), obesity (OR, 3.72; P = 0.017), metabolic syndrome (OR, 4.69; P < 0.001) and de-novo diabetes (OR, 2.79; P = 0.018), were predictive. Significant fibrosis (≥F2) was presented in 58-86%. The mean survival in NAFLD and control group was 166.3 and 173.6 months, respectively (P = 0 0.50). CONCLUSION De-novo NAFLD at fifth-year post-liver transplantation is frequently and associated with cardiovascular comorbidity. Male sex, obesity, de-novo diabetes and metabolic syndrome were factors associated with de-novo NAFLD. A significant proportion of patients had advanced fibrosis. This group trends toward worse patients' survival.
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Affiliation(s)
- Javier Tejedor-Tejada
- Department of Gastroenterology, Hepatology and Liver Transplantation Unit, Hospital Universitario Rio Hortega, Valladolid, Spain
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Lombardi R, Pisano G, Fargion S, Fracanzani AL. Cardiovascular involvement after liver transplantation: role of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. EXPLORATION OF MEDICINE 2021. [DOI: 10.37349/emed.2021.00030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Patients submitted to liver transplantation (LT) are exposed to high risk of cardiovascular (CV) complications which are the main determinants of both short-term and long-term morbidity and mortality in LT. Non-alcoholic fatty liver disease (NAFLD) is a very frequent condition in general population and is associated with a high risk of cardiovascular disease (CVD) which represents the first cause of death of these patients. NAFLD is predicted to become the first indication to LT and nowadays is also frequently detected in patients submitted to LT for other indications. Thus, the risk of CVD in patients submitted to LT is forecasted to increase in the next years. In this review the extent of CV involvement in patients submitted to LT and the role of NAFLD, either recurring after transplantation or as de novo presentation, in increasing CV risk is analysed. The risk of developing metabolic alterations, including diabetes, hypertension, dyslipidemia and weight gain, all manifestations of metabolic syndrome, occurring in the first months after LT, is depicted. The different presentations of cardiac involvement, represented by early atherosclerosis, coronary artery disease, heart failure and arrhythmias in patients with NAFLD submitted to LT is described. In addition, the tools to detect cardiac alterations either before or after LT is reported providing the possibility for an early diagnosis of CVD and an early therapy able to reduce morbidity and mortality for these diseases. The need for long-term concerted multidisciplinary activity with dietary counseling and exercise combined with drug treatment of all manifestations of metabolic syndrome is emphasized.
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Affiliation(s)
- Rosa Lombardi
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy 2Department of Pathophysiology and Transplantation, University of the Study of Milan, 20122 Milan, Italy
| | - Giuseppina Pisano
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Silvia Fargion
- Department of Pathophysiology and Transplantation, University of the Study of Milan, 20122 Milan, Italy
| | - Anna Ludovica Fracanzani
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy 2Department of Pathophysiology and Transplantation, University of the Study of Milan, 20122 Milan, Italy
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Gitto S, Falcini M, Marra F. Metabolic Disorders After Liver Transplantation. Metab Syndr Relat Disord 2020; 19:65-69. [PMID: 33104408 DOI: 10.1089/met.2020.0068] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Early after surgery, liver transplant (LT) recipients often develop weight gain due to an increase of caloric intake and fat mass (without recovery of muscle frame). This modification of body composition together with a negative metabolic impact of immunosuppressive drugs leads to a high prevalence of all the main metabolic disorders. Indeed, as expected, transplanted patients show a higher cardiovascular risk in comparison with general population. Notably, seeing the increase of mean age of transplanted population, metabolic disorders represent the true challenge for the transplant community. Considering the lack of evidences or clear indications about prevention, early diagnosis and treatment of metabolic disorders after LT, it would be mandatory to develop targeted further studies on this matter.
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Affiliation(s)
- Stefano Gitto
- Internal Medicine and Liver Unit, Department of Experimental and Clinical Medicine, University Hospital Careggi, University of Florence, Florence, Italy
| | - Margherita Falcini
- Internal Medicine and Liver Unit, Department of Experimental and Clinical Medicine, University Hospital Careggi, University of Florence, Florence, Italy
| | - Fabio Marra
- Internal Medicine and Liver Unit, Department of Experimental and Clinical Medicine, University Hospital Careggi, University of Florence, Florence, Italy
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Immunosuppressive drug withdrawal late after liver transplantation improves the lipid profile and reduces infections. Eur J Gastroenterol Hepatol 2019; 31:1444-1451. [PMID: 31095525 DOI: 10.1097/meg.0000000000001435] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Treatment with immunosuppressive drugs (IS) after transplantation is accompanied by severe side effects. A limited number of studies have investigated the effect of IS withdrawal on IS-related comorbidities after liver transplantation (LTx) and the results are contradictory. PATIENTS AND METHODS We determined in a retrospective case-control study the clinical effects of complete IS withdrawal in operationally tolerant (TOL) LTx recipients who discontinued IS 10.8 ± 5.1 years after LTx (n = 13) compared with a completely matched control (CTRL) group with a regular IS regimen (n = 22). TOL recipients have been IS and rejection free for 4.0 ± 2.8 years. RESULTS IS withdrawal in TOL recipients resulted in lower low-density lipoprotein levels (P = 0.027), whereas this was not observed in the CTRL group. Furthermore, persistent infections in individual recipients were resolved successfully by IS withdrawal. TOL recipients also had significantly fewer de novo infections after IS withdrawal (TOL pre vs. post withdrawal P = 0.0247) compared with recipients continued on IS during the same follow-up period (post withdrawal TOL vs. CTRL P = 0.044). Unfortunately, no improvement in kidney function, and lower rates of de novo occurrences of diabetes, hypertension, cardiovascular diseases, and malignancies were observed in the TOL group after IS withdrawal compared with the CTRL group during the same follow-up time period. CONCLUSION IS withdrawal late after LTx reduces infection rates and low-density lipoprotein levels, but other IS-related side effects persist late after LTx. An accurate tolerance immune profile enabling identification of tolerant LTx recipients eligible for safe IS withdrawal earlier after transplantation is needed to prevent the development of irreversible IS-related side effects.
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Fabrizi F, Dixit V, Martin P, Messa P. Chronic Kidney Disease after Liver Transplantation: Recent Evidence. Int J Artif Organs 2018. [DOI: 10.1177/039139881003301105] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Chronic kidney disease is a common complication after liver transplantation with an incidence ranging between 20% and 80%. Studies of renal function after liver transplantation have yielded conflicting results: the wide range in incidence rates of chronic kidney disease (CKD) following liver transplantation is related to the methods for measuring kidney function, and various criteria for defining renal dysfunction, among others. An important cause of CKD among liver transplant recipients is calcineurin inhibitor-based immunosuppression. Additional predictors of CKD post-liver transplantation include pre-transplant kidney function, peri-operative acute kidney failure, age, and hepatitis C. A recent meta-analysis of observational studies revealed that, in the subgroup of studies provided with glomerular filtration rate at baseline, the summary estimate of relative risk and 95% confidence intervals (CI) for developing chronic renal failure among liver transplant recipients with diminished renal function at transplant was 2.12 (95% CI, 1.01–4.46, p=0.047). Acute renal insufficiency is common immediately after liver transplantation, whereas the course of CKD after liver transplantation appears progressive over time. Only preliminary information exists on kidney pathological findings in recipients of liver transplants with CKD. Introduction of the Model for End-stage Liver Disease for the allocation of liver grafts has not increased the occurrence of renal dysfunction following liver transplantation. Chronic kidney disease following liver transplantation increases cardiovascular burden dramatically. The use of mycophenolic acid- or sirolimus-based immunosuppression in calcineurin-inhibitors sparing protocols is an area of intense research.
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Affiliation(s)
- Fabrizio Fabrizi
- Division of Nephrology, Maggiore Hospital, IRCCS Foundation, Milan - Italy
- Division of Hepatology, School of Medicine, University of Miami, Miami, Florida - USA
| | - Vivek Dixit
- Division of Digestive Diseases, UCLA School of Medicine, Los Angeles, California - USA
| | - Paul Martin
- Division of Hepatology, School of Medicine, University of Miami, Miami, Florida - USA
| | - Piergiorgio Messa
- Division of Nephrology, Maggiore Hospital, IRCCS Foundation, Milan - Italy
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EXP CLIN TRANSPLANTExp Clin Transplant 2018; 16. [DOI: 10.6002/ect.2017.0217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register]
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Saxena V, Terrault NA. Recurrent Primary Disease After Liver Transplantation. ZAKIM AND BOYER'S HEPATOLOGY 2018:784-815.e14. [DOI: 10.1016/b978-0-323-37591-7.00053-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Satapathy SK, Jones OD, Vanatta JM, Kamal F, Kedia SK, Jiang Y, Nair SP, Eason JD. Outcomes of Liver Transplant Recipients With Autoimmune Liver Disease Using Long-Term Dual Immunosuppression Regimen Without Corticosteroid. Transplant Direct 2017; 3:e178. [PMID: 28706981 PMCID: PMC5498019 DOI: 10.1097/txd.0000000000000693] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Revised: 04/15/2017] [Accepted: 05/01/2017] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Liver transplant (LT) recipients with autoimmune liver disease (primary sclerosing cholangitis, primary biliary cholangitis, autoimmune hepatitis) are at increased risk of developing acute cellular rejection (ACR), and in many cases graft failure due to recurrent disease. We describe our experience with dual immunosuppression without steroid maintenance and analyze its effect on disease recurrence; ACR; patient and graft survivals; and complications, such as sepsis and de novo malignancy. METHODS We included 74 consecutive LT recipients (April 2006 to April 2013) with autoimmune liver disease (primary sclerosing cholangitis, 20; primary biliary cholangitis, 23; autoimmune hepatitis, 31) from a single transplant center. Immunosuppression protocol included rabbit antithymocyte globulin for induction and mycophenolate mofetil with tacrolimus or sirolimus/everolimus indefinitely for maintenance. RESULTS Overall 1-, 3-, 5-, and 7-year patient survival was 95.9%, 90.4%, 82,2% and 74.9%, re-graft-free survival was 93.2%, 86.3%, 79.9%, and 72.8%, respectively (median follow-up, 5.5 years). In a multivariate Cox regression analysis, sepsis during post-LT period (P = 0.040; hazard ratio [HR], 2.52; 95% confidence interval [CI], 1.04-6.11), steroid use for ACR (P = 0.037; HR, 2.60; 95% CI, 1.06-6.34), and younger age (<40 years) at LT (P = 0.038; HR, 2.53; 95% CI, 1.05-6.10) predicted graft survival, whereas steroid use for ACR was the only variable that was predictive of overall patient survival (P = 0.004; HR, 4.10; 95% CI, 1.59-10.52). Overall, 34 biopsy-proven ACR was noted in 22 LT recipients (30%), 13 (17.5%) had disease recurrence, and 34 episodes of sepsis occurred in 19 patients. CONCLUSIONS Dual immunosuppression protocol in LT recipients with autoimmune liver disease without corticosteroid maintenance had acceptable rates of survival and ACR without predisposing patients to the adverse effects of long-term steroid therapy.
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Affiliation(s)
- Sanjaya K. Satapathy
- Methodist University Hospital Transplant Institute, University of Tennessee Health Sciences Center, Memphis, TN
| | - Ollie D. Jones
- Department of Gastroenterology, University of Tennessee Health Sciences Center, Memphis, TN
| | - Jason M. Vanatta
- Methodist University Hospital Transplant Institute, University of Tennessee Health Sciences Center, Memphis, TN
| | - Faisal Kamal
- Department of Internal Medicine, University of Tennessee Health Sciences Center, Memphis, TN
| | | | - Yu Jiang
- School of Public Health, University of Memphis, Memphis, TN
| | - Satheesh P. Nair
- Methodist University Hospital Transplant Institute, University of Tennessee Health Sciences Center, Memphis, TN
| | - James D. Eason
- Methodist University Hospital Transplant Institute, University of Tennessee Health Sciences Center, Memphis, TN
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13
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Thoefner LB, Rostved AA, Pommergaard HC, Rasmussen A. Risk factors for metabolic syndrome after liver transplantation: A systematic review and meta-analysis. Transplant Rev (Orlando) 2017; 32:69-77. [PMID: 28501338 DOI: 10.1016/j.trre.2017.03.004] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Revised: 02/10/2017] [Accepted: 03/10/2017] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Metabolic syndrome is associated with increased risk of cardiovascular events, which contributes to the elevated mortality rate among liver transplant recipients. The objective of this systematic review and meta-analysis was to assess the prevalence and risk factors for metabolic syndrome after liver transplantation. METHODS The databases Medline and Scopus were searched for observational studies evaluating prevalence and risk factors for metabolic syndrome after liver transplantation. Meta-analyses were performed based on odds ratios (ORs) from multivariable analyses. The Newcastle-Ottawa Scale was used for assessment of bias. RESULTS The literature search generated 1815 records of which 16 articles were included comprising 3539 patients. The post-transplant prevalence of metabolic syndrome was 39%. Eight studies were eligible for meta-analyses, which showed that pre-transplant diabetes (OR=3.54, 95% confidence interval (CI): 2.51-4.98) and pre-transplant obesity (OR=2.44, 95% CI: 1.48-4.03) were risk factors for metabolic syndrome. Six out of seven studies reported that recipients with metabolic syndrome had a higher incidence of cardiovascular events. Four studies showed that survival was not affected by metabolic syndrome. CONCLUSIONS The prevalences of metabolic syndrome and new-onset metabolic syndrome were high after liver transplantation. Metabolic syndrome was associated with cardiovascular events, but not poorer survival. Patients with pre-transplant diabetes and -obesity are at high risk of metabolic syndrome and should be under careful surveillance in order to prevent, earlier diagnose, and treat metabolic syndrome and thereby limit the risk of cardiovascular events.
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Affiliation(s)
- Line Buch Thoefner
- Rigshospitalet - University of Copenhagen, Department of Surgical Gastroenterology and Transplantation, Abdominal Centre, Blegdamsvej 9, 2100 Copenhagen, Denmark.
| | - Andreas Arendtsen Rostved
- Rigshospitalet - University of Copenhagen, Department of Surgical Gastroenterology and Transplantation, Abdominal Centre, Blegdamsvej 9, 2100 Copenhagen, Denmark
| | - Hans-Christian Pommergaard
- Rigshospitalet - University of Copenhagen, Department of Surgical Gastroenterology and Transplantation, Abdominal Centre, Blegdamsvej 9, 2100 Copenhagen, Denmark
| | - Allan Rasmussen
- Rigshospitalet - University of Copenhagen, Department of Surgical Gastroenterology and Transplantation, Abdominal Centre, Blegdamsvej 9, 2100 Copenhagen, Denmark
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14
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Daniel KE, Eickhoff J, Lucey MR. Why do patients die after a liver transplantation? Clin Transplant 2017; 31. [PMID: 28039946 DOI: 10.1111/ctr.12906] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/11/2016] [Indexed: 12/13/2022]
Abstract
BACKGROUND As more patients achieve long-term survival, it has become important to understand mortality in liver transplantation (LT) recipients. METHODS We conducted retrospective reviews of long-term outcome in two adult LT cohorts: 85 031 in the United Network for Organ Sharing (UNOS) database and 1458 transplanted at the University of Wisconsin (UW). RESULTS During median follow-up of 3.2 years (UNOS) and 6.6 years (UW), 35.1% of UNOS patients and 44.2% of UW patients died; 43.1% of all UNOS deaths occurred in year 1 compared to 25.1% in the UW cohort. Deaths due to infection (other than viral hepatitis) or cardiovascular (CV) causes were most frequent in year 1 in both cohorts and then persisted at lower rates. In contrast, death from malignancy increased after year 1 to peak in years 1-5. Deaths due to rejection, hepatitis, or graft failure were infrequent. In the UW cohort, de novo malignancy was more common than recurrent tumor and correlated with smoking history. CONCLUSIONS A coordinated holistic approach that focuses on limiting immunosuppression, infection, risky behaviors, and CV risks, while screening for cancer, is needed to extend the healthy lives of LT recipients.
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Affiliation(s)
- Kim E Daniel
- Departments of Medicine and Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Jens Eickhoff
- Departments of Medicine and Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Michael R Lucey
- Departments of Medicine and Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
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15
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Pisano G, Fracanzani AL, Caccamo L, Donato MF, Fargion S. Cardiovascular risk after orthotopic liver transplantation, a review of the literature and preliminary results of a prospective study. World J Gastroenterol 2016; 22:8869-8882. [PMID: 27833378 PMCID: PMC5083792 DOI: 10.3748/wjg.v22.i40.8869] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 08/27/2016] [Accepted: 09/28/2016] [Indexed: 02/06/2023] Open
Abstract
Improved surgical techniques and greater efficacy of new anti-rejection drugs have significantly improved the survival of patients undergoing orthotopic liver transplantation (OLT). This has led to an increased incidence of metabolic disorders as well as cardiovascular and cerebrovascular diseases as causes of morbidity and mortality in OLT patients. In the last decade, several studies have examined which predisposing factors lead to increased cardiovascular risk (i.e., age, ethnicity, diabetes, NASH, atrial fibrillation, and some echocardiographic parameters) as well as which factors after OLT (i.e., weight gain, metabolic syndrome, immunosuppressive therapy, and renal failure) are linked to increased cardiovascular mortality. However, currently, there are no available data that evaluate the development of atherosclerotic damage after OLT. The awareness of high cardiovascular risk after OLT has not only lead to the definition of new but generally not accepted screening of high risk patients before transplantation, but also to the need for careful patient follow up and treatment to control metabolic and cardiovascular pathologies after transplant. Prospective studies are needed to better define the predisposing factors for recurrence and de novo occurrence of metabolic alterations responsible for cardiovascular damage after OLT. Moreover, such studies will help to identify the timing of disease progression and damage, which in turn may help to prevent morbidity and mortality for cardiovascular diseases. Our preliminary results show early occurrence of atherosclerotic damage, which is already present a few weeks following OLT, suggesting that specific, patient-tailored therapies should be started immediately post OLT.
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Early Predictors of Long-term Outcomes of HCV-negative Liver Transplant Recipients Having Survived the First Postoperative Year. Transplantation 2016; 100:382-90. [PMID: 26683515 DOI: 10.1097/tp.0000000000001038] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
BACKGROUND The non-improvement in >1-year post-liver transplant (LT) survival and diminishing importance of hepatitis C (HCV) with modern antivirals justify identification of early factors predictive of long-term outcome post-LT in HCV-negative recipients. METHODS This nationwide study included all 631 HCV-negative adult patients transplanted in Finland 1982-2013 with at least 1-year graft survival (6311 person-year follow-up). We tested 37 variables, including immunosuppression, for their association with >1-year combined graft loss/mortality, late rejection, cancer, or infections. RESULTS Significant multivariate predictors of graft loss/mortality were male gender (HR 2.40, P = 0.001), pretransplant hepatocellular (HR 2.92, P = 0.001) or biliary cancer (HR 12.7, P < 0.001), glomerular filtration rate (HR 0.89, P = 0.002), hypertension (HR 0.44, P < 0.001), early posttransplant infections (HR 1.52-1.67, P = 0.007-0.03), and alkaline phosphatase (ALP) (HR 1.05, P < 0.001). Elevated ALP at 1 year, affecting 30% of patients, predicted both graft loss and rejection, independent of immunologic stability, etiology, and immunosuppression type. Area under the curve of ALP in predicting graft loss from rejection was 0.81 (95% CI 0.71-0.90) and 0.85 (95% CI 0.72-0.98, P = 0.001) among patients under 50. Among immunologically stable patients who underwent transplantation after 2000, antimetabolite use at 1 year was associated with improved survival (P = 0.04), specifically in the subgroup with native-liver hepatocellular or biliary cancer (P = 0.02). CONCLUSIONS Easily measurable, widely available, and noninvasive factors known at 1 year post-LT can help stratify patients according to their long-term risk of death or graft loss, and thus facilitate a personalization of long-term follow-up. ALP deserves routine monitoring, and the cause for an elevated ALP should be sought.
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Abstract
Liver transplantation (LT) is the most effective treatment modality for end stage liver disease caused by many etiologies including autoimmune processes. That said, the need for transplantation for autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC), but not for primary sclerosing cholangitis (PSC), has decreased over the years due to the availability of effective medical treatment. Autoimmune liver diseases have superior transplant outcomes than those of other etiologies. While AIH and PBC can recur after LT, recurrence is of limited clinical significance in most, but not all cases. Recurrent PSC, however, often progresses over years to a stage requiring re-transplantation. The exact incidence and the predisposing factors of disease recurrence remain debated. Better understanding of the pathogenesis and the risk factors of recurrent autoimmune liver diseases is required to develop preventive measures. In this review, we discuss the current knowledge of incidence, diagnosis, risk factors, clinical course, and treatment of recurrent autoimmune liver disease (AIH, PBC, PSC) following LT.
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Goldaracena N, Spetzler VN, Sapisochin G, J E, Moritz K, Cattral MS, Greig PD, Lilly L, McGilvray ID, Levy GA, Ghanekar A, Renner EL, Grant DR, Selzner M, Selzner N. Should We Exclude Live Donor Liver Transplantation for Liver Transplant Recipients Requiring Mechanical Ventilation and Intensive Care Unit Care? Transplant Direct 2015; 1:e30. [PMID: 27500230 PMCID: PMC4946477 DOI: 10.1097/txd.0000000000000543] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Accepted: 08/15/2015] [Indexed: 12/29/2022] Open
Abstract
Patients with acute and chronic liver disease often require admission to intensive care unit (ICU) and mechanical ventilation support before liver transplantation (LT). Rapid disease progression and high mortality on LT waiting lists makes live donor LT (LDLT) an attractive option for this patient population.
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Affiliation(s)
- Nicolas Goldaracena
- Multi Organ Transplant Program, Department of Surgery, Toronto General Hospital, Toronto, ON, Canada
| | - Vinzent N Spetzler
- Multi Organ Transplant Program, Department of Surgery, Toronto General Hospital, Toronto, ON, Canada
| | - Gonzalo Sapisochin
- Multi Organ Transplant Program, Department of Surgery, Toronto General Hospital, Toronto, ON, Canada
| | - Echeverri J
- Multi Organ Transplant Program, Department of Surgery, Toronto General Hospital, Toronto, ON, Canada
| | - Kaths Moritz
- Multi Organ Transplant Program, Department of Surgery, Toronto General Hospital, Toronto, ON, Canada
| | - Mark S Cattral
- Multi Organ Transplant Program, Department of Surgery, Toronto General Hospital, Toronto, ON, Canada
| | - Paul D Greig
- Multi Organ Transplant Program, Department of Surgery, Toronto General Hospital, Toronto, ON, Canada
| | - Les Lilly
- Multi Organ Transplant Program, Department of Surgery, Toronto General Hospital, Toronto, ON, Canada
| | - Ian D McGilvray
- Multi Organ Transplant Program, Department of Surgery, Toronto General Hospital, Toronto, ON, Canada
| | - Gary A Levy
- Department of Medicine, Toronto General Hospital, Toronto, ON, Canada
| | - Anand Ghanekar
- Multi Organ Transplant Program, Department of Surgery, Toronto General Hospital, Toronto, ON, Canada
| | - Eberhard L Renner
- Department of Medicine, Toronto General Hospital, Toronto, ON, Canada
| | - David R Grant
- Multi Organ Transplant Program, Department of Surgery, Toronto General Hospital, Toronto, ON, Canada
| | - Markus Selzner
- Multi Organ Transplant Program, Department of Surgery, Toronto General Hospital, Toronto, ON, Canada
| | - Nazia Selzner
- Department of Medicine, Toronto General Hospital, Toronto, ON, Canada
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Åberg F, Gissler M, Karlsen TH, Ericzon BG, Foss A, Rasmussen A, Bennet W, Olausson M, Line PD, Nordin A, Bergquist A, Boberg KM, Castedal M, Pedersen CR, Isoniemi H. Differences in long-term survival among liver transplant recipients and the general population: a population-based Nordic study. Hepatology 2015; 61:668-677. [PMID: 25266201 DOI: 10.1002/hep.27538] [Citation(s) in RCA: 102] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2014] [Accepted: 09/25/2014] [Indexed: 12/11/2022]
Abstract
UNLABELLED Dramatic improvement in first-year outcomes post-liver transplantation (LT) has shifted attention to long-term survival, where efforts are now needed to achieve improvement. Understanding the causes of premature death is a prerequisite for improving long-term outcome. Overall and cause-specific mortality of 3,299 Nordic LT patients (1985-2009) having survived 1 year post-LT were divided by expected rates in the general population, adjusted for age, sex, calendar date, and country to yield standardized mortality ratios (SMRs). Data came from the Nordic Liver-Transplant Registry and WHO mortality-indicator database. Stagnant patient survival rates >1 year post-LT were 21% lower at 10 years than expected survival for the general population. Overall SMR for death before age 75 (premature mortality) was 5.8 (95% confidence interval [CI] 5.4-6.3), with improvement from 1985-1999 to 2000-2010 in hepatitis C (HCV) (SMR change 23.1-9.2), hepatocellular carcinoma (HCC) (SMR 38.4-18.8), and primary sclerosing cholangitis (SMR 11.0-4.2), and deterioration in alcoholic liver disease (8.3-24.0) and acute liver failure (ALF) (5.9-7.6). SMRs for cancer and liver disease (recurrent or transplant-unrelated disease) were elevated in all indications except primary biliary cirrhosis (PBC). Absolute mortality rates underestimated the elevated premature mortality from infections (SMR 22-693) and kidney disease (SMR 13-45) across all indications, and from suicide in HCV and ALF. SMR for cardiovascular disease was significant only in PBC and alcoholic liver disease, owing to high mortality in the general population. Transplant-specific events caused 16% of deaths. CONCLUSION standardized premature mortality provided an improved picture of long-term post-LT outcome, showing improvement over time in some indications, not revealed by overall absolute mortality rates. Causes with high premature mortality (infections, cancer, kidney and liver disease, and suicide) merit increased attention in clinical patient follow-up and future research.
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Affiliation(s)
- Fredrik Åberg
- Transplantation and Liver Surgery Clinic, Helsinki University Hospital, Helsinki, Finland; Department of Gastroenterology, Helsinki University Hospital, Helsinki, Finland
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20
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Younossi ZM, Kanwal F, Saab S, Brown KA, El-Serag HB, Kim WR, Ahmed A, Kugelmas M, Gordon SC. The impact of hepatitis C burden: an evidence-based approach. Aliment Pharmacol Ther 2014; 39:518-31. [PMID: 24461160 DOI: 10.1111/apt.12625] [Citation(s) in RCA: 81] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2013] [Revised: 10/11/2013] [Accepted: 12/30/2013] [Indexed: 12/08/2022]
Abstract
BACKGROUND Infection with the hepatitis C virus (HCV) has been considered a major cause of mortality, morbidity and resource utilisation in the US. In addition, HCV is the main cause of hepatocellular cancer (HCC) in the US. Recent developments in the diagnosis and treatment of HCV, including new recommendations pertaining to screening for HCV by the Centers for Disease Control and Prevention and newer treatment regimens with high efficacy, short duration and the potential for interferon-free therapies, have energised the health care practitioners regarding HCV management. AIM To assess the full impact of HCV burden on clinical, economic and patient-reported outcomes. METHODS An expert panel was convened to assess the full impact of HCV burden on a number of important outcomes using an evidence-based approach predicated on Grading of Recommendations Assessment, Development and Evaluation methodology. The literature was summarised, graded using an evidence-based approach and presented during the workshop. Workshop presentations were intended to review recent, relevant evidence-based literature and provide graded summary statements pertaining to HCV burden on topics including the relationships between HCV and the development of important outcomes. RESULTS The associations of HCV with cirrhosis, HCC, liver-related mortality, type 2 diabetes mellitus, rheumatological diseases and quality of life impairments are supported by strong evidence. Also, there is strong evidence that sustained viral eradication of HCV can improve important outcomes such as mortality and quality of life. CONCLUSIONS The current evidence suggests that HCV has been associated with tremendous clinical, economic and quality of life burden.
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Affiliation(s)
- Z M Younossi
- Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, USA; Department of Medicine, Center for Liver Disease, Inova Fairfax Hospital, Falls Church, VA, USA
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21
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Te HS. Recurrent hepatitis C: the bane of transplant hepatology. Hepatology 2014; 59:21-3. [PMID: 23813788 DOI: 10.1002/hep.26591] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2013] [Accepted: 06/12/2013] [Indexed: 12/17/2022]
Affiliation(s)
- Helen S Te
- Center for Liver Diseases, University of Chicago Medical Center, Chicago, IL
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22
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Benítez C, Londoño MC, Miquel R, Manzia TM, Abraldes JG, Lozano JJ, Martínez-Llordella M, López M, Angelico R, Bohne F, Sese P, Daoud F, Larcier P, Roelen DL, Claas F, Whitehouse G, Lerut J, Pirenne J, Rimola A, Tisone G, Sánchez-Fueyo A. Prospective multicenter clinical trial of immunosuppressive drug withdrawal in stable adult liver transplant recipients. Hepatology 2013; 58:1824-1835. [PMID: 23532679 DOI: 10.1002/hep.26426] [Citation(s) in RCA: 245] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2012] [Accepted: 03/22/2013] [Indexed: 12/12/2022]
Abstract
UNLABELLED Lifelong immunosuppression increases morbidity and mortality in liver transplantation. Discontinuation of immunosuppressive drugs could lessen this burden, but the safety, applicability, and clinical outcomes of this strategy need to be carefully defined. We enrolled 102 stable liver recipients at least 3 years after transplantation in a single-arm multicenter immunosuppression withdrawal trial. Drugs were gradually discontinued over a 6 to 9-month period. The primary endpoint was the development of operational tolerance, defined as successful immunosuppressive drug cessation maintained for at least 12 months with stable graft function and no histopathologic evidence of rejection. Out of the 98 recipients evaluated, 57 rejected and 41 successfully discontinued all immunosuppressive drugs. In nontolerant recipients rejection episodes were mild and resolved over 5.6 months (two nontolerant patients still exhibited mild gradually improving cholestasis at the end of follow-up). In tolerant recipients no progressive clinically significant histological damage was apparent in follow-up protocol biopsies performed up to 3 years following drug withdrawal. Tolerance was independently associated with time since transplantation (odds ratio [OR] 1.353; P = 0.0001), recipient age (OR 1.073; P = 0.009), and male gender (OR 4.657; P = 0.016). A predictive model incorporating the first two clinical variables identified subgroups of recipients with very high (79%), intermediate (30%-38%), and very low (0%) likelihood of successful withdrawal. CONCLUSION When conducted at late timepoints after transplantation, immunosuppression withdrawal is successful in a high proportion of carefully selected liver recipients. A combination of clinical parameters could be useful to predict the success of this strategy. Additional prospective studies are now needed to confirm these results and to validate clinically applicable diagnostic biomarkers.
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Affiliation(s)
- Carlos Benítez
- Liver Unit, Hospital Clinic Barcelona, IDIBAPS, CIBEREHD, University of Barcelona, Barcelona, Spain
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23
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Galbois A, Das V, Carbonell N, Guidet B. Prognostic scores for cirrhotic patients admitted to an intensive care unit: which consequences for liver transplantation? Clin Res Hepatol Gastroenterol 2013; 37:455-66. [PMID: 23773487 DOI: 10.1016/j.clinre.2013.05.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2013] [Accepted: 05/03/2013] [Indexed: 02/06/2023]
Abstract
Mortality is increased in cirrhotic patients admitted in ICU whatever the admission reason. Prognosis scores assessed in critically ill cirrhotic patients in ICU can be classified in three main categories: liver-specific (CTP and MELD) scores, general (SAPS II and APACHE) scores, and organ failure (OSF and SOFA) scores. The components of the liver-specific scores can be influenced by the acute disease indicating the admission to ICU but those of the non liver-specific scores can be influenced by the underlying liver cirrhosis. Many studies reported that organ failure scores are the best predictors of outcome in cirrhotic patients in ICU. We may wonder if cirrhotic patients with acute organ failures should receive prioritization for organ allocation to save their life or should be denied for a potential futile LT. According to recent studies, the SOFA score is associated with a higher risk of death for patients waiting for LT but could not be associated with a worse outcome after LT. It becomes of paramount importance to correctly identify the cirrhotic patients who will maximally benefit from LT after admission to ICU. The EASL-CLIF Consortium defines the CLIF-SOFA score, redefining the SOFA score with cut-off levels based on mortality prediction. The CLIF-SOFA could represent the ideal score in ICU since it is based on organ failures with cut-off values specifically identified in cirrhotic patients. The validation of the CLIF-SOFA score in critically ill cirrhotic patients admitted to ICU and its usefulness to identify patients who could benefit from LT should be the next steps.
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Affiliation(s)
- Arnaud Galbois
- AP-HP, Hôpital Saint-Antoine, Service de Réanimation Médicale, 75012 Paris, France; UPMC, Université Paris 06, Sorbonne Universités, 75006 Paris, France; INSERM, UMR_S 938, CdR Saint-Antoine, 75012 Paris, France.
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24
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Teperman L, Moonka D, Sebastian A, Sher L, Marotta P, Marsh C, Koneru B, Goss J, Preston D, Roberts JP. Calcineurin inhibitor-free mycophenolate mofetil/sirolimus maintenance in liver transplantation: the randomized spare-the-nephron trial. Liver Transpl 2013; 19:675-89. [PMID: 23775875 DOI: 10.1002/lt.23658] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2012] [Accepted: 04/08/2013] [Indexed: 12/12/2022]
Abstract
Mycophenolate mofetil (MMF) and sirolimus (SRL) have been used for calcineurin inhibitor (CNI) minimization to reduce nephrotoxicity following liver transplantation. In this prospective, open-label, multicenter study, patients undergoing transplantation from July 2005 to June 2007 who were maintained on MMF/CNI were randomized 4 to 12 weeks after transplantation to receive MMF/SRL (n = 148) or continue MMF/CNI (n = 145) and included in the intent-to-treat population. The primary efficacy endpoints were the mean percentage change in the calculated glomerular filtration rate (GFR) and a composite of biopsy-proven acute rejection (BPAR), graft lost, death, and lost to follow-up 12 months after transplantation. Patients were followed for a median of 519 days after randomization. MMF/SRL was associated with a significantly greater renal function improvement from baseline with a mean percentage change in GFR of 19.7 ± 40.6 (versus 1.2 ± 39.9 for MMF/CNI, P = 0.0012). The composite endpoint demonstrated the noninferiority of MMF/SRL versus MMF/CNI (16.4% versus 15.4%, 90% confidence interval = -7.1% to 9.0%). The incidence of BPAR was significantly greater with MMF/SRL (12.2%) versus MMF/CNI (4.1%, P = 0.02). Graft loss (including death) occurred in 3.4% of the MMF/SRL-treated patients and in 8.3% of the MMF/CNI-treated patients (P = 0.04). Malignancy-related deaths were less frequent with MMF/SRL. Adverse events caused withdrawal for 34.2% of the MMF/SRL-treated patients and for 24.1% of the MMF/CNI-treated patients (P = 0.06). The use of MMF/SRL is an option for liver transplant recipients who can benefit from improved renal function but is associated with an increased risk of rejection (but not graft loss).
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Affiliation(s)
- Lewis Teperman
- Mary Lea Johnson Richards Organ Transplant Center, New York University School of Medicine, New York, NY 10016, USA.
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25
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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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26
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Karvellas CJ, Lescot T, Goldberg P, Sharpe MD, Ronco JJ, Renner EL, Vahidy H, Poonja Z, Chaudhury P, Kneteman NM, Selzner M, Cook EF, Bagshaw SM. Liver transplantation in the critically ill: a multicenter Canadian retrospective cohort study. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2013; 17:R28. [PMID: 23394270 PMCID: PMC4056692 DOI: 10.1186/cc12508] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/13/2012] [Accepted: 01/25/2013] [Indexed: 12/21/2022]
Abstract
Introduction Critically ill cirrhosis patients awaiting liver transplantation (LT) often receive prioritization for organ allocation. Identification of patients most likely to benefit is essential. The purpose of this study was to examine whether the Sequential Organ Failure Assessment (SOFA) score can predict 90-day mortality in critically ill recipients of LT and whether it can predict receipt of LT among critically ill cirrhosis listed awaiting LT. Methods We performed a multicenter retrospective cohort study consisting of two datasets: (a) all critically-ill cirrhosis patients requiring intensive care unit (ICU) admission before LT at five transplant centers in Canada from 2000 through 2009 (one site, 1990 through 2009), and (b) critically ill cirrhosis patients receiving LT from ICU (n = 115) and those listed but not receiving LT before death (n = 106) from two centers where complete data were available. Results In the first dataset, 198 critically ill cirrhosis patients receiving LT (mean (SD) age 53 (10) years, 66% male, median (IQR) model for end-stage liver disease (MELD) 34 (26-39)) were included. Mean (SD) SOFA scores at ICU admission, at 48 hours, and at LT were 12.5 (4), 13.0 (5), and 14.0 (4). Survival at 90 days was 84% (n = 166). In multivariable analysis, only older age was independently associated with reduced 90-day survival (odds ratio (OR), 1.07; 95% CI, 1.01 to 1.14; P = 0.013). SOFA score did not predict 90-day mortality at any time. In the second dataset, 47.9% (n = 106) of cirrhosis patients listed for LT died in the ICU waiting for LT. In multivariable analysis, higher SOFA at 48 hours after admission was independently associated with lower probability of receiving LT (OR, 0.89; 95% CI, 0.82 to 0.97; P = 0.006). When including serum lactate and SOFA at 48 hours in the final model, elevated lactate (at 48 hours) was also significantly associated with lower likelihood of receiving LT (0.32; 0.17 to 0.61; P = 0.001). Conclusions SOFA appears poor at predicting 90-day survival in critically ill cirrhosis patients after LT, but higher SOFA score and elevated lactate 48 hours after ICU admission are associated with a lower probability receiving LT. Older critically ill cirrhosis patients (older than 60) receiving LT have worse 90-day survival and should be considered for LT with caution.
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27
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Sogawa H, Shrager B, Jibara G, Tabrizian P, Roayaie S, Schwartz M. Resection or transplant-listing for solitary hepatitis C-associated hepatocellular carcinoma: an intention-to-treat analysis. HPB (Oxford) 2013; 15:134-41. [PMID: 23036070 PMCID: PMC3719920 DOI: 10.1111/j.1477-2574.2012.00548.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2012] [Accepted: 06/08/2012] [Indexed: 12/12/2022]
Abstract
OBJECTIVES The relative roles of liver resection (LR) and liver transplantation (LT) in the treatment of a solitary hepatocellular carcinoma (HCC) remain unclear. This study was conducted to provide a retrospective intention-to-treat comparison of these two curative therapies. METHODS Records maintained at the study centre for all patients treated with LR or listed for LT for hepatitis C-associated HCC between January 2002 and December 2007 were reviewed. Inclusion criteria required: (i) an initial diagnosis of a solitary HCC lesion measuring ≤ 5 cm, and (ii) Child-Pugh class A or B cirrhosis. The primary endpoint analysed was intention-to-treat survival. RESULTS A total of 75 patients were listed for transplant (LT-listed group) and 56 were resected (LR group). Of the 75 LT-listed patients, 23 (30.7%) were never transplanted because they were either removed from the waiting list (n = 13) or died (n = 10). Intention-to-treat median survival was superior in the LR group compared with the LT-listed group (61.8 months vs. 30.6 months), but the difference did not reach significance. Five-year recurrence was higher in the LR group than in the 52 LT patients (71.5% vs. 30.5%; P < 0.001). CONCLUSIONS In the context of limited donor organ availability, partial hepatectomy represents an efficacious primary approach in properly selected patients with hepatitis C-associated HCC.
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Affiliation(s)
- Hiroshi Sogawa
- Recanati/Miller Transplantation Institute, Mount Sinai Medical CenterNew York, NY, USA
| | - Brian Shrager
- Division of Surgical Oncology, Department of Surgery, Mount Sinai Medical CenterNew York, NY, USA
| | - Ghalib Jibara
- Division of Surgical Oncology, Department of Surgery, Mount Sinai Medical CenterNew York, NY, USA
| | - Parissa Tabrizian
- Division of Surgical Oncology, Department of Surgery, Mount Sinai Medical CenterNew York, NY, USA
| | - Sasan Roayaie
- Division of Surgical Oncology, Department of Surgery, Mount Sinai Medical CenterNew York, NY, USA
| | - Myron Schwartz
- Recanati/Miller Transplantation Institute, Mount Sinai Medical CenterNew York, NY, USA
- Division of Surgical Oncology, Department of Surgery, Mount Sinai Medical CenterNew York, NY, USA
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Ota T, Rocha R, Wei LM, Toyoda Y, Gleason TG, Bermudez C. Surgical outcomes after cardiac surgery in liver transplant recipients. J Thorac Cardiovasc Surg 2012; 145:1072-1076. [PMID: 23246061 DOI: 10.1016/j.jtcvs.2012.09.099] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2012] [Revised: 09/04/2012] [Accepted: 09/21/2012] [Indexed: 12/29/2022]
Abstract
OBJECTIVE This was a single-center retrospective study to assess the surgical outcomes and predictors of mortality of liver transplant recipients undergoing cardiac surgery. METHODS From 2000 to 2010, 61 patients with a functioning liver allograft underwent cardiac surgery. The mean interval between liver transplantation and cardiac surgery was 5.4 ± 4.4 years. Of the 61 patients, 33 (54%) were in Child-Pugh class A and 28 in class B. The preoperative and postoperative data were reviewed. RESULTS The overall in-hospital mortality was 6.6%. The survival rate was 82.4% ± 5.1% at 1 year and 50.2% ± 8.2% at 5 years. Cox regression analysis identified preoperative encephalopathy (odds ratio, 5.2; 95% confidence interval, 1.8-15.5; P = .003) and pulmonary hypertension (odds ratio, 3.5; 95% confidence interval, 1.3-9.4; P = .045) as independent predictors of late mortality. The preoperative Model for End-Stage Liver Disease (MELD) scores of patients who died in-hospital or late postoperatively were significantly greater statistically than the scores of the others (in-hospital death, 23.7 ± 7.8 vs 13.1 ± 4.5, P < .001; late death, 15.2 ± 6.1 vs 12.3 ± 4.1, P = .038). The Youden index identified an optimal MELD score cutoff value of 13.5 (sensitivity, 56.0%; specificity, 67.6%). Kaplan-Meier survival analysis successfully demonstrated that the survival rate of the MELD score less than 13.5 (MELD <13.5) group was significantly greater than that of the MELD >13.5 group (MELD <13.5 group, 93.8% ± 4.2% at 1 year and 52.4% ± 11.8% at 5 years; MELD >13.5 group, 66.9% ± 9.6% at 1 year and 46.1% ± 11.1% at 5 years; P = .027). In contrast, the survival rate when stratified by Child-Pugh class (class A vs B) was not significantly different. CONCLUSIONS Cardiac surgery in the liver allograft recipients was associated with acceptable surgical outcomes. Preoperative encephalopathy and pulmonary hypertension were independent predictors of late mortality. The cutoff value of 13.5 in the MELD score might be useful for predicting surgical mortality in cardiac surgery.
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Affiliation(s)
- Takeyoshi Ota
- Division of Cardiac Surgery, Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pa
| | - Rodolfo Rocha
- Division of Cardiac Surgery, Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pa
| | - Lawrence M Wei
- Division of Cardiac Surgery, Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pa
| | - Yoshiya Toyoda
- Division of Cardiac Surgery, Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pa
| | - Thomas G Gleason
- Division of Cardiac Surgery, Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pa
| | - Christian Bermudez
- Division of Cardiac Surgery, Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pa.
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Deuffic-Burban S, Deltenre P, Buti M, Stroffolini T, Parkes J, Mühlberger N, Siebert U, Moreno C, Hatzakis A, Rosenberg W, Zeuzem S, Mathurin P. Predicted effects of treatment for HCV infection vary among European countries. Gastroenterology 2012; 143:974-85.e14. [PMID: 22863764 DOI: 10.1053/j.gastro.2012.05.054] [Citation(s) in RCA: 99] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2011] [Revised: 05/25/2012] [Accepted: 05/30/2012] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS The dynamics of hepatitis C virus (HCV) infection, as well as screening practices and access to therapy, vary among European countries. It is important to determine the magnitude of the effects of such differences on incidence and mortality of infection. We compared the dynamics of infection and screening and treatment practices among Belgium, France, Germany, Italy, Spain, and the United Kingdom. We also assessed the effects of treatment with pegylated interferon and additional effects of triple therapy with protease inhibitors. METHODS We created a country-specific Markov model of HCV progression based on published epidemiologic data (on HCV prevalence, screening, genotype, alcohol consumption among patients, and treatments) and reports of competitive and hepatocellular carcinoma mortality for the 6 countries. The model was used to predict the incidence of HCV-related cirrhosis and its mortality until 2021 for each country. RESULTS From 2002 to 2011, antiviral therapy reduced the cumulative incidence of cirrhosis by 7.1% and deaths by 3.4% overall. Reductions in incidence and mortality values ranged from 4.0% and 1.9%, respectively, in Italy to 16.3% and 9.0%, respectively, in France. From 2012 to 2021, antiviral treatment of patients with HCV genotype 1 infection that includes protease inhibitor-based triple therapy will reduce the cumulative incidence of cirrhosis by 17.7% and mortality by 9.7% overall. The smallest reduction is predicted for Italy (incidence reduced by 10.1% and mortality by 5.4%) and the highest is for France (reductions of 34.3% and 20.7%, respectively). CONCLUSIONS Although HCV infection is treated with the same therapies in different countries, the effects of the therapies on morbidity and mortality vary significantly. In addition to common guidelines that are based on virologic response-guided therapy, there is a need for public health policies based on population-guided therapy.
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Carbone M, Lenci I, Baiocchi L. Prevention of hepatitis C recurrence after liver transplantation: An update. World J Gastrointest Pharmacol Ther 2012; 3:36-48. [PMID: 22966482 PMCID: PMC3437445 DOI: 10.4292/wjgpt.v3.i4.36] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2011] [Revised: 06/20/2012] [Accepted: 06/28/2012] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C related liver failure and hepatocarcinoma are the most common indications for liver transplantation in Western countries. Recurrent hepatitis C infection of the allograft is universal and immediate following liver transplantation, being associated with accelerated progression to cirrhosis, graft loss and death. Graft and patient survival is reduced in liver transplant recipients with recurrent Hepatitis C virus (HCV) infection compared to HCV-negative recipients. Many variables may impact on recurrent HCV liver disease. Overall, excess immunosuppression is believed to be a key factor; however, no immunosuppressive regimen has been identified to be more beneficial or less harmful. Donor age limitations, exclusion of moderately to severely steatotic livers and minimization of ischemic times could be a potential strategy to minimize the severity of HCV disease in transplanted subjects. After transplantation, antiviral therapy based on pegylated IFN alpha with or without ribavirin is associated with far less results than that reported for immunocompetent HCV-infected patients. New findings in the field of immunotherapy and genomic medicine applied to this context are promising.
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Affiliation(s)
- Marco Carbone
- Marco Carbone, Liver Unit, Queen Elizabeth Hospital, Birmingham, B15 2TH, United Kingdom
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31
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Outcome of liver transplantation for recipients with hepatitis B and hepatitis C virus coinfection: analysis of the UNOS data. Transplantation 2011; 92:809-14. [PMID: 21832961 DOI: 10.1097/tp.0b013e31822d4dc3] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Coinfection by Hepatitis B virus (HBV) and hepatitis C virus (HCV) has been reported to increase risk of graft failure for liver transplant recipients. But other studies have controverted that finding. The aim of this study was to determine whether-after adjustments for other important predictors-HBV/HCV coinfection was associated with worse liver graft survival than HBV or HCV mono-infection. METHODS A retrospective cohort study examined Organ Procurement and Transplantation Network/United Network Organ Sharing data for 48,654 deceased-donor primary liver-only transplants that were performed on adults between January 1, 1995, and August 31, 2009, and that included recipient and donor HBV/HCV status. Recipients were classified into four groups: the HBV/HCV coinfected [B+/C+]; HBV mono-infected [B+/C-]; HCV mono-infected [B-/C+]; and hepatitis uninfected [B-/C-]. Kaplan-Meier methods were used to calculate liver graft survival rates, Cox proportional hazard models were used to estimate the effect of hepatitis virus infection, and adjusted for potential confounders. RESULTS Graft survival rates were highest with B+/C-: 85.3% 1-year survival and 63.0% 10-year survival. Graft survival with B+/C+ was superior to survival with B-/C+: 83.5% 1-year survival and 53.6% 10-year survival vs. B-/C+: 82.9% 1-year survival and 46.1% 10-year survival. Survival with B-/C-: 83.6% 1-year survival and 56.6% 10-year survival was superior to survival with B+/C+ (shown above). After adjustment for confounders, and with the coinfected as reference, B-/C+ recipients had a higher risk of graft loss (hazard ratio, 1.35; 95% CI, 1.10-1.66); the other two groups had a lower risk. CONCLUSIONS Our results suggested-despite reports to the contrary-statistically better graft outcomes with HBV/HCV coinfection than with HCV mono-infection.
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Shirali AC, Look M, Du W, Kassis E, Stout-Delgado HW, Fahmy TM, Goldstein DR. Nanoparticle delivery of mycophenolic acid upregulates PD-L1 on dendritic cells to prolong murine allograft survival. Am J Transplant 2011; 11:2582-92. [PMID: 21883921 DOI: 10.1111/j.1600-6143.2011.03725.x] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Conventional immunosuppressive drug delivery requires high systemic drug levels to provide therapeutic benefit, but frequently results in toxic side effects. Novel drug delivery methods, such as FDA-approved poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), are promising drug delivery platforms to reduce drug doses and minimize toxicity. Using murine models of skin transplantation, we investigated whether PLGA NPs would effectively deliver mycophenolic acid (MPA), a common clinical immunosuppressant, and avoid the toxicity of conventional drug delivery. We found that intermittent treatment with NPs encapsulated with MPA (NP-MPA) resulted in a significant extension of allograft survival than intermittent conventional MPA treatment even though the concentration of MPA within NP-MPA was a 1000-fold lower than conventional drug. Importantly, recipients who were administered NP-MPA intermittently avoided drug toxicity, whereas those treated with daily conventional drug manifested cytopenias. Dendritic cells (DCs) endocytosed NP-MPA to upregulate programmed death ligand-1 (PD-L1) and displayed a decreased ability to prime alloreactive T cells. Importantly, the ability of NP-MPA to promote allograft survival was partly PD-L1 dependent. Collectively, this study indicates that NPs are potent drug delivery tools that extend allograft survival without drug toxicity.
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Affiliation(s)
- A C Shirali
- Department of Internal Medicine and Immunobiology, Yale University, New Haven, CT, USA
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Klintmalm GB, Davis GL, Teperman L, Netto GJ, Washburn K, Rudich SM, Pomfret EA, Vargas HE, Brown R, Eckhoff D, Pruett TL, Roberts J, Mulligan DC, Charlton MR, Heffron TG, Ham JM, Douglas DD, Sher L, Baliga PK, Kinkhabwala M, Koneru B, Abecassis M, Millis M, Jennings LW, Fasola CG. A randomized, multicenter study comparing steroid-free immunosuppression and standard immunosuppression for liver transplant recipients with chronic hepatitis C. Liver Transpl 2011; 17:1394-403. [PMID: 21850690 DOI: 10.1002/lt.22417] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
This randomized, prospective, multicenter trial compared the safety and efficacy of steroid-free immunosuppression (IS) to the safety and efficacy of 2 standard IS regimens in patients undergoing transplantation for hepatitis C virus (HCV) infection. The outcome measures were acute cellular rejection (ACR), severe HCV recurrence, and survival. The patients were randomized (1:1:2) to tacrolimus (TAC) and corticosteroids (arm 1; n = 77), mycophenolate mofetil (MMF), TAC, and corticosteroids (arm 2; n = 72), or MMF, TAC, and daclizumab induction with no corticosteroids (arm 3; n = 146). In all, 295 HCV RNA-positive subjects were enrolled. At 2 years, there were no differences in ACR, HCV recurrence (biochemical evidence), patient survival, or graft survival rates. The side effects of IS did not differ, although there was a trend toward less diabetes in the steroid-free group. Liver biopsy samples revealed no significant differences in the proportions of patients in arms 1, 2, and 3 with advanced HCV recurrence (ie, an inflammation grade ≥ 3 and/or a fibrosis stage ≥ 2) in years 1 (48.2%, 50.4%, and 43.0%, respectively) and 2 (69.5%, 75.9%, and 68.1%, respectively). Although we have found that steroid-free IS is safe and effective for liver transplant recipients with chronic HCV, steroid sparing has no clear advantage in comparison with traditional IS.
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34
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Abstract
In this article the epidemiology of substance use and substance disorders in the United States and their association with liver disease are reviewed. The relevance of tobacco use and issues of candidacy as it pertains to substance use are discussed. The use of alcohol while on the waitlist and short sobriety are also addressed. The merits of monitoring of patients are discussed, and the outcomes of these patients after liver transplantation are examined. The article concludes with a summary of recommendations for clinicians working with these patients and possible future directions for both clinical care and research.
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Affiliation(s)
- Andrea DiMartini
- Consultation Liaison to the Liver Transplant Program, Starzl Transplant Institute, University of Pittsburgh Medical Center, PA 15213, USA.
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35
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Abstract
BACKGROUND Late survival is not improving after liver transplantation. In this study, possible reasons for this were investigated. METHODS Mortality rates and causes of death were ascertained in 4483 adult primary liver allograft recipients surviving 1 year or more from engraftment, identified through the UK Transplant Database and transplanted between 1994 and 2007. Associations with death, cause of death, and retransplantation were assessed. RESULTS Mortality in those surviving beyond 1 year in UK liver transplant recipients was more than twice that expected in the general population and had not improved during the study period, independent of cause of liver disease, recipient age, recipient gender, and donor age. The major causes of death were malignancy (30.6%), multisystem failure (10.0%), infection (9.8%), cardiac disease (8.7%), and graft failure (9.8%). Associations with death after 1 year were pretransplant etiologies alcohol-related liver disease (hazard ratio [HR]=2.10), autoimmune hepatitis or cryptogenic (HR=1.68), hepatitis C virus (HR=2.51), and hepatocellular carcinoma (HR=4.19). Associations with retransplantation were recipient age (HR=0.95 per year), donor age (HR=1.02 per year), and hepatitis C virus (HR=2.04). Hepatocellular carcinoma and recipient age were associated with cancer-related death (odds ratio=1.87 and 1.02 per year). Recipient age was associated with cardiac death (odds ratio=1.06 per year). CONCLUSIONS Strategies to reduce late mortality after liver transplantation are required. These may include prevention of disease recurrence, improved recipient selection, and addressing risk factors for death in late survivors of liver transplantation.
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Charlton M. Telaprevir, boceprevir, cytochrome P450 and immunosuppressive agents--a potentially lethal cocktail. Hepatology 2011; 54:3-5. [PMID: 21710471 DOI: 10.1002/hep.24470] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Mas V, Maluf D, Archer KJ, Potter A, Suh J, Gehrau R, Descalzi V, Villamil F. Transcriptome at the time of hepatitis C virus recurrence may predict the severity of fibrosis progression after liver transplantation. Liver Transpl 2011; 17:824-35. [PMID: 21618696 DOI: 10.1002/lt.22309] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Allograft gene expression analysis may provide insights into the mechanisms involved in liver damage during hepatitis C virus recurrence (HCVrec) after orthotopic liver transplantation (OLT) and allow the identification of patients who have a higher risk of developing severe disease. Forty-three OLT recipients with hepatitis C virus (HCV) were evaluated. Genomewide gene expression analysis was performed with formalin-fixed, paraffin-embedded (FFPE) liver biopsy samples obtained from 21 OLT recipients with HCV at the time of clinical HCVrec, which was defined as increased alanine aminotransferase levels and detectable HCV RNA levels in serum. Patients were classified into 3 groups according to the severity of the fibrosis in the liver biopsies at 36 months post-OLT : group 1 (G1) for mild fibrosis (F0-F1), group 2 for moderate fibrosis (F2), and group 3 (G3) for severe fibrosis (F3-F4). No significant differences were observed between the groups with respect to donor age, histology during HCVrec, treated episodes of acute cellular rejection, or immunosuppression therapy. The results were validated in the remaining 22 OLT recipients with HCV using quantitative real-time polymerase chain reaction. Fifty-seven beadtypes showed significantly different expression (P < 0.001) between the groups during HCVrec. In G3, the gene expression of interleukin-28RA (IL-28RA), IL-28, and angiotensin-converting enzyme was up-regulated. Samples from G1 and G3 were used to determine whether a multigenetic classifier could be derived to predict the group class. The final model included the intercept and 9 bead types. Pairwise scatter plots of these 9 bead types revealed that G1 and G3 were well separated with respect to each gene. Our analysis has demonstrated the utility of a set of molecular markers indicating HCVrec severity early after OLT.
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Affiliation(s)
- Valeria Mas
- Division of Transplantation, Department of Surgery, Virginia Commonwealth University, Richmond, VA 23298-0057, USA.
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38
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Taner CB, Bulatao IG, Keaveny AP, Willingham DL, Pungpapong S, Perry DK, Rosser BG, Harnois DM, Aranda-Michel J, Nguyen JH. Use of liver grafts from donation after cardiac death donors for recipients with hepatitis C virus. Liver Transpl 2011; 17:641-9. [PMID: 21618684 DOI: 10.1002/lt.22258] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV) infection is the most common indication for orthotopic liver transplantation in the United States. Although studies have addressed the use of expanded criteria donor organs in HCV(+) patients, to date the use of liver grafts from donation after cardiac death (DCD) donors in HCV(+) patients has been addressed by only a limited number of studies. This retrospective analysis was undertaken to study the outcomes of DCD liver grafts used in HCV(+) recipients. Seventy-seven HCV(+) patients who received DCD liver grafts were compared to 77 matched HCV(+) patients who received donation after brain death (DBD) liver grafts and 77 unmatched non-HCV patients who received DCD liver grafts. There were no differences in 1-, 3-, and 5-year patient or graft survival among the groups. Multivariate analysis showed that the Model for End-Stage Liver Disease score [hazard ratio (HR) = 1.037, 95% confidence interval (CI) = 1.006-1.069, P = 0.018] and posttransplant cytomegalovirus infection (HR = 3.367, 95% CI = 1.493-7.593, P = 0.003) were significant factors for graft loss. A comparison of the HCV(+) groups for fibrosis progression based on protocol biopsy samples up to 5 years post-transplant did not show any difference; in multivariate analysis, HCV genotype 1 was the only factor that affected progression to stage 2 fibrosis (genotype 1 versus non-1 genotypes: HR = 2.739, 95% CI = 1.047-7.143, P = 0.040). In conclusion, this match-controlled, retrospective analysis demonstrates that DCD liver graft utilization does not cause untoward effects on disease progression or patient and graft survival in comparison with DBD liver grafts in HCV(+) patients.
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Affiliation(s)
- C Burcin Taner
- Department of Transplantation, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
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Gondos A, Doehler B, Opelz G, Brenner H. From cancer to transplantation: an evaluation of period analysis for calculating up-to-date long-term survival estimates. Am J Epidemiol 2010; 172:613-20. [PMID: 20650955 DOI: 10.1093/aje/kwq160] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
The timeliness of survival monitoring is particularly important in a field such as transplantation medicine, where progress occurs rapidly. Period analysis, a method successfully applied for improving the timeliness of survival monitoring in population-based cancer survival analysis, could potentially be useful in the field of transplantation as well. Using data from the Collaborative Transplant Study, the authors compared the ability of traditional, cohort-based analysis methods and the period analysis method to provide timely 5-year graft and patient survival estimates for kidney, heart, and liver transplants in 6 age groups (0-17, 18-29, 30-39, 40-49, 50-59, >or=60 years) on 378 occasions between 1990-1992 and 2000-2002. Overall, period estimates provided superior predictions for the survival of most recent transplants on 344 of 378 occasions (91%); in the organ-specific analysis, this proportion ranged between 83% for heart and 100% for kidney graft survival. This evaluation provides evidence that the period analysis method can improve the timeliness of survival monitoring in solid organ transplantation. The method appears useful for providing more up-to-date long-term survival estimates than traditional methods, and its use in pertinent studies is encouraged.
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Affiliation(s)
- Adam Gondos
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany.
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40
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Kashyap R, Safadjou S, Chen R, Mantry P, Sharma R, Patil V, Maloo M, Ryan C, Marroquin C, Barry C, Ramaraju G, Maliakkal B, Orloff M. Living donor and deceased donor liver transplantation for autoimmune and cholestatic liver diseases--an analysis of the UNOS database. J Gastrointest Surg 2010; 14:1362-9. [PMID: 20617395 DOI: 10.1007/s11605-010-1256-1] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2010] [Accepted: 06/07/2010] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Autoimmune hepatitis and cholestatic liver diseases have more favorable outcomes after liver transplantation as compared to viral hepatitis and alcoholic liver diseases. However, there are only few reports comparing outcomes of both living donor liver transplants (LDLT) and deceased donor liver transplants (DDLT) for these conditions. AIM We aim to study the survival outcomes of patients undergoing LT for autoimmune and cholestatic diseases and to identify possible risk factors influencing survival. Survival outcomes for LDLT vs. DDLT are also to be compared for these diseases. PATIENTS AND METHODS A retrospective analysis of the UNOS database for patients transplanted between February 2002 until October 2006 for AIH, PSC, and PBC was performed. Survival outcomes for LDLT and DDLT patients were analyzed and factors influencing survival were identified. RESULTS Among all recipients the estimated patient survival at 1, 3, and 5 years for LDLT was 95.5%, 93.6%,and 92.5% and for DDLT was 90.9%, 86.5%, and 84.9%, respectively (p = 0.002). The estimated graft survival at 1, 3, and 5 years for LDLT was 87.9%, 85.4%, and 84.3% and for DDLT 85.9%, 80.3%, and 78.6%, respectively (p = 0.123). On multivariate proportional hazard regression analysis after adjusting for age and MELD score, the effect of donor type was not found to be significant. CONCLUSION The overall survival outcomes of LDLT were similar to DDLT in our patients with autoimmune and cholestatic liver diseases. It appears from our study that after adjusting for age and MELD score donor type does not significantly affect the outcome.
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Affiliation(s)
- Randeep Kashyap
- Department of Surgery, Division of Solid Organ Transplantation, University of Rochester Medical Center, P.O. Box SURG, 601 Elmwood Avenue, Rochester, NY 14642, USA.
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41
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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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Dhillon N, Walsh L, Krüger B, Ward SC, Godbold JH, Radwan M, Schiano T, Murphy BT, Schröppel B. A single nucleotide polymorphism of Toll-like receptor 4 identifies the risk of developing graft failure after liver transplantation. J Hepatol 2010; 53:67-72. [PMID: 20400193 DOI: 10.1016/j.jhep.2009.12.044] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2009] [Revised: 12/05/2009] [Accepted: 12/29/2009] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS While studies in animal models have linked Toll-like receptor (TLR) 4 signaling to the pathophysiology of ischemia/reperfusion (IR) injury and liver fibrosis, the relevance of TLR4 activation after human liver transplantation is unknown. The TLR4 single nucleotide polymorphism (SNP) D299G is situated within the extracellular domain and diminishes receptor binding to danger-associated molecular patterns. METHODS We studied the influence of TLR4 D299G on IR injury and graft survival in 430 deceased donor LT recipients. Compared with livers expressing wild-type (WT) alleles, livers with a TLR4 loss-of-function allele were significantly more likely to have initial good graft function (IGGF) (OR 2.20, p=0.01). In contrast, there was no effect of recipient TLR4 genotype on the rate of IGGF. RESULTS The effect of TLR4 D299G on long-term graft survival was analyzed based on hepatitis C virus (HCV) serostatus. In HCV infected recipients, multivariate Cox regression analysis demonstrated a significant association between the presence of recipient, but not donor TLR4 D299G and long-term graft failure (HR 2.48, CI 1.28-4.81; p=0.007). There was no difference in graft survival between TLR4 mutant and WT recipients among non-HCV infected recipients. CONCLUSIONS Collectively, these results demonstrate the differential effects of donor and recipient TLR4 signaling in human liver transplantation. Donor TLR4 contributed to sterile injury following cold preservation and the recipient TLR4 genotype was linked with poor allograft survival among HCV infected recipients.
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Affiliation(s)
- Navdeep Dhillon
- Division of Nephrology, Mount Sinai School of Medicine, New York, NY 10029, USA
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McCaughan GW, Shackel NA, Strasser SI, Dilworth P, Tang P. Minimal but significant improvement in survival for non-hepatitis C-related adult liver transplant patients beyond the one-year posttransplant mark. Liver Transpl 2010; 16:130-7. [PMID: 20104480 DOI: 10.1002/lt.21978] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Although 1-year survival rates following liver transplantation over the last 20 years may have improved, there is doubt about improvement in long-term survival. We examined survival with and without initial 12-month mortality in adult liver transplant recipients over a 20-year period. Patient and allograft survival for 3 different time periods was compared: 1986-1994 (group 1, n = 547), 1995-2000 (group 2, n = 735), and 2000-2005 (group 3, n = 749). After this, all deaths in the first 12 months of each group were removed. Patient and allograft survival was then once again compared across the 3 groups. There was significant improvement in both patient and allograft survival across the 20-year period (P < 0.001). Overall patient and allograft survival improved in non-hepatitis C virus (HCV) patients but not in HCV patients. A similar comparison with deaths in the first year removed, however, showed no difference in patient survival (P = 0.07) and only a marginal improvement in allograft survival (P = 0.048) between the 3 time periods. When patients were divided into HCV-positive and HCV-negative groups with deaths in the first year removed, there was, however, improved patient and allograft survival in the HCV-negative group but not in the HCV-positive group. The causes of death between 1 and 5 years were then compared. There were 48 deaths in period 1, 63 in period 2, and 43 in period 3 (P = not significant). There were more deaths due to cardio/cerebrovascular disease and hepatitis B virus recurrence in the first time period, but there were more deaths due to recurrent HCV and de novo malignancy in later time periods. In conclusion, although overall survival following liver transplantation in adults seems to be improving over time, the long-term results are not, particularly in HCV patients.
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Affiliation(s)
- Geoffrey W McCaughan
- Australian National Liver Transplant Unit, Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia.
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44
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45
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Watt K, Veldt B, Charlton M. A practical guide to the management of HCV infection following liver transplantation. Am J Transplant 2009; 9:1707-13. [PMID: 19538491 DOI: 10.1111/j.1600-6143.2009.02702.x] [Citation(s) in RCA: 90] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Hepatitis C-associated liver failure is the most common indication for liver transplantation, with virological recurrence near ubiquitous. Approximately 30% of HCV-infected recipients will die or lose their allograft or develop cirrhosis secondary to hepatitis C recurrence by the fifth postoperative year, with the proportion increasing with duration of follow-up. Strategies for minimizing the frequency of severe HCV recurrence include avoidance of older donors, early diagnosis/treatment of CMV and minimization of immunosuppression, particularly T-cell depleting therapies and pulsed corticosteroid treatment of acute cellular rejection. Patients should be offered treatment with peginterferon and ribavirin before LT if MELD </= 17 or as soon as histological evidence of recurrence of HCV is apparent post-LT. Because of the high frequency of hemotoxicity and renal insufficiency, ribavirin should be dosed according to renal function.
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Affiliation(s)
- K Watt
- Department of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN, USA
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Boudville N, Salama M, Jeffrey GP, Ferrari P. The inaccuracy of cystatin C and creatinine-based equations in predicting GFR in orthotopic liver transplant recipients. Nephrol Dial Transplant 2009; 24:2926-30. [PMID: 19506046 DOI: 10.1093/ndt/gfp255] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND As survival with an orthotopic liver transplant (OLT) improves, the incidence of chronic kidney disease in OLT recipients increases. Measurement of kidney function using creatinine-based estimates is often inaccurate, while cystatin C may overcome the biases that effect creatinine. The aim of this study was to assess the accuracy of creatinine- and cystatin C-based equations to estimate kidney function in long-term OLT recipients. METHODS This was a cross-sectional study performed on OLT recipients within a single liver transplant centre where creatinine (n = 41) and cystatin C (n = 30) were measured and glomerular filtration rate (GFR) estimated using the Modification of Diet and Renal Disease (MDRD), Cockcroft-Gault (CG), Hoek, Larsson, Filler and Le Bricon equations. Comparison was made with the nuclear GFR (nGFR) (n = 41) measured through 51-Cr EDTA clearance. RESULTS The mean age of recipients was 56 +/- 13 years, and they were 6.5 +/- 4.7 years post-OLT. Fifty-six percent of recipients had a nGFR < or =60 mL/min/1.73 m(2). nGFR correlated significantly with all predictive equations (P < 0.001). The MDRD, CG and Le Bricon equations had the smallest degree of bias (-7.6, -7.3 and 3.4 mL/min/1.73 m(2), respectively), with 22%, 22% and 27% of estimates, respectively, being within 10% of nGFR measurements. In OLT recipients with nGFR < or =60 mL/min/1.73 m(2), the degree of bias of both the creatinine-base MDRD and cystatin-based Hoek equations was within 2 mL/min/1.73 m(2) difference between the measured and estimated GFR, but 41% and 36% of estimates were within 10% of the nGFR measurement. CONCLUSIONS Therefore, the degree of inaccuracy in cystatin C- and creatinine-based predictive equations brings into question their clinical utility in OLT recipients. We have no evidence that cystatin C is superior to creatinine in this population.
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Does interferon use prior to liver transplant influence hepatitis C outcomes following transplantation? Transplantation 2009; 86:1795-8. [PMID: 19104424 DOI: 10.1097/tp.0b013e3181914188] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND The most frequent reason for orthotopic liver transplantation (OLT) in the United States is due to complications of hepatitis C (HCV). Recent reports have shown decreased survival for HCV after OLT. Of note, the use of interferon (IFN) products has become wide spread with the majority of HCV patients being treated before transplant. AIM To review the outcomes of HCV patients who have received IFN products before liver transplant compared with HCV patients those who have never received IFN. METHOD Single-center, retrospective review of patients transplanted for HCV since December 1998 (n=131). Primary endpoint is the effect of IFN exposure before transplant on posttransplant outcomes. RESULTS Patients receiving before transplant (pre-IFN group; n=45) had a more aggressive recurrence of HCV with earlier recurrence (181.1+/-236 days vs. 303.4+/- 327 days; P=0.031), frequency of recurrence [41/45 (91.1%) vs. 62/86 (72.1%); P=0.013], and 1-year recurrence free survival [20% (+/-0.06) vs. 48.2% (+/-0.05); P=0.005]. Survival difference was noted in the pre-IFN group at 1 year and 3 years [79.7% (+/-0.06) vs. 90.5% (+/-0.03); 65.7 (+/-0.08) vs. 75.9% (+/-0.05); P=0.05] when compared with patients not receiving IFN (n=86) before transplant. CONCLUSIONS Based on this study, interferon use before transplant for the HCV patient indicates poor outcomes After OLT. Because of the increasing numbers of HCV patients coming to transplant, validation of these results should be of utmost importance.
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Walter T, Scoazec JY, Guillaud O, Hervieu V, Chevallier P, Boillot O, Dumortier J. Long-term antiviral therapy for recurrent hepatitis C after liver transplantation in nonresponders: biochemical, virological, and histological impact. Liver Transpl 2009; 15:54-63. [PMID: 19109834 DOI: 10.1002/lt.21652] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
More than 50% of patients with a recurrent posttransplant hepatitis C virus infection fail to respond to antiviral treatment. The aim of this study was to evaluate the interest of a long-term antiviral treatment maintained for more than 48 weeks. Seventy treated patients, with a histological follow-up > 1 year, were enrolled in this observational, retrospective study. The duration of antiviral treatment, tolerance, and occurrence of virological, biochemical, and histological responses were recorded. Thirty-two patients were nonresponders after 48 weeks of treatment. Combined antiviral therapy was maintained for >12 months in 26 and for >18 months in 21. Twelve patients had to discontinue their treatment. At 48 weeks, the rates of virological response and sustained virological response were 37% and 24.3%, respectively; at the end of the follow-up, they were 48.5% and 35.7%. Virological response was significantly associated with a higher incidence of biochemical and histological response, regardless of its time of occurrence (before or after 6 months). Even in the absence of virological response, the rate of progression of fibrosis was significantly slowed in patients treated for more than 6 months. Our results show the feasibility, safety, and efficacy of long-term antiviral therapy in nonresponder patients with a recurrent posttransplant hepatitis C virus infection.
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Affiliation(s)
- Thomas Walter
- Unité de Transplantation Hépatique, Fédération des Spécialités Digestives, Hôpital Edouard Herriot, France
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Lake J, Patel D, David K, Richwine J, Morris J. The association between MMF and risk of progressive renal dysfunction and death in adult liver transplant recipients with HCV. Clin Transplant 2009; 23:108-15. [DOI: 10.1111/j.1399-0012.2008.00916.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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Ward HJ. Nutritional and Metabolic Issues in Solid Organ Transplantation: Targets for Future Research. J Ren Nutr 2009; 19:111-22. [DOI: 10.1053/j.jrn.2008.10.020] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
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