Treatment of acute cellular rejection in liver transplantation
- Scott J Cotler, MD
Scott J Cotler, MD
- Professor of Medicine
- Director, Division of Hepatology
- Loyola University Medical Center
- Section Editor
- Robert S Brown, Jr, MD, MPH
Robert S Brown, Jr, MD, MPH
- Section Editor — Liver Transplantation
- Vice Chair, Transitions of Care, Department of Medicine
- Interim Chief, Division of Gastroenterology and Hepatology
- Weill Cornell Medical College
- Professor of Clinical Medicine, Columbia University College of Physicians & Surgeons
Acute cellular rejection following liver transplantation has decreased in incidence with the use of potent immunosuppressive agents, but it still affects 15 to 25 percent of liver transplantation recipients [1,2]. Most episodes occur within one month post-transplantation, although acute cellular rejection may present later . A retrospective analysis of 970 liver transplantations found an 11 percent incidence of late acute cellular rejection (>90 days post-transplantation) that was associated with recent changes in and lower levels of immunosuppression . In addition to the type and level of immunosuppression, certain transplantation-related characteristics may influence the risk of rejection. As an example, patients who receive an organ from a living related donor may have a lower rate of acute cellular rejection compared with deceased donor liver transplantation recipients [1,5].
The consequences of acute cellular rejection are variable. While it can predispose to steroid-resistant rejection and graft loss, most episodes do not have long-term adverse effects except in hepatitis C virus (HCV)-positive patients  (see 'Hepatitis C' below). Furthermore, acute cellular rejection identified by protocol liver biopsy in the absence of biochemical dysfunction often resolves without increasing immunosuppression . There is even a suggestion that such subclinical immune activation might be beneficial in inducing a degree of tolerance . The timing of rejection might affect outcomes. In a large retrospective study, compared with patients without an episode of rejection, early acute rejection was associated with better graft survival and late acute rejection was associated with reduced graft survival . Patients who developed late acute cellular rejection had a 28 percent rate of chronic rejection and a 6 percent risk of graft failure.
This topic will review the treatment of acute cellular rejection following liver transplantation. The diagnosis of acute cellular rejection following liver transplantation is discussed separately. (See "Liver transplantation: Diagnosis of acute cellular rejection".)
The diagnosis of acute cellular rejection is usually suspected by elevations in serum aminotransferase and alkaline phosphatase levels, which typically precede clinical symptoms of jaundice and fever. However, biochemical parameters are not sensitive or specific for detecting acute cellular rejection and do not correlate with its severity . Thus, the diagnosis should be confirmed by liver biopsy before initiating treatment for rejection. Histologic features include endothelitis, nonsuppurative cholangitis, and mixed mononuclear cell portal inflammation . (See "Liver transplantation: Diagnosis of acute cellular rejection".)
Antibody-mediated rejection (AMR) is a rare cause of allograft injury and loss after ABO-compatible liver transplantation that can be confused with and overlap with acute cellular rejection. Proposed features of AMR in liver transplants include donor-specific HLA alloantibodies in serum, microvascular endothelial cell injury on biopsy, and linear C4d positivity in liver sinusoids, in the absence of other causes of liver injury [11,12].
- Maluf DG, Stravitz RT, Cotterell AH, et al. Adult living donor versus deceased donor liver transplantation: a 6-year single center experience. Am J Transplant 2005; 5:149.
- Gruttadauria S, Vasta F, Mandalà L, et al. Basiliximab in a triple-drug regimen with tacrolimus and steroids in liver transplantation. Transplant Proc 2005; 37:2611.
- Wiesner RH, Menon KV. Late hepatic allograft dysfunction. Liver Transpl 2001; 7:S60.
- Thurairajah PH, Carbone M, Bridgestock H, et al. Late acute liver allograft rejection; a study of its natural history and graft survival in the current era. Transplantation 2013; 95:955.
- Liu LU, Bodian CA, Gondolesi GE, et al. Marked Differences in acute cellular rejection rates between living-donor and deceased-donor liver transplant recipients. Transplantation 2005; 80:1072.
- Seiler CA, Renner EL, Czerniak A, et al. Early acute cellular rejection: no effect on late hepatic allograft function in man. Transpl Int 1999; 12:195.
- Bartlett AS, Ramadas R, Furness S, et al. The natural history of acute histologic rejection without biochemical graft dysfunction in orthotopic liver transplantation: a systematic review. Liver Transpl 2002; 8:1147.
- Goddard S, Adams DH. Methylprednisolone therapy for acute rejection: too much of a good thing? Liver Transpl 2002; 8:535.
- Abraham SC, Furth EE. Receiver operating characteristic analysis of serum chemical parameters as tests of liver transplant rejection and correlation with histology. Transplantation 1995; 59:740.
- Banff schema for grading liver allograft rejection: an international consensus document. Hepatology 1997; 25:658.
- Kozlowski T, Rubinas T, Nickeleit V, et al. Liver allograft antibody-mediated rejection with demonstration of sinusoidal C4d staining and circulating donor-specific antibodies. Liver Transpl 2011; 17:357.
- O'Leary JG, Kaneku H, Demetris AJ, et al. Antibody-mediated rejection as a contributor to previously unexplained early liver allograft loss. Liver Transpl 2014; 20:218.
- Volpin R, Angeli P, Galioto A, et al. Comparison between two high-dose methylprednisolone schedules in the treatment of acute hepatic cellular rejection in liver transplant recipients: a controlled clinical trial. Liver Transpl 2002; 8:527.
- Adams DH, Neuberger JM. Patterns of graft rejection following liver transplantation. J Hepatol 1990; 10:113.
- Adams DH, Neuberger JM. Treatment of acute rejection. Semin Liver Dis 1992; 12:80.
- Schluger LK, Sheiner PA, Thung SN, et al. Severe recurrent cholestatic hepatitis C following orthotopic liver transplantation. Hepatology 1996; 23:971.
- Rosen HR, Shackleton CR, Higa L, et al. Use of OKT3 is associated with early and severe recurrence of hepatitis C after liver transplantation. Am J Gastroenterol 1997; 92:1453.
- Charlton M, Seaberg E. Impact of immunosuppression and acute rejection on recurrence of hepatitis C: results of the National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database. Liver Transpl Surg 1999; 5:S107.
- Berenguer M, Prieto M, Córdoba J, et al. Early development of chronic active hepatitis in recurrent hepatitis C virus infection after liver transplantation: association with treatment of rejection. J Hepatol 1998; 28:756.
- Samonakis DN, Germani G, Burroughs AK. Immunosuppression and HCV recurrence after liver transplantation. J Hepatol 2012; 56:973.
- Burton JR Jr, Rosen HR. Acute rejection in HCV-infected liver transplant recipients: The great conundrum. Liver Transpl 2006; 12:S38.
- Demetris AJ, Eghtesad B, Marcos A, et al. Recurrent hepatitis C in liver allografts: prospective assessment of diagnostic accuracy, identification of pitfalls, and observations about pathogenesis. Am J Surg Pathol 2004; 28:658.
- Gedaly R, Clifford TM, McHugh PP, et al. Prevalent immunosuppressive strategies in liver transplantation for hepatitis C: results of a multi-center international survey. Transpl Int 2008; 21:867.
- Sreekumar R, Rasmussen DL, Wiesner RH, Charlton MR. Differential allograft gene expression in acute cellular rejection and recurrence of hepatitis C after liver transplantation. Liver Transpl 2002; 8:814.
- Charlton M, Everson GT, Flamm SL, et al. Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients With Advanced Liver Disease. Gastroenterology 2015; 149:649.
- Gaber AO, First MR, Tesi RJ, et al. Results of the double-blind, randomized, multicenter, phase III clinical trial of Thymoglobulin versus Atgam in the treatment of acute graft rejection episodes after renal transplantation. Transplantation 1998; 66:29.
- Ramirez CB, Doria C, di Francesco F, et al. Anti-IL2 induction in liver transplantation with 93% rejection-free patient and graft survival at 18 months. J Surg Res 2007; 138:198.
- Koch M, Niemeyer G, Patel I, et al. Pharmacokinetics, pharmacodynamics, and immunodynamics of daclizumab in a two-dose regimen in liver transplantation. Transplantation 2002; 73:1640.
- Fernandes ML, Lee YM, Sutedja D, et al. Treatment of steroid-resistant acute liver transplant rejection with basiliximab. Transplant Proc 2005; 37:2179.
- Orr DW, Portmann BC, Knisely AS, et al. Anti-interleukin 2 receptor antibodies and mycophenolate mofetil for treatment of steroid-resistant rejection in adult liver transplantation. Transplant Proc 2005; 37:4373.
- Klintmalm GB, Ascher NL, Busuttil RW, et al. RS-61443 for treatment-resistant human liver rejection. Transplant Proc 1993; 25:697.
- Klupp J, Bechstein WO, Platz KP, et al. Mycophenolate mofetil added to immunosuppression after liver transplantation--first results. Transpl Int 1997; 10:223.
- McDiarmid SV. Mycophenolate mofetil in liver transplantation. Clin Transplant 1996; 10:140.
- Hebert MF, Ascher NL, Lake JR, et al. Four-year follow-up of mycophenolate mofetil for graft rescue in liver allograft recipients. Transplantation 1999; 67:707.
- Pfitzmann R, Klupp J, Langrehr JM, et al. Mycophenolatemofetil for immunosuppression after liver transplantation: a follow-up study of 191 patients. Transplantation 2003; 76:130.
- Akamatsu N, Sugawara Y, Tamura S, et al. Efficacy of mycofenolate mofetil for steroid-resistant acute rejection after living donor liver transplantation. World J Gastroenterol 2006; 12:4870.
- Mehrabi A, Fonouni H, Kashfi A, et al. The role and value of sirolimus administration in kidney and liver transplantation. Clin Transplant 2006; 20 Suppl 17:30.
- Trotter JF. Sirolimus in liver transplantation. Transplant Proc 2003; 35:193S.
- Zaghla H, Selby RR, Chan LS, et al. A comparison of sirolimus vs. calcineurin inhibitor-based immunosuppressive therapies in liver transplantation. Aliment Pharmacol Ther 2006; 23:513.
- Neff GW, Montalbano M, Tzakis AG. Ten years of sirolimus therapy in orthotopic liver transplant recipients. Transplant Proc 2003; 35:209S.
- Montalbano M, Neff GW, Yamashiki N, et al. A retrospective review of liver transplant patients treated with sirolimus from a single center: an analysis of sirolimus-related complications. Transplantation 2004; 78:264.
- Kneteman NM, Oberholzer J, Al Saghier M, et al. Sirolimus-based immunosuppression for liver transplantation in the presence of extended criteria for hepatocellular carcinoma. Liver Transpl 2004; 10:1301.
- Gibbs JF, Husberg BS, Klintmalm GB, et al. Outcome analysis of FK 506 therapy for acute and chronic rejection. Transplant Proc 1993; 25:622.
- Demetris AJ, Fung JJ, Todo S, et al. Conversion of liver allograft recipients from cyclosporine to FK506 immunosuppressive therapy--a clinicopathologic study of 96 patients. Transplantation 1992; 53:1056.
- Soin AS, Rasmussen A, Jamieson NV, et al. CsA levels in the early posttransplant period--predictive of chronic rejection in liver transplantation? Transplantation 1995; 59:1119.