Liver transplantation in adults: Treatment of acute T cell-mediated (cellular) rejection of the liver allograft

INTRODUCTION — The use of potent immunosuppressive agents for induction and maintenance therapy for liver transplantation has reduced the incidence of acute rejection, which is defined as liver allograft dysfunction associated with specific pathologic changes in the graft. With use of immunosuppression protocols, acute T cell-mediated (cellular) rejection (TCMR) occurs in approximately 10 to 30 percent of liver transplantation recipients [1-4].

Acute rejection can be broadly categorized into TCMR and antibody-mediated (previously known as humoral) rejection (AMR). A liver allograft biopsy is required to establish the diagnosis and determine the severity of rejection in order to guide treatment.

The focus of this topic is treatment of acute TCMR of the liver allograft. The clinical features and diagnostic evaluation of patients with suspected acute TCMR are discussed separately. (See "Liver transplantation in adults: Clinical manifestations and diagnosis of acute T-cell mediated (cellular) rejection of the liver allograft".)

The approach to immunosuppression following liver transplantation is discussed separately. (See "Liver transplantation in adults: Initial and maintenance immunosuppression".)

Infectious complications in liver transplant recipients are discussed separately. (See "Infectious complications in liver transplantation".)

PRETREATMENT EVALUATION — Therapy for patients with acute TCMR of the liver allograft is guided by pretreatment evaluation, which excludes other causes of graft dysfunction and determines the severity of rejection. The diagnostic evaluation typically includes the following tests (see "Liver transplantation in adults: Clinical manifestations and diagnosis of acute T-cell mediated (cellular) rejection of the liver allograft", section on 'Diagnostic evaluation'):

●Liver biochemical tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin).

●Drug concentration levels for patients on tacrolimus or cyclosporine.

●Laboratory tests to exclude infection for patients with suspected infection (eg, cytomegalovirus [CMV] antigen). (See "Infectious complications in liver transplantation".)

●Liver ultrasound with Doppler study to exclude hepatic artery or portal vein thrombosis or signs of biliary obstruction.

●Biopsy of liver allograft to determine rejection severity and to assess for other conditions (eg, ischemic injury, biliary abnormality, drug-induced liver injury, viral infection such as CMV, recurrence of primary liver disease, antibody-mediated rejection [AMR]). (See 'Defining severity of rejection' below.)

AMR is a less common cause of allograft injury and loss after ABO-compatible liver transplantation that can mimic or overlap with acute TCMR. The differential diagnosis of acute TCMR of the liver allograft is discussed in more detail separately. (See "Liver transplantation in adults: Clinical manifestations and diagnosis of acute T-cell mediated (cellular) rejection of the liver allograft", section on 'Differential diagnosis'.)

MANAGEMENT

Goals of therapy — Treatment goals for patients with acute TCMR include:

●Improving liver biochemical tests and liver histology

●Preventing chronic rejection

●Avoiding adverse impact on long-term graft survival [5]

Measures for all patients

Optimizing baseline immunosuppression — For all patients with histologic evidence of acute TCMR of the liver allograft, the baseline maintenance immunosuppressive regimen is assessed and optimized, while the specific approach depends on the patient's drug regimen and baseline kidney function. (See 'Defining severity of rejection' below.)

Options for optimizing immunosuppression are the following:

●Tacrolimus – For patients on tacrolimus as part of their baseline regimen, the dose is often adjusted to target a higher drug level. For example, for patients with a tacrolimus level in the 3 to 5 ng/ml range, the dose might be increased to achieve tacrolimus levels in the 5 to 7 ng/mL range provided that the patient has no or only mild chronic kidney disease at baseline (estimated glomerular filtration rate [eGFR] >60 mL/min/1.73 m²) and does not develop calcineurin-related nephrotoxicity. Acute and chronic nephrotoxicity related to tacrolimus are discussed separately. (See "Cyclosporine and tacrolimus nephrotoxicity".)

Tacrolimus is used for primary immunosuppression at most liver transplantation centers; however, patients with acute TCMR who are being treated with cyclosporine may be switched to tacrolimus [6,7]. Indirect evidence has suggested that switching from cyclosporine to tacrolimus may provide benefit for some patients with acute rejection [8,9]. In a series of 18 patients with acute TCMR refractory to initial therapy with either glucocorticoids or muromonab-CD3 (OKT3, no longer available), conversion to tacrolimus was associated with liver biochemical and histologic improvement in 10 patients (56 percent) [9].

Tacrolimus dosing, adverse effects, and efficacy as primary immunosuppression are discussed separately. (See "Liver transplantation in adults: Initial and maintenance immunosuppression", section on 'Calcineurin inhibitors'.)

●Mycophenolate – For patients on mycophenolate, the dose may be increased.

For patients who are not receiving an antimetabolite agent as part of the baseline immunosuppressive regimen, mycophenolate may be added. Antimetabolite agents interfere with the synthesis of nucleic acids and inhibit the proliferation of both T and B lymphocytes. Mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS) is the antimetabolic agent used for most liver and kidney transplant recipients in the United States; azathioprine is occasionally used. (See "Kidney transplantation in adults: Maintenance immunosuppressive therapy".)

The recommended dose of MMF is 2 g daily by mouth in two divided doses. Adverse effects of mycophenolate include gastrointestinal symptoms (ie, diarrhea, nausea, anorexia) and dose-related bone marrow suppression. Initiating MMF at a reduced dose (ie, 500 mg twice daily) and then titrating the dose upward may improve tolerability.

EC-MPS, an enteric-coated formulation of mycophenolate, was developed to try to improve the upper gastrointestinal tolerability of mycophenolate. However, EC-MPS and MMF doses are not equivalent. The dosing range for mycophenolate sodium is 360 to 720 mg orally twice daily. For specific dosing information, refer to the drug database included within UpToDate and the drug label, while dosing conversion is also discussed separately. (See "Kidney transplantation in adults: Maintenance immunosuppressive therapy", section on 'Mycophenolate'.)

The use of MMF has been associated with improvement in liver biochemical tests and histology for liver transplantation recipients with acute rejection [10-13]. In an observational study of 47 patients with acute rejection refractory to glucocorticoids, adding MMF to the existing drug regimen (ie, tacrolimus or cyclosporine) was associated with normalization of liver biochemical tests in 38 patients (81 percent) [12].

Defining severity of rejection — A classification system for acute TCMR was developed by a panel of experts who agreed on a nomenclature and histopathologic criteria for grading acute rejection (ie, Banff classification) [14].The management of patients with histologic evidence of acute TCMR is guided by histopathologic severity of rejection. (See 'Pretreatment evaluation' above and "Liver transplantation in adults: Clinical manifestations and diagnosis of acute T-cell mediated (cellular) rejection of the liver allograft", section on 'Establishing the diagnosis'.)

Three specific histologic features associated with acute TCMR are (table 1):

●Mixed portal inflammatory infiltrate

●Bile duct epithelial inflammation and damage

●Venous endothelial inflammation

Each of these parameters is given a score, and the sum of the scores is called the rejection activity index (RAI) [14,15]. Rejection severity is determined by RAI values. Mild rejection has been regarded as RAI ≤4, while classification of RAI values has varied among studies [14-21]. (See 'Patients with RAI ≤4' below and 'Patients with RAI ≥5' below.)

Patients with RAI ≤4 — Initial treatment for patients with mild acute TCMR based on histologic evidence (ie, rejection activity index [RAI] ≤4) typically includes optimizing the baseline immunosuppressive regimen (algorithm 1). However, the specific approach depends on the patient's existing immunosuppressive medications. (See 'Measures for all patients' above.)

Monitoring laboratory testing is required after augmenting the baseline immunosuppressive regimen. We obtain liver biochemical tests (ie, alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) weekly after adjusting immunosuppressive medications. For patients who do not have improvement in liver biochemical tests within four weeks or who have increasing elevations in liver tests, we generally repeat the biopsy of the liver allograft to reassess rejection severity. Patients without histologic improvement or with histologic progression after optimizing immunosuppression are regarded as having moderate to severe rejection and are typically treated with glucocorticoids. (See 'Patients with RAI ≥5' below.)

Patients with histologic improvement or resolution are continued on maintenance immunosuppression. (See "Liver transplantation in adults: Initial and maintenance immunosuppression".)

Patients with RAI ≥5

Initial therapy — For patients with biopsy-proven moderate to severe acute TCMR (ie, RAI ≥5), initial therapy consists of high-dose glucocorticoids (eg, methylprednisolone) followed by a glucocorticoid taper, in addition to optimizing the maintenance immunosuppression regimen (algorithm 1) [16,22,23]. (See "Liver transplantation in adults: Initial and maintenance immunosuppression".)

Methylprednisolone dosing varies among liver transplantation centers. We administer methylprednisolone in a daily bolus dose of 500 mg or 1000 mg intravenously for one to three days. A typical oral glucocorticoid taper would be to start prednisone 40 to 80 mg daily and to gradually reduce the dose over four weeks until a maintenance dose is reached (eg, prednisone 5 mg daily) or prednisone is discontinued.

For most patients with acute TCMR, biochemical response (ie, improvement of liver biochemical tests) to initial glucocorticoid therapy (in addition to optimizing the baseline immunosuppressive regimen) typically occurs within three to five days. For patients who do not have biochemical improvement within five days, biopsy of the liver allograft is repeated. If histology is consistent with acute TCMR, we typically give a second course of bolus methylprednisolone. For patients without a biochemical response within five days of a second course of bolus methylprednisolone, subsequent pharmacologic options include antithymocyte globulin (ATG).

For patients who do not respond to initial bolus glucocorticoid therapy and who have biopsy-confirmed acute TCMR, some liver transplantation centers do not give a second course of bolus methylprednisolone but proceed directly to subsequent therapy (eg, ATG). (See 'Therapy for nonresponders' below.)

While most patients respond to glucocorticoid therapy, few high-quality studies have compared the efficacy of various glucocorticoid regimens for the treatment of acute TCMR [24]. In a trial including 38 patients with acute TCMR of the liver allograft, methylprednisolone (1 g bolus intravenously) followed by a six day glucocorticoid taper (ie, from 200 mg daily to 20 mg daily) resulted in higher rates of histologic resolution of acute rejection compared with methylprednisolone 1 g boluses given for three consecutive days (83 versus 50 percent) [24]. In addition, infection rates were lower in patients given a single methylprednisolone dose followed by prednisone taper (55 versus 90 percent).

Managing glucocorticoid-related toxicity — The major complication of glucocorticoids is increased susceptibility to infection, especially oral candidiasis, cytomegalovirus (CMV), Aspergillus, Pneumocystis jirovecii (previously referred to as P. carinii), and bacterial pathogens [24]. Other potential problems include hyperglycemia, hypertension, peptic ulcer disease, and psychiatric disturbances including euphoria and depression.

For patients with acute TCMR who are treated with high-dose glucocorticoids, our approach to managing treatment-related toxicity includes (see "Major adverse effects of systemic glucocorticoids"):

●During the glucocorticoid bolus therapy phase of treatment:

•Blood glucose levels are monitored daily.

•For ulcer prophylaxis, a proton pump inhibitor is given daily and is continued during the glucocorticoid taper. (See "Peptic ulcer disease: Treatment and secondary prevention", section on 'Maintenance antisecretory therapy'.)

●For all patients treated with high-dose glucocorticoids, antimicrobial and antiviral prophylaxis includes:

•CMV polymerase chain reaction (PCR) testing is performed monthly for three months, and for high-risk recipients (ie, donor CMV positive/recipient CMV negative), CMV prophylaxis is given for three months. The approach to CMV prophylaxis in the liver transplant recipient is discussed separately:

-(See "Infectious complications in liver transplantation", section on 'Cytomegalovirus'.)

-(See "Prophylaxis of infections in solid organ transplantation", section on 'Cytomegalovirus'.)

-(See "Approach to the diagnosis of cytomegalovirus infection".)

•For P. jirovecii prophylaxis, trimethoprim-sulfamethoxazole is given for three months. Prevention of P. jirovecii pneumonia is discussed separately. (See "Infectious complications in liver transplantation", section on 'Antibacterial prophylaxis' and "Prophylaxis of infections in solid organ transplantation", section on 'Pneumocystis pneumonia'.)

Therapy for nonresponders — While most patients with acute TCMR rejection respond to optimizing baseline immunosuppression and glucocorticoid therapy, some patients do not respond to initial antirejection treatment [22,25]. Therapeutic options such as ATG have been used to treat patients with glucocorticoid-refractory rejection.

Antithymocyte globulin — ATG is an option for patients with glucocorticoid-refractory acute TCMR that has been confirmed with biopsy of the liver allograft. ATG is a polyclonal immune globulin that induces T lymphocyte depletion in the peripheral blood primarily by complement-dependent cell lysis [26]. ATG also contains some B cell-specific antibodies that inhibit B cell proliferation and induce B cell apoptosis.

Prior to initiating ATG, we obtain quantitative PCR testing for CMV and Epstein-Barr virus (EBV). The risk of and monitoring for viral infections in transplant recipients are discussed separately. (See "Infectious complications in liver transplantation" and "Infection in the solid organ transplant recipient", section on 'CMV and EBV' and "Overview of diagnostic tests for cytomegalovirus infection".)

The optimal ATG dosing for treating glucocorticoid-refractory TCMR has not been well defined. We typically administer ATG 1.5 mg/kg daily, intravenously, for five to seven days. The ATG dose is titrated to achieve an absolute lymphocyte count ≤200 cells/microL. Prior to the first two doses of ATG, patients receive preinfusion therapy with a glucocorticoid (methylprednisolone or hydrocortisone), diphenhydramine, and acetaminophen to minimize infusion reactions. In addition, some patients receive preinfusion therapy prior to the subsequent doses of ATG.  

During ATG therapy, we may lower the mycophenolate dose or discontinue it, and we may also lower the tacrolimus dose.

Liver biochemical tests are obtained daily to assess response to therapy. White blood cell, absolute lymphocyte, and platelet counts are obtained daily to monitor for adverse effects.

We obtain a liver biopsy on day 7 of ATG therapy in patients without improvement in liver biochemistries to assess for histologic response.

Patients with glucocorticoid-refractory acute TCMR continue antimicrobial and antiviral prophylaxis that was initiated during glucocorticoid bolus therapy. (See 'Initial therapy' above.)

Limited data have suggested that ATG therapy was associated with histologic improvement in patients with glucocorticoid-refractory acute rejection of the liver allograft [22,27,28]. In a case series of 20 patients who had 21 episodes of acute TCMR, ATG therapy was associated with histologic improvement or resolution by day seven for 18 patients (90 percent) [22]. Three-year graft and patient survival rates were 60 and 65 percent, respectively.

Other pharmacologic options — Basiliximab is a monoclonal antibody that binds to the interleukin-2 (IL-2) receptor on T cells, and it has been used as induction immunosuppressive therapy after liver transplantation [29]. Basiliximab blocks IL-2-mediated T cell proliferation, and thus inhibits the T-cell response to alloantigens that produces allograft damage in patients with acute TCMR. (See "Kidney transplantation in adults: Induction immunosuppressive therapy", section on 'Basiliximab'.)

Limited data have suggested that IL-2 antibody therapy was associated with resolution of acute TCMR in some patients who did not respond to glucocorticoid therapy [30-32]. In a study including 16 patients with glucocorticoid-resistant acute TCMR, IL-2 receptor antibody therapy (ie, basiliximab or daclizumab [no longer available]) was associated with resolution of glucocorticoid-refractory rejection in 12 patients (75 percent) [31]. Of the remaining four patients, two developed chronic rejection, one required repeat liver transplantation, and one died with graft failure.

In a case report, belatacept was used for treating a liver transplant recipient with recurrent, late onset TCMR characterized by de novo donor specific antibodies [33]. Belatacept is a fusion protein that binds CD80/86 on antigen-presenting cells (APC) and blocks costimulation of T cells by APC ligands by preventing binding of CD80/86 to CD28 on T cells [34].

Repeat liver transplantation — Approximately five percent of liver transplantation recipients who develop acute TCMR progress to chronic rejection despite antirejection therapy [22] (see 'Outcomes' below). Some patients with chronic rejection may require retransplantation, and management of such patients requires a multidisciplinary approach (transplant hepatology, transplant surgery, pharmacology). Adjusting immunosuppression for patients with chronic rejection during the perioperative period is individualized, and the goal is to reduce the risk of infectious complications. (See "Infectious complications in liver transplantation".)

OUTCOMES — Data have suggested that up to 4 percent of liver transplantation recipients develop chronic rejection [35,36]. The risk of chronic rejection appears to be increased in patients who have had repeated episodes of acute TCMR [37].

Studies of the long-term impact of acute TCMR have used different post-transplant time points to define early and late rejection and have yielded mixed results [38-42]. Older studies suggested that early acute rejection (ie, within three months of liver transplantation) did not adversely affect graft or patient outcomes [38-40]. In contrast, data from two large cohorts of liver transplant recipients (Adult to Adult Living Donor Liver Transplantation [A2ALL] and Scientific Registry of Transplant Recipients [SRTR] cohorts) found that acute rejection within six months post-transplant was associated with higher risk of graft failure (hazard ratio [HR] 1.91, 95% CI 1.21-3.01; and HR 1.77, 95% CI 1.63-1.92, respectively) and death (HR 1.86, 95% CI 1-3.47; and HR 1.66, 95% CI 1.52-1.83, respectively) [41]. In a subsequent study of 787 transplant recipients who underwent protocol liver biopsies, late TCMR (ie, >6 weeks after transplant) was associated with increased risk of graft loss or mortality, whereas early, mild TCMR (ie, within six weeks of transplant) was not associated with adverse outcomes [42]. (See "Liver transplantation in adults: Clinical manifestations and diagnosis of acute T-cell mediated (cellular) rejection of the liver allograft", section on 'Epidemiology'.)

The impact of successfully treating acute TCMR on graft outcomes has not been well studied. Greater histologic severity of acute TCMR, later onset of rejection, and lack of response to antirejection therapy have been associated with worse graft outcomes (eg, progression to chronic rejection, graft loss) [41-44].

SPECIAL POPULATIONS

Patients with subclinical rejection — Subclinical acute TCMR rejection of the liver allograft is detected in patients with histologic evidence of acute rejection on biopsy without elevated liver biochemical tests (eg, aspartate aminotransferase [AST], alanine aminotransferase [ALT]). However, subclinical acute rejection is rarely recognized because protocol biopsies in the absence of abnormal liver biochemical tests are not routinely performed at most transplantation centers. The use of protocol biopsies is generally restricted to patients undergoing investigational immunosuppressive treatments, and whether antirejection therapy improves outcomes for patients with subclinical rejection is uncertain. Older data have suggested that patients with subclinical rejection may experience histologic improvement without modifying immunosuppression and that such subclinical immune activation might be beneficial for inducing a degree of tolerance [5,44].

Patients with hepatitis C virus infection — Management of acute TCMR in patients with hepatitis C virus (HCV) infection has required special attention because some histologic features, such as bile duct injury and portal lymphocytic inflammation, are found in both acute TCMR and recurrent HCV infection (see "Hepatitis C virus infection in liver transplant candidates and recipients", section on 'Evaluation of HCV infection post-transplant'). Thus, differentiating acute rejection in the setting of HCV infection from HCV infection alone can be difficult on histologic grounds. (See "Liver transplantation in adults: Clinical manifestations and diagnosis of acute T-cell mediated (cellular) rejection of the liver allograft", section on 'Establishing the diagnosis'.)

During the era of peginterferon therapy for HCV infection, glucocorticoid or T-cell depletion therapies were associated with more severe histologic HCV recurrence, accelerated progression to fibrosis, and increased mortality [45-49]. However, the availability of safe and effective HCV therapy with direct-acting antivirals has revolutionized the approach to HCV management in liver transplant candidates and recipients [50,51]. Thus, the need to differentiate HCV recurrence from acute TCMR is uncommon because many patients are successfully treated for HCV infection before liver transplantation, and those who are not treated pretransplantation often receive antiviral therapy early post-transplantation.

Patients with autoimmune liver disease — Autoimmune liver disease has been associated with an increased risk of glucocorticoid-refractory acute rejection. In a study of 413 living donor liver transplant recipients, autoimmune liver disease was associated with higher rates of glucocorticoid-refractory acute TCMR compared with recipients with other causes of liver disease (53 versus 40 percent) [4]. In addition, autoimmune liver disease was associated with increased risk of acute TCMR (odds ratio [OR] 2.61; 95% CI 1.48-4.60). (See "Management of autoimmune hepatitis", section on 'Disease course'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Liver transplantation".)

SUMMARY AND RECOMMENDATIONS

●Background – The use of potent immunosuppressive agents for induction and maintenance therapy following liver transplantation has reduced the incidence of acute T cell-mediated (cellular) rejection (TCMR), which is defined as liver allograft dysfunction associated with specific histologic changes in the graft. With use of immunosuppression protocols, acute TCMR occurs in approximately 10 to 30 percent of liver transplantation recipients. (See 'Introduction' above.)

●Goals of therapy – For patients with acute TCMR, the goals of treatment are (see 'Goals of therapy' above):

•Improving liver biochemical tests and liver histology

•Preventing chronic rejection

•Avoiding adverse impact on long-term graft and patient survival

●General measures – For all patients with histologic evidence of acute TCMR of the liver allograft, the baseline immunosuppressive regimen is optimized, while the specific approach depends on the patient's existing regimen and baseline kidney function. For example, higher levels of tacrolimus may be targeted or an antimetabolite (mycophenolate) may be added to the baseline drug regimen. (See 'Optimizing baseline immunosuppression' above.)

●Defining severity of rejection – The management of patients with histologic evidence of acute TCMR is guided by histopathologic severity of rejection and the rejection activity index (RAI) (table 1). Mild rejection has been regarded as RAI ≤4, while classification of RAI values has varied among studies. (See 'Defining severity of rejection' above.)

●Patients with moderate to severe TCMR – For patients with biopsy-proven moderate to severe acute TCMR (ie, RAI ≥5), we suggest glucocorticoid therapy in addition to optimizing baseline immunosuppression (Grade 2C). We typically administer methylprednisolone in a daily bolus dose of 500 mg or 1000 mg intravenously for one to three days, followed by a gradual prednisone taper (algorithm 1). (See 'Patients with RAI ≥5' above.)

For all patients treated with high-dose glucocorticoids, antimicrobial and antiviral prophylaxis includes (see 'Managing glucocorticoid-related toxicity' above and "Prophylaxis of infections in solid organ transplantation" and "Liver transplantation in adults: Initial and maintenance immunosuppression", section on 'Managing glucocorticoid-related toxicity'):

•Cytomegalovirus (CMV) polymerase chain reaction (PCR) testing is performed monthly for three months, and for high-risk recipients (ie, donor CMV positive/recipient CMV negative) CMV prophylaxis is given for three months.

•For P. jirovecii prophylaxis, trimethoprim-sulfamethoxazole is given for three months.

The indications for and duration of antimicrobial and antiviral prophylaxis for liver transplant recipients are discussed in more detail separately. (See "Infectious complications in liver transplantation".)

●Outcomes – The impact of successfully treating acute TCMR on graft outcomes has not been well studied. Greater histologic severity of acute TCMR, later onset of rejection (>3 months post-transplant), and lack of response to antirejection therapy have been associated with worse graft outcomes (eg, progression to chronic rejection, graft loss). (See 'Outcomes' above.)