Autoimmune hepatitis that recurs following a liver transplant can impair both graft survival and overall survival, results of a large international study showed.
Among 736 patients with autoimmune hepatitis who underwent liver transplant and were followed for up to 20 years, those who had recurrent AIH had a more than 10-fold higher risk for graft failure and a more than twofold higher risk of death, compared with patients who did not have recurrences, reported Aldo J. Montano-Loza, MD, MSc, PhD, from the University of Alberta, Edmonton.
“Recurrent disease impacts graft and overall survival, highlighting the need for improved management strategies,” he said in an oral abstract presentation during the International Liver Congress sponsored by the European Association for the Study of the Liver.
AIH is characterized by the presence of high IgG levels, autoantibodies, and histologic evidence of interface hepatitis. Most patients with AIH respond to immunosuppressive therapy, but some have progression to end-stage liver disease; for these patients, a liver transplant can be lifesaving, with 1-year survival of approximately 90%, and 5-year survival of about 70%, he said.
AIH frequently recurs after transplant, and although previous studies have suggested that recurrent disease does not adversely affect either graft survival or long-term survival, those studies had limited patient numbers and inadequate follow-up, Dr. Montano-Loza said.
He cited two recent studies, one from UNOS, the United Network for Organ Sharing, and the other from ELTR, the European Liver Transplant Registry, that showed that overall survival after liver transplant was worse for patients with AIH, compared with those who underwent transplant for other autoimmune liver diseases.
Multicenter retrospective study
To get a better picture of long-term posttransplant outcomes in patients with AIH, investigators in 33 centers in North and South America, Europe, and Asia conducted a retrospective cohort study. Their goal was to establish the frequency of recurrent AIH, identify clinical factors and biomarkers for higher risk of recurrence, and evaluate the association between recurrent AIH and both patient and graft survival.
They accomplished this by performing chart reviews, including data on demographics, IgG levels before transplant, and Model for End-Stage Liver Disease scores.
They also collected data on serum liver function tests within the first year after transplant, posttransplant infections, rejection episodes, and immunosuppressive regimens, as well as variables such as donor age and sex, sex mismatch between donor and recipients, calendar year of transplant, and transplant volume for AIH at each center.
Of the 736 patients, 563 (76%) were female. The mean age at AIH diagnosis was 34 years, and the mean age at transplant was 42 years. About one-fifth of patients (21%) had concomitant autoimmune diseases.
Posttransplant immunosuppression regimens included the usual suspects: tacrolimus in 78% of patients, cyclosporine in 11%, prednisone in 76%, mycophenolate mofetil in 55%, and azathioprine in 10%.
In all, 147 of the 736 patients had a diagnosis of recurrent AIH. The investigators found that the cumulative probability of recurrent AIH was 49% after 20 years of follow-up.
Risk factors identified
In multivariate analysis controlling for age, concomitant disease, immunosuppressive regimens, organ-sex mismatch, acute rejection, liver function tests, bilirubin, and IgG, factors significantly associated with AIH recurrence included age 42 or younger at the time of transplant (hazard ratio, 3.15; P = .02), use of mycophenolate mofetil after transplant (HR, 3.06; P = .005), donor/recipient sex mismatch (HR, 2.57; P = .003), and high IgG levels pretransplant (HR, 1.04; P = .004).
Among 529 patients who had a liver biopsy after transplant, factors that remained as significant predictors of AIH recurrence were posttransplant mycophenolate mofetil (HR, 2.75; P = .003), donor/recipient sex mismatch (HR, 2.03; P = .02), and pretransplant IgG levels (HR, 1.04 per each g/L; P = .001).
An analysis of features associated with graft survival showed that recurrent AIH was associated with significantly increased risk for graft failure (HR, 10.79; P < .001). Patients with high bilirubin levels 1 year after transplantation were also at higher risk for failure (HR, 1.004 per micromol/L; P < .001).
Factors significantly associated with survival were recurrence of AIH (HR for death, 2.53; P = .001), elevated ALT at 12 months after transplant (HR, 1.002; P = .004), and elevated bilirubin at 12 months (HR, 1.003 per micromol/L; P < .001).
The investigators acknowledged that the study was limited by the retrospective design and by the fact that the diagnosis of recurrent AIH may have differed between centers that performed liver biopsy according to protocol and those that performed them only when clinically indicated, which may have resulted in differences in time to diagnosis.
Possible explanations for risk factors
In the question-and-answer session following his presentation, comoderator moderator Philip N. Newsome, PhD, from University Hospitals Birmingham (England), asked: “In terms of age, is that a reflection of worse disease, or is it adherence, or is it a combination, and should we be managing those patients more aggressively with immunosuppression?”
“We consider age is more a reflection of an aggressive disease,” Dr. Montano-Loza said. “Basically, in the univariate analysis we found that patients with a diagnosis at a younger age and even a transplant at a younger age were definitely associated with a higher risk of recurrence, so we think this is more related to an aggressive [disease] behavior in younger patient that translates into worse clinical outcomes.”
He added that patients younger than 40 who require transplants should be closely monitored for recurrence.
“Actually, we could make the argument that maybe these patients will benefit from protocol biopsies,” he said.
He noted that 15% of patients had significant fibrosis at the time of recurrent AIH diagnosis, and that the recurrences were not detected by laboratory monitoring alone.
Asked by an audience member why mycophenolate mofetil was associated with increased risk for recurrence, Dr. Montano-Loza replied that the retrospective nature of the data precludes the possibility of a definitive answer, but he noted that, for patients with other autoimmune liver diseases, the type of immunosuppression used has an impact on recurrence rates.
“For example, cyclosporine has a protective effect for patients transplanted for primary biliary cholangitis,” he said.
He said it may also be possible that there is a rebound effect leading to recurrence when patients are taken off mycophenolate or switched to another agent.
The study was supported by grants to individual researchers. Dr. Montano-Loza and Dr. Newsome reported having no relevant conflicts of interest.