Recurrence of Disease After Liver Transplantation

Epidemiology

The incidence of AIH recurrence has recently been reviewed by Liberal et al. ; it was found to be about 40% at 10 years after LT, despite adequate post-transplantation immunosuppressive treatment. Diagnostically, it may be difficult to discriminate the recurrence of AIH from acute cellular rejection on biochemical grounds, which likely contributes to the considerable range in the appearance rate of recurrent disease. The demonstration of interface hepatitis in liver histology is frequently used for the diagnosis of recurrence, together with increased immunoglobulin G and elevated transaminase levels. Typically, recurrent AIH reacts favorably to steroids and azathioprine. The incidence of SC recurrence varies from 10% to 50% within 5 years after transplantation.

Based on reviewing the published literature, Soufi et al. reported an overall incidence of 16% recurrence within a median of 38 months after transplantation. Between the two subgroups of SC (PSC and ASC) recurrent disease seems to develop at a higher incidence in the ASC overlap patients.

Diagnosis of Recurrence

Whereas the diagnosis of AIH needs to be differentiated from acute cellular rejection and viral infection, recurrent SC could be mistaken for post-transplantation biliary complications, including ischemic-type biliary lesions, or chronic rejection. Box 26.1 shows the diagnostic criteria used for recurrent AIH.

The initial indications for SC recurrence may be elevated biliary markers, such as gamma-glutamyltransferase (GGT) and, although less discriminative at pediatric age, alkaline phosphatase, with or without elevated bilirubin levels. Imaging diagnostics are then indicated including ultrasound, followed by magnetic resonance cholangiography. Soufi et al. recently summarized the diagnostic criteria for recurrent PSC ( Box 26.2 ). Liver histology in the case of recurrent PSC typically shows cholestasis, bile duct abnormalities (e.g., ductular reaction, ductular damage, ductopenia), and fibrosis (mostly in the portal area), but onion skin fibrosis is rarely seen.

Risk Factors for Recurrence

For AIH, González-Koch et al. described in a cohort of patients (predominantly adult) with AIH type 1 that recipient human leukocyte antigen (HLA) DR3- or HLA DR4-positive status is a risk for recurrence, regardless of donor HLA status. However, no data on HLA status as a risk factor for (exclusively) pediatric patients are available.

Bazerbachi et al. examined the patient-related risk factors for recurrence of PSC on 113 transplanted pediatric patients from the 36 centers of the Pediatric PSC Consortium. Patients transplanted at a young age or with overlap syndrome had a higher risk of recurrence of PSC, whereas gender or IBD presence was not significantly associated with recurrence of the disease. Initial transplantation for PSC at a young age (< 10 years) was also reported as a risk factor for the disease recurrence in a different cohort by Venkat et al. The activity of IBD, particularly of ulcerative colitis, has been suggested as a risk factor for recurrent disease in adult patients; this supports the goal of optimizing the control of IBD activity as much as possible after transplantation.

Treatment

The treatment of recurrent AIH is basically similar to that of pre-transplantation, namely immunosuppression, but the specific strategies for increasing immunosuppression after transplantation have not been rigorously compared in a randomized fashion. The acute treatment can consist of high-dose prednisolone together with administering azathioprine or mycophenolate mofetil for long-term treatment as an adjunct to a regular post-transplantation calcineurin inhibitor regimen, such as cyclosporin or tacrolimus.

There is still debate on the indications for continued corticosteroid immunosuppression treatment after transplantation for AIH. There is less debate on the usefulness of introducing azathioprine and keeping the level of 6-thioguanine, its active metabolite, between 235 and 450 pmol/8 × 10 ⁸ erythrocytes.

Similar to SC before transplantation, the current treatment options for recurrent SC after LT are limited. In the case of dominant strictures or biliary casts, endoscopic retrograde cholangiopancreatography or percutaneous transhepatic cholangiography is indicated, followed by dilation and transient stenting. The increased risk of recurrent cholangitis can be minimized by giving prophylactic antibiotics after effective treatment of the acute episode, but frequently this is only a temporary solution. Recurrent cholangitis is an indication to consider retransplantation.

The frequently used ursodeoxycholic acid may improve the biochemistry, but no solid data are available to indicate that it changes the natural progressive cause of (recurrent) SC. Other compounds, such as norursodeoxycholic acid, a derivative of ursodeoxycholic acid, or Cilofexor, a farnesoid X receptor agonist, are currently under clinical evaluation outside the transplantation setting in phase III trials in adult patients; these may lead to new treatment options in the future.