The recurrence of underlying disease is relatively low in cases of pediatric liver transplantation (LT) compared with adults. The underlying liver disease does not recur in biliary atresia or in most forms of metabolic liver disease. The most important indications that can be complicated by disease recurrence after transplantation at pediatric age are the following:
Autoimmune liver disease
Familial cholestatic syndromes, particularly bile salt export pump deficiency (also known as progressive familial intrahepatic cholestasis type 2 ).
Additionally, this chapter will discuss three conditions that occur less frequently but have clinically important consequences after LT: Langerhans cell histiocytosis (LCH), giant cell Coombs-positive hepatitis of infancy, and graft disease after LT for FIC1 deficiency (also known as progressive familial intrahepatic cholestasis [FIC] type 1 ).
Autoimmune Liver Disease
Autoimmune liver disease (AILD) is generally considered to consist of autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), and the overlap between the two, also known as autoimmune sclerosing cholangitis (ASC). In ASC, features of both AIH, such as elevated immunoglobulin (Ig)G levels, autoantibodies, and interface hepatitis, and of PSC, such as bile duct disease, are present. Overlap syndrome, or ASC, is more prominent as a third AILD category in pediatric than in adult patients. Because the distinction between PSC and ASC may not always be easy or sustained over time, the two categories can be grouped as sclerosing cholangitis (SC).
AIH is responsible for 2% to 5% of LT in pediatric patients and PSC for 3%. On the other hand, the percentage of AIH and SC patients who need LT during the course of their disease is considerable, varying in the different studies between 10% and 50% in the first decade after the diagnosis. In a recent large retrospective cohort of children with PSC, 30% of patients had undergone LT at 10 years after the initial diagnosis. In about 70% of AILD patients, the hepatic disease concurs with inflammatory bowel disease, either Crohn disease or ulcerative colitis. PSC with inflammatory bowel disease (IBD) seems to have a slightly more favorable prognosis than isolated forms of PSC patients.
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.
Pre-transplantation medical history of autoimmune hepatitis
Increased immunoglobin G, antinuclear antibody, and/or smooth muscle antibody positivity
Histological features (may be masked by immunosuppression):
Lymphocytic interface hepatitis (with or without plasma cells)
Acute lobular hepatitis with focal hepatocyte necrosis, acidophil bodies with lymphoplasmacytic cells
Hepatocytic pseudorosetting and perivenular lymphoplasmacytic inflammation
Confluent and bridging necrosis with lymphoplasmacytic infiltration
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.
Minimally 6 months after liver transplantation
Biochemical indications compatible with cholestasis (elevated gamma-glutamyl transferase, aminotransferase, bilirubin, and serum bile acid levels)
Imaging indications of multifocal bile duct irregularity, beading, and/or stricture (e.g., with magnetic resonance cholangiopancreatography, endoscopic retrograde cholangiopancreatography, percutaneous cholangiography)
Exclusion of post-transplantation complications, including anastomotic biliary stricture, hepatic artery thrombosis, and chronic ductopenic rejection
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.
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.
Recurrent disease in the case of AILD negatively affects the graft and patient survival. There has been only limited evidence on the fraction of patients requiring retransplantation for recurrent disease, but this may range from 20% to 30% (see Liberal et al. and Venkat et al. ) and, in adults, even up to two-thirds of patients with PSC. Based on an analysis of the United Network for Organ Sharing (UNOS) database, graft loss because of disease recurrence was identified in 19% of transplanted pediatric patients with AIH as an underlying indication for transplantation and in 17% of patients with PSC.
Because only limited follow-up data on pediatric series have been available, it is likely that the currently reported data on retransplantation in pediatric patients are actually an underestimation. This is supported by the fact that the diagnosis of “recurrent AIH” strongly increases with the length of follow-up after transplantation. Furthermore, prognosis for the recurrence of PSC seems worse than for the recurrence of AIH, which seems more amenable to intensifying immunosuppressive treatment. This includes the use of inhibitors of the mammalian target of rapamycin signaling pathway ( Fig. 26.1 ).
Progressive Familial Intrahepatic Cholestasis Type 2
Progressive familial intrahepatic cholestasis (PFIC) is a group of genetic cholestatic liver diseases. However, only some patients with severe mutations in the ABCB11 gene encoding the canalicular bile salt export pump (BSEP) are at risk of recurrent disease after LT. Pathological mutations in the ABCB11 gene can result in a reduction or complete loss of functional BSEP protein at the canalicular membrane. The ABCB11 mutations that result in the complete absence of functional BSEP are associated with a severe phenotype. Table 26.1 shows examples of severe BSEP mutations. BSEP deficiency has also been implied in an increased risk of developing hepatocellular carcinoma at an early age (< 5 years). The alpha-fetoprotein (AFP) level has not been a completely reliable predictor of HCC development and has only been shown to be elevated in 8 of 11 published cases.
|Nucleotide Change||Protein Change||Reference(s)|
|c.150 + 3A > G|
|c.611 + 1G > A||,|
|c.908 + 1G > T||,|
|c.1062T > A||p.Tyr354X|
|c.1243C > T||p.Arg415X|
|c.1416T > A||p.y472*||,|
|c.1548T > G||p.Ile528SerfsX21||,|
|c.1550G > A||p.Arg517His||,|
|c.1558A > T||p.Arg520X|
|c.1621A > C||p.Ile54Leu||,|
|c.1723C > T||p.Arg575X||, , –|
|c.1763C > T||p.Ala588Val|
|c.2012-8T > G||,|
|c.2178 + 1 G > A||, , ,|
|c.2343 + 1G > T|
|c.2611-2A > T|
|c.2787_2788ins GAGAT||p.Lys930Glu fsX79||,|
|c.3169C > T||p.Arg1057X||,|
|c.3213 + 1_3213 + 2delinsA|
|c.3213 + 1delG||p.Asp1072ThrfsX25||,|
|c.3268C > T||p.R1090X||,|
|c.3643C > T||p.Gln1215X|