Asymptomatic Allograft Fibrosis in Pediatric Liver Transplantation: Potential Clinical Implications.

Allograft fibrosis is a common histopathologic finding following pediatric liver transplantation. The prevalence and severity of fibrosis are believed to increase over time.1,2 Despite multiple studies, the etiopathogenesis and potential clinical implications of allograft fibrosis remain incompletely understood because it is often detected in protocol biopsies from asymptomatic children with normal or near-normal liver tests. In this issue of Transplantation, Hartleif et al3 performed a retrospective study that aimed to evaluate the prevalence of allograft fibrosis and its impact on long-term outcomes for patients who underwent liver transplantation in childhood. The study included 494 patients across 12 international transplant centers who had normal or near-normal liver biochemistry. On their 10-y protocol biopsies, 370 patients (75%) were found to have variable degrees of fibrosis, including periportal/pericentral fibrosis (51%), bridging fibrosis (18%), and cirrhosis (6%). Patients with cirrhosis were more likely to die or require retransplantation in the subsequent 5 y in comparison with those with less severe fibrosis (8% versus 1%–2%). The authors observed significant progression of fibrosis between the 5- and 10-y biopsies and between the 5- and 15-y biopsies, but no significant change after the 10-y biopsy. Interestingly, the degree of inflammation at 5-y biopsies was not a predictor of future fibrosis. There was no association of graft fibrosis with biliary or vascular complications, although the most common underlying liver disease for liver transplantation in this cohort was biliary atresia. There appeared to be an association with immunosuppression (cyclosporine versus tacrolimus) and prior rejection, but the association seemed weak despite statistical significance. Furthermore, maintenance or introduction of low-dose steroids did not appear to prevent fibrosis progression from 5 to 10 y. The findings of this study are noteworthy because they provide important insights into long-term outcomes for a large number of asymptomatic patients with graft fibrosis after pediatric liver transplantation. According to their data, fibrosis develops mainly within the first 10 y following transplantation and does not progress significantly after 10 y. In fact, mild to moderate graft fibrosis does not largely affect patient or graft survival up to 20 y. These findings corroborate the observations by other investigators with smaller patient cohorts. In a recent multicenter study that included 78 pediatric patients,4 moderate fibrosis (defined as liver allograft fibrosis score [LAFSc] 3–5) and severe fibrosis (LAFSc >6) were detected in 56% and 14% of patients, respectively, when biopsied at a median of 8.2 y (range, 5.9–11.6 y) posttransplantation. The following biopsy, performed at a median of 4.7 y later (range, 4.3–5.1 y), showed fibrosis progression (LAFSc increase by ≥3) in only 13% and regression (LAFSc decrease by ≥3) in 5% of their patients. The LAFSc distribution was found to change very modestly on the second biopsies, with 62% having LAFSc 4 to 6 and 5% having LAFSc ≥7. Similarly, a recent study from Italy that included 80 pediatric liver transplant recipients showed mild or moderate allograft fibrosis in 74% of their patients at 6 mo after transplantation and 90% by 5 y using LAFSc.5 Fibrosis progression from mild to moderate occurred mainly from 2 to 5 y but remained stable at the 10-y biopsies, although only 18 patients had biopsies at 10 y. No severe fibrosis was detected in this cohort. Taken together, these findings suggest that allograft fibrosis in pediatric liver transplant recipients with normal or near-normal liver biochemistry is not a progressive process, at least during the second decade after transplantation. This may have important management implications because therapeutic intervention with intensified immunosuppression in an attempt to counteract fibrosis progression may not be necessary. Although unexplained inflammation or idiopathic posttransplant hepatitis is also a common finding in protocol biopsies,1,2 its etiological association with allograft fibrosis is not firmly established. Other suggested risk factors for fibrosis include prolonged cold ischemia time, reduced graft size, high donor/recipient age ratio, vascular and biliary complications, calcineurin inhibitor monotherapy following steroid withdrawal, low tacrolimus trough level within 1 y, recurrent episodes of rejection, high levels of autoantibodies, and the presence of donor-specific antibodies (DSAs).3–5 Unlike in adults, recurrence of underlying liver diseases is a rare cause of late graft dysfunction in the pediatric population. Asymptomatic allograft fibrosis, along with inflammation, appears to fit the current definition of chronic antibody-mediated rejection (cAMR).6 In fact, an association between DSA and fibrosis has been well documented.7–9 However, cAMR is a diagnosis of exclusion with an estimated prevalence of 8% to 15% in recipients who present with persistent or de novo DSAs, specially targeting HLA class II.10 Although cAMR may be an important contributor, its relatively low prevalence makes it difficult to explain the high prevalence of allograft fibrosis. It is unfortunate that DSA and tissue deposition of complement component 4d (C4d) could not be investigated in the study by Hartleif et al.3 However, it is worth mentioning that C4d immunostaining is neither a specific nor a sensitive marker of AMR in liver transplantation. Overall, this retrospective multicenter study by Hartleif et al expands our understanding of the long-term outcomes of asymptomatic allograft fibrosis in pediatric liver transplantation. Together with observations by other investigators, it highlights the importance of monitoring for fibrosis in the early years posttransplantation (ie, within the first 10 y or even the first 6 mo) when fibrosis develops and progresses. Although protocol biopsies remain the only tool to detect asymptomatic fibrosis and help identify patients with cirrhosis or severe fibrosis that may carry a higher risk of allograft failure, it does not help predict who will progress in patients with mild or moderate fibrosis. Liver stiffness measurement as a possible noninvasive alternative to biopsy to detect fibrosis in the long term needs to be validated. Future research is needed to further understand the etiopathogenetic mechanisms that initiate and promote fibrosis in the early years after transplantation so that intervention strategies to prevent or mitigate the development of severe fibrosis can be effectively implemented.