Aim

To characterize a population of children post liver transplant according to clinical, serological, histological, genetic and immunological parameters; elucidate the mechanistic basis for allograft injury, the determinants for progression and treatment response, and provide a platform for long-term graft preservation.

Background

Paediatric Liver transplantation (OLT) has dramatically improved the natural history and outcome for infants and children with liver disease as > 80% now survive > 20-years. Over the past 25 years, more than 12000 paediatric liver transplants have been performed in Europe, with remarkable progress in procedural techniques, immunosuppressive regimens and outcome. Such success has lead to a growing population of survivors, which in turn has raised a significant challenge as to how to preserve allograft function into late adult life. Our understanding of the long-term histological changes and evolution of these grafts is just emerging.

Several paediatric centres have evaluated serial protocol liver biopsies after transplantation to assess histological changes. An increasing prevalence of chronic graft hepatitis (CH) and/or fibrosis over time (1,2,3,4), despite normal or near normal biochemical liver function tests has been increasingly recognised as an important complication of liver transplantation. In one study, 158 asymptomatic children underwent protocol liver biopsies at 1, 5, and 10 years after OLT. The commonest histological abnormality was CH present in 22%, 43%, and 64% of allograft biopsies at 1, 5, and 10 years, respectively (p<.0001). The prevalence of fibrosis also increased with time: 52%, 81% and 91% at 1, 5, and 10 years, respectively (p< .0001). By 10 years 15% had progressed to cirrhosis. There was no evidence of viral infection and no association with immunosuppressive medication (2, 5). On multivariate analysis, the only factor predictive of chronic hepatitis was autoantibody positivity. Other studies have also recently suggested possible associations between donor-specific alloantibodies (DSAs) and chronic liver allograft injury, while some European and US centres have reported similar fibrosis prevalence (6,7,8). The implication of a surreptitious immune-mediated injury has prompted centres to introduce long-term, low dose steroids as part of their immunosuppression (IS) regimen, although the benefit of these changes remains unknown. To date no large scale, multicentre studies have been performed.

Our preliminary data, which include 6 European transplant centres, confirms the rising incidence of CH, (43% at 5yrs, 53% at 10yrs) and fibrosis (54% at 5 yrs, 79% by 10yrs) over time. It appears that children treated with long-term low dose steroids are significantly less likely to have CH compared to those not on steroids at 5 years and 10years, However, this improvement in CH was not associated with decreased graft fibrosis at 10 years. GIGOLO aims at filling this gap in knowledge by exploring the causes for graft injury and fibrosis and identifying the most suitable form of treatment. Statements of need and relevance

We need to:

I. Describe the nature of graft injury and its effects on allograft function from childhood through transition into late adult life

II. Develop standardised recommendations for performing protocol biopsies, methods of histological assessment and nomenclature relating to graft injury

III. Determine the role for existing serological markers and alloantibodies (including donor specific antibodies) in identifying at risk cohorts

IV. Identify the disease mechanisms (genetic, immunological) of graft injury, along with non-invasive markers for the presence of disease and treatment response