Ductular reaction on protocol biopsy post liver transplant corresponds to concurrent fibrosis and does not predict fibrogenesis

Background and Aims: Ductular reaction (DR) is identified by using CK7 staining and represents a ductular phenotype, possibly arising from proliferation of cholangiocytes and progenitor cells. DR has been linked to hepatic fibrosis progression in HCV and hemochromatosis. It is frequently seen on protocol biopsies (PB) post-liver transplant (LT) and given its origin it’s unclear if its linked to fibrogenesis or hepatocyte regeneration after an insult. This was analyzed in the current study using paired PB’s to test if CK7 quantification on the baseline PB could predict the course of fibrogenesis in the follow up PB. Methods: Children who underwent LT from 2012 to 2014 and had ≥2 PB at an interval of 1-2 years between each other were included. The first PB was labeled as “baseline biopsy” and the successive biopsy as “follow-up biopsy.” The change of fibrosis severity between the “baseline” and “follow-up” biopsy was termed as “prospective change in fibrosis.” Each biopsy was evaluated for inflammation and fibrosis using the Metavir and LAFSc system. The baseline biopsy was stained with CK7 and digitally evaluated to obtain “CK7 – positive area percentage” i.e. CK7-stained area expressed as percentage of the total biopsy area. The association between CK7-positive area percentage on baseline biopsy and “prospective change in fibrosis” scores, ductular reaction, lobular inflammation, and portal tract inflammation was assessed using ordinal logistic regression models. Results: Our study included 64 pared PB from 32 children. The baseline PB stained for CK7, were taken at a mean of 2.89 years post-LT. The time interval between the two paired PB’s was 1.41 years. CK7-positive area percentage was significantly associated with baseline fibrosis, extent of ductular reaction (p = 0.006) and portal tract inflammation (p = 0.01). There was a no significant association between the CK7-positive area percentage of the baseline biopsy and the “prospective change in fibrosis” as assessed by the Metavir score (p = 0.36) or cumulative LAFSc (p = 0.25) or with recipient or donor age, donor type, HLA antibodies, or recipient or donor gender. Conclusions: Ductular reaction, CK7 expression is significantly associated with extent of portal tract inflammation and concurrent severity of fibrosis but does not predict the future course of fibrogenesis.