Clinico-pathological features of liver disease following paediatric bone marrow transplantation

Objectives: The knowledge on clinico-pathological features of liver injury following paediatric bone marrow transplantation (BMT), including liver graft versus host disease (L-GVHD), is scarce. Previous studies showed that the main target of hepatic damage is the biliary tract. We aimed to describe the features of bile duct injury in a cohort of children who consecutively underwent BMT for haematological disorders, and correlate them to clinical signs of liver disease. Methods: from 2013 to 2015 protocol biopsies were scheduled for every child listed for BMT at our haemato-oncology unit. All patients showing significant clinical and/or histological liver disease were scheduled for follow up biopsies. Histology samples were reviewed and scored according to a previously reported semi-quantitative system1, and compared with liver function tests (ALT, GGT, bilirubin, serum bile acid). Features of bile duct disease (ductular proliferation, biliary metaplasia, bile duct atrophy and ductopenia) were also reported separately. Ductopenia (bile duct to portal tract ratio <0.5) was evaluated on cytokeratin 7 stained histology slices. Overt L-GVHD was diagnosed when clinical cholestatic disease and histology consistent with GVHD were present, after exclusion of other causes. Results: 50 BMTs in 44 patients (28 males, mean age 9.3 years) were carried out in the study period; overall 97 liver biopsies were performed and 89 were available for review; 45 patients had one, 30 had two, 15 had three and 5 had 4 liver biopsies taken following BMT. The mean L-GVHD score was 6.3, 5.8, 5.6 and 4.6 at the respective number of serial biopsies taken during the follow up. Bile duct proliferation was diagnosed in 81/89 (91%), metaplasia in 33/89 (37%), atrophy in 72/89 (81%). Ductopenia was diagnosed in 83/89 samples (93%), and was persisting in 11/27, worsening in 16/27 pts who had a second biopsy. Ductopenia, bile duct proliferation and atrophy were the main features in all patients who had three or four follow up biopsies, whereas metaplasia tended to disappear. Over a mean follow up of 1.4 years (SD ±0.7), 16 patients (32%) developed overt L-GVHD, 9 died of systemic complications and 7 are alive, 4 of whom with liver disease. All the other patients, at the last follow up, have normal liver tests. Conclusion: Ductopenia is found in almost all children undergoing a liver biopsy following BMT, is persisting and often accompanied by ductular proliferation and atrophy. The clinico-pathological correlation, though, reveal that only a minority of such patients develops a clinical liver disease which, when fully expressed, is associated with a poor prognosis.