Co-existing regeneration mechanisms in severe alcohol-related steatohepatitis

Background: Keratin 7 positive (K7+) cells are considered to be activated in case of impaired hepatocyte replication. Their exact role and their interaction with hepatocytes and macrophages also implicated in liver regeneration remain poorly characterized in humans. The aim of this study is to evaluate hepatocyte, K7+ cells and macrophage populations in severe alcohol-related steatohepatitis (sASH) and to link them with liver injury and patients’ outcomes. Methods: Immunohistochemical and morphometric studies for total K7+ cells, macrophages (CD68+ cells), proliferative hepatocytes (Ki67+ hepatocytes) and proliferative K7+ cells (double K7+ and Ki67+) were performed on liver biopsies of patients with sASH recruited prospectively in 16 different centres. Patients were divided into improvers or non-improvers, according to mortality and model for end-stage liver disease (MELD) score change at 3 months. Results: Fifty-seven cases were included for histological and morphometrical assessment. Liver total K7+ cell expansion was positively correlated to the severity of the disease evaluated by the MELD score. A proportion of these K7+ cells were proliferating. The number of proliferating K7+ cells was less than the number of proliferating hepatocytes. Increased hepatocyte replication was correlated to a higher proliferative K7+ cell count. A higher number of macrophages was associated with a higher proliferation of both hepatocytes and K7+ cells. No difference of total K7+ cells, proliferative K7+ cells, proliferative hepatocytes or macrophages was observed between improvers and non-improvers. Conclusions: In biopsy-proven cases of sASH, proliferation of hepatocytes and K7+ cells occurs in parallel. This could suggest that liver progenitor cells begin to replicate even in the absence of massive hepatocyte senescence in humans, or that proliferating progenitor cells are capable of giving rise to hepatocytes with replicative skills. This is associated with macrophagic expansion, which is therefore considered beneficial. However, in this severe, life-threatening disease, these mechanisms remain insufficient to improve patient prognosis.