Background: The clinical outcome of alcoholic hepatitis (AH) is partly influenced by impaired liver cell proliferation and insufficient tissue repair. The role of stem cell therapy in this setting remains unclear. We aimed to study histological features, cytokine profile and hepatic gene expression at baseline and during follow-up in patients with AH and liver failure treated with the standard of care (SOC) alone or in association with stem cell transplantation (SCT). Methods: Immunohistochemical studies for macrophage expansion, proliferative hepatocytes, total and proliferative liver progenitor cells (LPC) as well as global microarray gene expression analysis were performed on liver biopsies of 58 AH patients (28 of whom received SCT) both at baseline and after 4 weeks of follow-up. Abstinent cirrhotics (n=12) were used as controls for baseline studies. Patients were qualified as “improvers” or “non-improvers” according to the presence/absence of a decrease of at least 3 points of MELD at 3 months as compared to baseline value. Results: Compared to controls, AH patients at baseline demonstrated a significant expansion of macrophages, invasion of LPC and a higher number of proliferating hepatocytes and LPC (p<0.001). The group of improvers (n=34) were characterized at baseline by a higher number of proliferating hepatocytes (p<0.01), proliferative LPC (double CK7+Ki67+ cells, p<0.01) and liver macrophages (p<0.05) as compared to non-improvers (n=24), in spite of similar clinical and biological variables. Up-regulated genes in improvers were associated with cell cycle mitosis together with an important expression of SPINK1, an acute phase protein linked with cell proliferation. On repeat biopsy, as compared to patients on SOC alone, those who received SCT showed a more important liver macrophagic expansion (p<0.01), but transcriptome data showed no significant changes in genes related to cell cycle. Conclusions: Baseline histology and hepatic gene expression differ according to clinical outcome in patients with AH. Higher liver macrophage expansion, increased proliferative hepatocyte and LPC number as well as up-regulation of cell proliferation related genes are associated with a favourable outcome (decrease in MELD score at 3 months). Stem cell transplantation has no effect on hepatocyte proliferation.
Lanthier, Nicolas ; Rubbia-Brandt, Laura ; Lin-Marq, Nathalie ; Clément, Sophie ; Frossard, Jean-Louis ; et. al. Hepatic cell proliferation and outcome in alcoholic hepatitis: histology, gene expression and effect of stem cell therapy..AASLD annual meeting (Boston, du 07/11/2014 au 11/11/2014). In: Hepatology, Vol. 60, no.S1, p. 795A (Oct 2015)