Sequential changes in human Ito cells and their relation to postnecrotic liver fibrosis in massive and submassive hepatic necrosis

To examine the relationship of Ito cells to postnecrotic liver fibrosis, liver specimens, obtained at autopsy from 17 patients with acute massive necrosis (AMN) and acute submassive hepatic necrosis (ASMN), were examined immunohistochemically. In normal adult livers, Ito cells positive for alpha-smooth muscle actin isoform (ASMA) were rarely seen, scattered along hepatic sinusoids. In contrast, in AMN the Ito cells in necrotic areas became strongly positive for ASMA. They were swollen with elongated cytoplasmic processes along collapsed sinusoidal walls. Around these ASMA-positive Ito cells, there were numerous infiltrated macrophages and lymphocytes present. There was no significant alteration of fibroblasts in the portal tracts. In the middle and late stages of ASMN, the spindle-shaped ASMA-positive Ito cells formed a continuous cellular network. New fibre formation was predominantly around them. In this immediate postnecrotic fibrosis, ASMA-positive stromal cells of Ito cell origin were distributed irregularly and were closely associated with reticulin and newly-formed collagen fibres. Regenerative nodules were surrounded by dense layers of ASMA-positive stromal cells. Throughout the stages of ASMN, portal fibroblasts remained negative for ASMA. We believe that Ito cells in necrotic areas show myofibroblastic transformation and play a central role in the postnecrotic liver fibrosis. Portal fibroblasts play no significant part in this type of fibrosis.