Identifying activated hepatic stellate cells in chronic and posttransplant recurrent hepatitis C

Hepatic stellate cells (HSC), or Ito cells, are the interstitial fat-storing cells of the liver that lie in the space of Disse. HSC are the main collagen-producing cells in the liver, and with liver injury, HSC differentiate toward myofibroblast-like cells and become “activated” to produce collagen. Alpha-smooth muscle actin ( SMA) is a widely accepted marker of activated HSC that can be identified by immunohistochemical staining. Identification of activated HSC, as indicated by SMA positivity, has been evaluated as an early indicator of fibrosis progression in patients with chronic hepatitis C virus (HCV) infection and recurrent HCV after liver transplantation. The issues related to this assessment have been discussed elsewhere. In this issue of Liver Transplantation, Carotti et al. have evaluated a marker of HSC activation—glial fibrillary acidic protein (GFAP)—in chronic HCV and recurrent HCV after liver transplantation. GFAP is the intermediate filament expressed by astrocytes in the central nervous system and is also expressed by HSC. The relationship between GFAP expression and HSC activation is controversial. Rat studies have suggested that GFAP is expressed in quiescent HSC and declines with HSC activation or is expressed early in HSC activation but declines with increasing SMA expression. GFAP expression in HSC has been documented in normal human liver and in chronic liver disease The precise role and temporal significance of GFAP in HSC activation in human liver are not yet clearly understood, but in some studies, expression appears to correlate with fibrosis. In the present study, Carotti et al. have evaluated GFAP and SMA expression in chronic hepatitis C and posttransplant recurrent hepatitis C, correlating expression levels with vascular remodeling and fibrosis progression. In prior studies, this group and others have outlined SMA and GFAP expression in chronic hepatitis, but the expression of GFAP in recurrent HCV post-transplantation and the use of GFAP as a potential marker of early HSC activation in this setting have not been evaluated. Two notable limitations of this study are that it was performed retrospectively and that the methods section makes no mention of whether the pathologists interpreting the immunohistochemical stains were blinded to the clinical parameters. The potential for introduction of bias in a nonblinded, retrospective study of this type cannot be overstated. As presented, this study does not indicate whether each sample was from a different patient or if any patient was represented in multiple sample groups [that is, were there any cases in which multiple biopsies (an HCV cirrhosis biopsy, a donor liver biopsy, and/or a recurrent HCV biopsy) were derived from the same patient? ]. A blinded, prospective assessment of GFAP expression from liver transplantation forward (prior to and through the course of HCV recurrence) would enable the assessment of GFAP as a marker of HCV recurrence. Carotti et al. found that the percentage of HSC expressing SMA was significantly greater in all 3 HCV groups (HCV chronic hepatitis, cirrhosis secondary to HCV, and recurrent hepatitis C after liver transplanta-