title: Hepatic progenitor cell proliferation and liver injury in α-1-antitrypsin deficiency.
abstract: OBJECTIVE
  Homozygous ZZ α-1-antitrypsin (a1AT) deficiency is a common genetic liver disease that causes liver injury and hepatocellular carcinoma (HCC). The a1AT mutant Z gene encodes a mutant protein that accumulates within hepatocytes leading to hepatocellular death and a hepatic regenerative response. However, the mechanisms linking hepatocellular injury to these responses are poorly understood. In this study, we examined liver injury and response in human liver and in transgenic mice for involvement of hepatic progenitor cells.
  
  
  METHODS
  Liver biopsy specimens of low-grade, early-stage human ZZ liver exhibiting minimal inflammation and minimal fibrosis (grade 1 and stage 1) were examined for hepatic progenitor cell (HPC) proliferation using immunoreactivity for cytokeratin-7 (CK-7). Transgenic mouse model liver and other selected human biopsies were also examined.
  
  
  RESULTS
  Increased CK-7-positive HPC proliferation was seen in human ZZ liver compared to normal liver, but was 5-fold less HPC proliferation than in grade- and stage-matched disease control hepatitis C-infected liver. Livers from PiZ mice, a model transgenic for the human a1AT mutant Z gene, which recapitulates the human injury, also showed HPC proliferation. Human ZZ liver and PiZ mice develop dysplasia in the liver and HCC. HCC in PiZ mice was also characterized by HPC proliferation. Progressive hepatic fibrosis with age in the PiZ mice is demonstrated for the first time in the present study.
  
  
  CONCLUSIONS
  Chronic injury in both ZZ human and PiZ mouse liver is associated with hepatic fibrosis and a unique magnitude of HPC proliferation within the hepatic proliferative response.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Brunt
authors.forename: Keith
authors.initials: K
authors.lastname: Blomenkamp
authors.forename: Muneeb
authors.initials: M
authors.lastname: Ahmed
authors.forename: Faiza
authors.initials: F
authors.lastname: Ali
authors.forename: Nancy
authors.initials: N
authors.lastname: Marcus
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Teckman
mesh_terms: D000818:Animals; D001706:Biopsy; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D005838:Genotype; D006526:Hepatitis C / Q000473:pathology; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D053552:Keratin-7 / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D008103:Liver Cirrhosis / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D013234:Stem Cells / Q000166:cytology*; D000515:alpha 1-Antitrypsin / Q000235:genetics / Q000378:metabolism*; D019896:alpha 1-Antitrypsin Deficiency / Q000150:complications / Q000378:metabolism / Q000473:pathology*
chemical_list: D053552:Keratin-7; D000515:alpha 1-Antitrypsin