title: Alpha-1-antitrypsin deficiency: from genoma to liver disease. PiZ mouse as model for the development of liver pathology in human.
abstract: OBJECTIVE
  Homozygous individuals with alpha-1-antitrypsin deficiency (AATD) type PiZ have an increased risk of chronic liver disease and hepatocellular carcinoma (HCC). It is noteworthy that HCCs are composed by hepatocytes without accumulation of AAT, but the reason for this remains unclear. The aim of this study was to determine liver pathology in PiZ mice, focusing the attention on the distribution of AAT globules in normal liver, regenerative foci and neoplastic nodules.
  
  
  METHODS
  Liver of 79 PiZ mice and 18 wild type (Wt) was histologically analysed for steatosis, clear cell foci, hyperplasia and neoplasia. The expression of human-AAT transgene and murine AAT, in non-neoplastic liver and in hyperplastic/neoplastic nodules was tested by qPCR and qRT-PCR. RT-PCR was used to study expression of hepatic markers: albumin, α-foetoprotein, transthyretin, AAT, glucose-6-phospate, tyrosine aminotransferase.
  
  
  RESULTS
  Liver pathology was seen more frequently in PiZ (47/79) than in Wt (5/18) and its development was age related. In older PiZ mice (18-24 m), livers showed malignant tumours (HCC and angiosarcoma) (17/50), hyperplastic nodules (28/50), non-specific changes (33/50), whereas only 9/50 were normal. Both human-AATZ DNA and mRNA showed no differences between tumours/nodules and normal liver, while murine-AAT mRNA was reduced in tumours/nodules.
  
  
  CONCLUSIONS
  Accumulation of AAT is associated with an increased risk of liver nodules. The presence of globule-devoid hepatocytes and the reduced expression of murine-AAT mRNA in hyperplastic and neoplastic nodules suggest that these hepatic lesions in AATD could originate from proliferating dedifferentiated cells, lacking AAT storage and becoming capable of AFP re-expression.
authors: Department of Pathology, Children's Hospital Bambino Gesù, IRCCS, Rome, Italy.
authors: Isabella
authors: I
authors: Giovannoni
authors: Francesco
authors: F
authors: Callea
authors: Marta
authors: M
authors: Stefanelli
authors: Riccardo
authors: R
authors: Mariani
authors: Filippo M
authors: FM
authors: Santorelli
authors: Paola
authors: P
authors: Francalanci
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood*; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D019298:Glucose-6-Phosphate / Q000097:blood; D006652:Histological Techniques; D007150:Immunohistochemistry; D008099:Liver / Q000473:pathology*; D051379:Mice; D011228:Prealbumin / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012709:Serum Albumin; D018709:Statistics, Nonparametric; D014444:Tyrosine Transaminase / Q000097:blood; D000515:alpha 1-Antitrypsin / Q000097:blood; D019896:alpha 1-Antitrypsin Deficiency / Q000473:pathology*; D000509:alpha-Fetoproteins / Q000378:metabolism
chemical_list: D015415:Biomarkers; D017931:DNA Primers; D011228:Prealbumin; D012709:Serum Albumin; D000515:alpha 1-Antitrypsin; D000509:alpha-Fetoproteins; D019298:Glucose-6-Phosphate; D014444:Tyrosine Transaminase
keywords: AAT globules hepatocellular carcinoma; alpha-1-antitrypsin deficiency; dedifferentiated cells; transgenic mouse