PMID- 24529185
OWN - NLM
STAT- MEDLINE
DCOM- 20150928
LR  - 20151119
IS  - 1478-3231 (Electronic)
IS  - 1478-3223 (Linking)
VI  - 35
IP  - 1
DP  - 2015 Jan
TI  - Alpha-1-antitrypsin deficiency: from genoma to liver disease. PiZ mouse as model 
      for the development of liver pathology in human.
PG  - 198-206
LID - 10.1111/liv.12504 [doi]
AB  - BACKGROUND & AIMS: 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, 
      alpha-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. CONCLUSION: 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.
CI  - (c) 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
FAU - Giovannoni, Isabella
AU  - Giovannoni I
AD  - Department of Pathology, Children's Hospital Bambino Gesu, IRCCS, Rome, Italy.
FAU - Callea, Francesco
AU  - Callea F
FAU - Stefanelli, Marta
AU  - Stefanelli M
FAU - Mariani, Riccardo
AU  - Mariani R
FAU - Santorelli, Filippo M
AU  - Santorelli FM
FAU - Francalanci, Paola
AU  - Francalanci P
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140311
PL  - United States
TA  - Liver Int
JT  - Liver international : official journal of the International Association for the 
      Study of the Liver
JID - 101160857
RN  - 0 (Biomarkers)
RN  - 0 (DNA Primers)
RN  - 0 (Prealbumin)
RN  - 0 (Serum Albumin)
RN  - 0 (alpha 1-Antitrypsin)
RN  - 0 (alpha-Fetoproteins)
RN  - 56-73-5 (Glucose-6-Phosphate)
RN  - EC 2.6.1.5 (Tyrosine Transaminase)
RN  - alpha-1-Antitrypsin Deficiency, Autosomal Recessive
SB  - IM
MH  - Animals
MH  - Biomarkers/*blood
MH  - DNA Primers/genetics
MH  - *Disease Models, Animal
MH  - Glucose-6-Phosphate/blood
MH  - Histological Techniques
MH  - Immunohistochemistry
MH  - Liver/*pathology
MH  - Mice
MH  - Prealbumin/metabolism
MH  - Real-Time Polymerase Chain Reaction
MH  - Serum Albumin
MH  - Statistics, Nonparametric
MH  - Tyrosine Transaminase/blood
MH  - alpha 1-Antitrypsin/blood
MH  - alpha 1-Antitrypsin Deficiency/*pathology
MH  - alpha-Fetoproteins/metabolism
OTO - NOTNLM
OT  - AAT globules hepatocellular carcinoma
OT  - alpha-1-antitrypsin deficiency
OT  - dedifferentiated cells
OT  - transgenic mouse
EDAT- 2014/02/18 06:00
MHDA- 2015/09/29 06:00
CRDT- 2014/02/18 06:00
PHST- 2013/10/28 00:00 [received]
PHST- 2014/02/08 00:00 [accepted]
PHST- 2014/02/18 06:00 [entrez]
PHST- 2014/02/18 06:00 [pubmed]
PHST- 2015/09/29 06:00 [medline]
AID - 10.1111/liv.12504 [doi]
PST - ppublish
SO  - Liver Int. 2015 Jan;35(1):198-206. doi: 10.1111/liv.12504. Epub 2014 Mar 11.