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Alpha-1-Antitrypsin in Pathogenesis of Hepatocellular Carcinoma

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2012
1657.pdf (689.3Kb)
Authors
Topić, Aleksandra
Ljujić, Mila
Radojković, Dragica
Article (Published version)
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Abstract
Context: Alpha-1-antitrypsin (A1AT) is the most abundant liver-derived, highly polymorphic, glycoprotein in plasma. Hereditary deficiency of alpha-1-antitrypsin in plasma (A1ATD) is a consequence of accumulation of polymers of A1AT mutants in endoplasmic reticulum of hepatocytes and other A1AT-producing cells. One of the clinical manifestations of A1ATD is liver disease in childhood and cirrhosis and/or hepatocellular carcinoma (HCC) in adulthood. Epidemiology and pathophysiology of liver failure in early childhood caused by A1ATD are well known, but the association with hepatocellular carcinoma is not clarified. The aim of this article is to review different aspects of association between A1AT variants and hepatocellular carcinoma, with emphasis on the epidemiology and molecular pathogenesis. The significance of A1AT as a biomarker in the diagnosis of HCC is also discussed. Evidence Acquisitions: Search for relevant articles were performed through Pub Med, HighWire, and Science Direct... using the keywords "alpha-1-antitrypsin", "liver diseases", "hepatocellular carcinoma", "SERPINA1". Articles published until 2011 were reviewed. Results: Epidemiology studies revealed that severe A1ATD is a significant risk factor for cirrhosis and HCC unrelated to the presence of HBV or HCV infections. However, predisposition to HCC in moderate A1ATD is rare, and probably happens in combination with HBV and/or HCV infections or other unknown risk factors. It is assumed that accumulation of polymers of A1ATD variants in endoplasmic reticulum of hepatocytes leads to damage of hepatocytes by gain-of-function mechanism. Also, increased level of A1AT was recognized as diagnostic and prognostic marker of HCC. Conclusions: Clarification of a carcinogenic role for A1ATD and identification of pro-inflammatory or some still unknown factors that lead to increased susceptibility to HCC associated with A1ATD may contribute to a better understanding of hepatic carcinogenesis and to the development of new drugs.

Keywords:
Alpha 1-Antitrypsin Deficiency / Carcinoma, Hepatocellular / Autophagy / Fucose
Source:
Hepatitis Monthly, 2012, 12, 10
Publisher:
  • Kowsar Publ, Hoensbroek
Funding / projects:
  • Complex diseases as a model system for phenotype modulation- structural and functional analysis of molecular biomarkers (RS-173008)

DOI: 10.5812/hepatmon.7042

ISSN: 1735-143X

PubMed: 23162602

WoS: 000314117000009

Scopus: 2-s2.0-84871476851
[ Google Scholar ]
35
37
URI
https://farfar.pharmacy.bg.ac.rs/handle/123456789/1659
Collections
  • Radovi istraživača / Researchers’ publications
Institution/Community
Pharmacy
TY  - JOUR
AU  - Topić, Aleksandra
AU  - Ljujić, Mila
AU  - Radojković, Dragica
PY  - 2012
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1659
AB  - Context: Alpha-1-antitrypsin (A1AT) is the most abundant liver-derived, highly polymorphic, glycoprotein in plasma. Hereditary deficiency of alpha-1-antitrypsin in plasma (A1ATD) is a consequence of accumulation of polymers of A1AT mutants in endoplasmic reticulum of hepatocytes and other A1AT-producing cells. One of the clinical manifestations of A1ATD is liver disease in childhood and cirrhosis and/or hepatocellular carcinoma (HCC) in adulthood. Epidemiology and pathophysiology of liver failure in early childhood caused by A1ATD are well known, but the association with hepatocellular carcinoma is not clarified. The aim of this article is to review different aspects of association between A1AT variants and hepatocellular carcinoma, with emphasis on the epidemiology and molecular pathogenesis. The significance of A1AT as a biomarker in the diagnosis of HCC is also discussed. Evidence Acquisitions: Search for relevant articles were performed through Pub Med, HighWire, and Science Direct using the keywords "alpha-1-antitrypsin", "liver diseases", "hepatocellular carcinoma", "SERPINA1". Articles published until 2011 were reviewed. Results: Epidemiology studies revealed that severe A1ATD is a significant risk factor for cirrhosis and HCC unrelated to the presence of HBV or HCV infections. However, predisposition to HCC in moderate A1ATD is rare, and probably happens in combination with HBV and/or HCV infections or other unknown risk factors. It is assumed that accumulation of polymers of A1ATD variants in endoplasmic reticulum of hepatocytes leads to damage of hepatocytes by gain-of-function mechanism. Also, increased level of A1AT was recognized as diagnostic and prognostic marker of HCC. Conclusions: Clarification of a carcinogenic role for A1ATD and identification of pro-inflammatory or some still unknown factors that lead to increased susceptibility to HCC associated with A1ATD may contribute to a better understanding of hepatic carcinogenesis and to the development of new drugs.
PB  - Kowsar Publ, Hoensbroek
T2  - Hepatitis Monthly
T1  - Alpha-1-Antitrypsin in Pathogenesis of Hepatocellular Carcinoma
VL  - 12
IS  - 10
DO  - 10.5812/hepatmon.7042
ER  - 
@article{
author = "Topić, Aleksandra and Ljujić, Mila and Radojković, Dragica",
year = "2012",
abstract = "Context: Alpha-1-antitrypsin (A1AT) is the most abundant liver-derived, highly polymorphic, glycoprotein in plasma. Hereditary deficiency of alpha-1-antitrypsin in plasma (A1ATD) is a consequence of accumulation of polymers of A1AT mutants in endoplasmic reticulum of hepatocytes and other A1AT-producing cells. One of the clinical manifestations of A1ATD is liver disease in childhood and cirrhosis and/or hepatocellular carcinoma (HCC) in adulthood. Epidemiology and pathophysiology of liver failure in early childhood caused by A1ATD are well known, but the association with hepatocellular carcinoma is not clarified. The aim of this article is to review different aspects of association between A1AT variants and hepatocellular carcinoma, with emphasis on the epidemiology and molecular pathogenesis. The significance of A1AT as a biomarker in the diagnosis of HCC is also discussed. Evidence Acquisitions: Search for relevant articles were performed through Pub Med, HighWire, and Science Direct using the keywords "alpha-1-antitrypsin", "liver diseases", "hepatocellular carcinoma", "SERPINA1". Articles published until 2011 were reviewed. Results: Epidemiology studies revealed that severe A1ATD is a significant risk factor for cirrhosis and HCC unrelated to the presence of HBV or HCV infections. However, predisposition to HCC in moderate A1ATD is rare, and probably happens in combination with HBV and/or HCV infections or other unknown risk factors. It is assumed that accumulation of polymers of A1ATD variants in endoplasmic reticulum of hepatocytes leads to damage of hepatocytes by gain-of-function mechanism. Also, increased level of A1AT was recognized as diagnostic and prognostic marker of HCC. Conclusions: Clarification of a carcinogenic role for A1ATD and identification of pro-inflammatory or some still unknown factors that lead to increased susceptibility to HCC associated with A1ATD may contribute to a better understanding of hepatic carcinogenesis and to the development of new drugs.",
publisher = "Kowsar Publ, Hoensbroek",
journal = "Hepatitis Monthly",
title = "Alpha-1-Antitrypsin in Pathogenesis of Hepatocellular Carcinoma",
volume = "12",
number = "10",
doi = "10.5812/hepatmon.7042"
}
Topić, A., Ljujić, M.,& Radojković, D.. (2012). Alpha-1-Antitrypsin in Pathogenesis of Hepatocellular Carcinoma. in Hepatitis Monthly
Kowsar Publ, Hoensbroek., 12(10).
https://doi.org/10.5812/hepatmon.7042
Topić A, Ljujić M, Radojković D. Alpha-1-Antitrypsin in Pathogenesis of Hepatocellular Carcinoma. in Hepatitis Monthly. 2012;12(10).
doi:10.5812/hepatmon.7042 .
Topić, Aleksandra, Ljujić, Mila, Radojković, Dragica, "Alpha-1-Antitrypsin in Pathogenesis of Hepatocellular Carcinoma" in Hepatitis Monthly, 12, no. 10 (2012),
https://doi.org/10.5812/hepatmon.7042 . .

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