Topic Aleksandra, Ljujic Mila, Radojkovic Dragica
University of Belgrade, Faculty of Pharmacy, Department of Medical Biochemistry, Belgrade, Serbia.
Hepat Mon. 2012 Oct;12(10 HCC):e7042. doi: 10.5812/hepatmon.7042. Epub 2012 Oct 30.
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.
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.
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.
Clarification of a carcinogenic role for A1ATD and identification of proinflammatory 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.
α1抗胰蛋白酶（A1AT）是血浆中最丰富的肝脏来源的、高度多态的糖蛋白。血浆中α1抗胰蛋白酶遗传性缺乏（A1ATD）是A1AT突变体聚合物在肝细胞和其他产生A1AT的细胞内质网中积累的结果。A1ATD的临床表现之一是儿童期肝病以及成年期肝硬化和/或肝细胞癌（HCC）。由A1ATD导致的儿童早期肝功能衰竭的流行病学和病理生理学已为人熟知，但与肝细胞癌的关联尚不清楚。本文旨在综述A1AT变体与肝细胞癌之间关联的不同方面，重点是流行病学和分子发病机制。还讨论了A1AT作为HCC诊断生物标志物的意义。
通过使用关键词“α1抗胰蛋白酶”、“肝脏疾病”、“肝细胞癌”、“SERPINA1”在PubMed、HighWire和Science Direct上搜索相关文章。对截至2011年发表的文章进行了综述。
流行病学研究表明，严重的A1ATD是肝硬化和HCC的重要危险因素，与HBV或HCV感染无关。然而，中度A1ATD患者患HCC的易感性罕见，可能与HBV和/或HCV感染或其他未知危险因素共同发生。据推测，A1ATD变体聚合物在肝细胞内质网中的积累通过功能获得机制导致肝细胞损伤。此外，A1AT水平升高被认为是HCC的诊断和预后标志物。
阐明A1ATD的致癌作用以及确定导致与A1ATD相关的HCC易感性增加的促炎或一些仍未知的因素，可能有助于更好地理解肝癌发生机制并开发新药。
