Heterozygous alpha-1 antitrypsin deficiency as a co-factor in the development of chronic

Alpha-1 antitrypsin (A1AT) is an acute-phase protein that is produced in liver cells. A1AT deficiency is a hereditary disease which is defined by the hepatic production of an abnormal protein that can not be released into the plasma. This leads to deficiency of plasma A1AT and subsequently to an impaired protection against proteases, resulting in pulmonary disease. Accumulation of the abnormal protein in hepatocytes can lead to liver damage. serum level measurement, phenotyping and liver biopsy can be used for establishing the diagnosis. Homozygous A1AT deficiency can cause neonatal hepatitis; in adults end-stage liver disease, cirrhosis and hepatocellular carcinoma can develop. There are strong arguments to consider heterozygous A1AT deficiency as an important co-factor in the aetiology of chronic liver disease. studies have shown that A1AT heterozygosity can be considered a modifier for hepatitis C virus, end-stage liver disease, cirrhosis and hepatocellular carcinoma. The accumulation of A1AT in the hepatocytes occurs more profoundly in a diseased liver, and as a consequence it affects the natural course of the liver disease. Therapeutic options include augmentation therapy (infusion of purified human plasma A1AT) in pulmonary disease; in end-stage liver disease liver transplantation is an option. for the future, other interventions such as gene therapy or strategies to inhibit polymerisation are promising. K E Y W o r d s Alpha-1-antitrypsin deficiency, hepatocellular carcinoma, heterozygosity, liver disease i N T r o d U C T i o N Alpha-1 antitrypsin (A1AT) is an acute-phase protein that is produced in liver cells. It is released into the plasma in response to an inflammatory stimulus. A1AT deficiency is a hereditary disease that is defined by the hepatic production of an abnormal protein that can not completely be released into the plasma. This leads to deficiency of plasma A1AT and subsequently to an impaired protection of the lungs against proteases. This results in pulmonary emphysema; hepatic accumulation of the abnormal protein can lead to chronic liver disease. This review gives an update of the present knowledge on partial A1AT deficiency in relation to various liver diseases. G E N E T i C s A N d ( P A T H o ) P H Y s i o l o G Y The A1AT molecule is a serum glycoprotein acting as an acute-phase protein. It is released during inflammatory processes from the hepatocyte, which results in increased plasma concentrations. The major physiological function © 2007 Van Zuiden Communications B.V. All rights reserved. r E V i E W Heterozygous alpha-1 antitrypsin deficiency as a co-factor in the development of chronic liver disease: a review K.F. Kok, P.J. Wahab, R.H. J. Houwen, J.P.H. Drenth, R.A. de Man, B. van Hoek, J.W. R. Meijer, F.L. A. Willekens, R.A. de Vries Departments of Hepato-Gastroenterology, Pathology and Clinical Chemistry, Rijnstate Hospital, Arnhem, the Netherlands, Department of Paediatric Gastroenterology, Wilhelmina Children’s Hospital/University Medical Centre Utrecht, the Netherlands, Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands, Department of Hepato-Gastroenterology, Erasmus MC Rotterdam, the Netherlands, Department of Gastroenterology and Hepatology, Leiden University Medical Centre, the Netherlands, corresponding author (presently at ): e-mail: karinkok@hetnet.nl J.P.H. Drenth was not involved in the handling and review process of this paper.