Alpha-1 Antitrypsin Deficiency-Mediated Liver Toxicity: Why Do Some Patients Do Poorly? What Do We Know So Far?

Alpha-1 antitrypsin deficiency (AATD) is a rare genetic disease caused by mutations in the SERPINA1 gene and is associated with a decreased level of circulating alpha-1 antitrypsin (AAT). Among all the known mutations in the SERPINA1 gene, homozygous for the Z allele is well-known to result in both lung and liver disease. Unlike the lung injury that occurs in adulthood with the environment (notably, tobacco) as a co-factor, the hepatic damage is more complicated. Despite a common underlying gene mutation, the liver disease associated with AATD presents a considerable variability in the age-of-onset and severity, ranging from transient neonatal cholestasis (in early childhood) to cirrhosis and liver cancer (in childhood and adulthood). Given that all the cofactors- genetics and/or environmental- have not been fully identified, it is still impossible to predict which individuals with AATD may develop severe liver disease. The discovery of these modifiers represents the major challenge for the detection, diagnosis, and development of new therapies to provide alternative options to liver transplantation. The aim of this current review is to provide an updated overview of our knowledge on why some AATD patients associated with liver damage progress poorly. JCOPDF