Pathophysiologically, accumulation of misfolded polymerized alpha-1 antitrypsin protein within the endoplasmic reticulum (ER) of hepatocytes is considered the main mechanism (i.e., toxic gain-of-function/proteotoxicity) promoting liver disease in these patients.[2], [3], [4] In contrast, the deficiency of circulating alpha-1 antitrypsin (i.e., loss-of-function) is the central mechanism underlying emphysema formation, which is the other major manifestation of AATD. This evidence concerns the gene SERPINA1 and alpha 1-antitrypsin deficiency.