JEFFREY H. TECKMAN, DONGFENG QU, AND DAVID H. PERLMUTTER a1-Antitrypsin (a1-AT) deficiency is the most common ge- Since we last reviewed this subject for HEPATOLOGY in 1991, 27 there have been several important advances in our netic cause of liver disease in children and the most frequent genetic diagnosis for which children undergo liver trans-understanding of pathogenesis. First, Sveger has reported on the outcome of the Swedish nationwide newborn screening plantation. 1 It is also the most common genetic cause of pulmonary emphysema in adults. Homozygous a1-ATZ pheno-study for a1-AT deficiency after 18 years. 28 This is the only prospective, unbiased study of the deficiency and shows that type (PiZZ) a1-AT deficiency affects 1 in 1,600 to 1 in 1,800 live births in almost every Northern European and US popu-only Ç10% of individuals with homozygous PiZZ a1-AT deficiency have, or have had, clinically significant liver injury. lation that has been examined. 2, 3 The a1-AT molecule is an Ç55-kd serum glycoprotein. Its This study provides further evidence that only a subgroup of these individuals develop liver injury. Second, a series of major physiological function is the inhibition of the destructive neutrophil proteases elastase, cathepsin G, and protein-studies on the structure of a1-AT and related members of the serpin supergene family have provided a more detailed ase 3. It is an acute phase protein in that its plasma concentration increases three-to fivefold during the host response understanding of why the a1-ATZ molecule is retained in the ER of liver cells. 29 These studies provide direct evidence for to tissue injury/inflammation. It is predominantly expressed by hepatocytes in the liver but is also synthesized by a num-an abnormality in the folding of a1-ATZ in the ER and suggest that the abnormally folded intermediate undergoes polymerber of diverse extrahepatic cell types and tissues. 4-9 The mutant a1-AT molecule in the common type of a1-AT ization in the ER. Third, a series of studies on the cell biological fate of a1-ATZ have provided evidence that the subgroup deficiency, PiZZ, is characterized by a single nucleotide substitution of lys for glu 342. 10-13 There is a selective decrease of a1-AT–deficient individuals which develop liver disease (‘‘susceptible hosts’’) have both an abnormality in the folding in the secretion of a1-AT, with the abnormal protein accumulating in the endoplasmic reticulum (ER). 14-21 The defect is of the a1-AT molecule, the intrinsic abnormality of a1-ATZ, and an alteration in the ER degradation pathway, a fundanot specific for liver cells, as it also affects extrahepatic sites of a1-AT synthesis such as macrophages14 and transfected mental quality control apparatus of the cell designed to degrade abnormally folded or unassembled polypeptides. 30-32 cell lines. 17-22 Site-directed mutagenesis studies have shown that this single amino acid substitution is sufficient to pro-Presumably, this results in a greater accumulation of the hepatotoxic a1-ATZ molecule in the ER and, therefore, a ducethecellulardefect. 17-22 Once translocated into the lumen of the ER, the mutant a1-AT protein is unable to traverse higher likelihood of liver injury. We will devote most of this review to the discussion of these three advances. the remainder of the secretory pathway presumably because it is abnormally folded.