Alpha-1-antitrypsin deficiency: Biochemistry and clinical manifestations

Alpha-1-antitrypsin (α1-AT) deficiency is a well known cause of emphysema in adults. A subgroup of deficient individuals develops liver injury during infancy and childhood. In fact, it is the most common cause of liver disease in children. Although lung injury is due to the decrease in α1-AT function in the lung, allowing uninhibited elasto-lytic destruction of its connective tissue integrity, liver injury is probably due to retention of the mutant α1-AT molecule in the endoplasmic reticulum (ER) of liver cells. Recent studies have shown that the mutant α1-AT molecule polymerizes in the ER by a novel loop-sheet insertion mechanism. Other recent studies show that the subgroup of deficient individuals is susceptible to liver injury by virtue of unlinked genetic traits and/or environmental factors which interfere with degradation of the mutant α1-AT molecules within the ER.