Resolution of the circulating pathogenic phenotype of alpha-1 antitrypsin deficiency following liver transplantation

Alpha-1 antitrypsin (AAT) is a protease inhibitor, normally found at a high concentration in monomeric form in the circulation from where it protects the lung tissue from proteolytic damage. Pathogenic variants of AAT self-assemble into flexible polymer chains that undergo toxic accumulation in the liver, underlying the development of liver disease; the corresponding deficiency in the circulation results in susceptibility to emphysema. AAT polymers formed by these variants are also detectable in the plasma; this study evaluated the dynamics of circulating monomeric and polymeric AAT after correction of the deficiency state with liver transplantation in four individuals homozygous for the Z deficiency allele (Glu342Lys). The resolution of the pathological circulating AAT phenotype was characterised by analysis of blood samples taken pre- and post-liver transplant using a panel of conformer-specific monoclonal antibodies and a novel ELISA with enhanced sensitivity for AAT polymers. Circulating wild-type M AAT, produced by the allograft liver, increased with a half-timeof 7-39 h, attaining a putative 'protective' threshold level 4-55 h post-transplant. Pre-transplant circulating polymer levels ranged from 5-26 μg/mL and declined post-surgery with a half-time of 2-9 h, levels were comparable to those of wild-type M AAT plasma when repeated >200 days post-transplant. The glycosylation profile of liver- and plasma-derived polymers and their progressive disappearance from circulation is consistent with their origin in, and canonical secretion from, the liver. To our knowledge this is the first post-transplant evaluation of the hybrid conformational profile of endogenous and donor tissue-derived AAT.