Background and aims: Alpha-1 antitrypsin (AAT) is a product of SERPINA1 gene mainly expressed by hepatocytes. Clinically relevant mutations in the SERPINA1 gene, such as Z (Glu342Lys), results in an expression of misfolded AAT protein having high propensity to polymerize, accumulate in hepatocytes and thus to enhance a risk for hepatocyte damage and subsequent liver disease. So far, the relationship between the Z-AAT accumulation and liver cell damage remains not completely understood. We present three-dimensional organoid culture systems, as a novel tool for modeling Z-AAT-related liver diseases. Methods: We have established liver organoids from liver biopsies of patients with homozygous (ZZ) and heterozygous (MZ) deficiency and normal (MM) genotypes of AAT. The features of these organoid models were characterized by analyzing AAT protein secretion and intracellular aggregation in MZ and ZZ genotypes as well as SERPINA1 expression in differentiated cultures. Results: Transcriptional analysis of differentiated organoid cultures by RNA-Seq showed hepatocyte-specific gene expression profile. Genes, such as ALB, APOB, CYP3A4 and SERPINA1, were validated and confirmed through quantitative-PCR analysis. The organoids from MZ and ZZ cases showed intracellular aggregation and lower secretion of AAT protein, and lower expression of ALB and APOB, as typically seen in hepatocytes from Z-AAT deficiency patients. Furthermore, organoids responded to external stimulus. Treatment with oncostatin M, a well-known inducer of SERPINA1, increased expression of the full-length transcripts (AAT-1C) as well as the short transcript of AAT (AAT-ST1C4). Conclusions: Liver organoid model recapitulates the key features of Z-AAT deficiency and provides a useful tool for disease modeling.

Background.: One method for increasing the donor pool for orthotopic liver transplantations (OLTs) is to use uncontrolled donation after circulation death (uDCDs). Methods.: From January 2006 to December 2016, we performed 75 OLTs using uDCD livers. The control group comprised a sample of 265 OLTs using livers of donations after brain death (DBDs). A comparative study was performed. Results.: Of 256 potential uDCD donors cannulated, 75 (29.3%) livers were accepted for OLT. The amount of hemoderivatives transfused was significantly higher in the uDCD group. The rate of primary nonfunction was also significantly higher (P = 0.031) in uDCD recipients (8%) than DBD recipients (1.5%). The overall rate of biliary complications was significantly higher (P = 0.001) in uDCD recipients (23 cases, 30.6%) than DBD recipients (28 cases, 10.6%). In the uDCD group, 1-, 3-, and 5-year patient survival rates were 82.7%, 73%, and 71.5%, respectively; in the DBD group, they were 89%, 83.7%, and 78.8%, respectively (P = 0.180). In the uDCD group, 1-, 3-, and 5-year graft survival rates were 73.3%, 65.1%, and 63.6%, respectively; in the DBD group, they were 87.1%, 81.9%, and 76.5%, respectively (P = 0.013). Multivariate analysis showed that independent risk factors for patient and graft survival were intraoperative transfusion of >6 units of packed red blood cell concentrates and recipients who were older than 60 years. Conclusions.: Although graft survival is significantly lower using uDCD livers, 5-year patient survival in recipients of DBD and uDCD livers is similar. After careful selection, the livers of uDCD can be selectively used for OLT.