Protein Aggregates in Heterozygous Alpha-1 Antitrypsin Phenotype Is a Marker for Progressive Disease

Alpha 1 antitrypsin deficiency (AATD) is a genetic disease caused by mutations in the SERPINA1 gene, leading to liver disease. This study investigates the role of heterozygous Pi∗Z (MZ) alleles and their histopathologic features in liver disease progression.

We extracted data from the Mayo Data Explorer, including noninvasive elastography and diagnostic pathology reports from patients with known AATD phenotypes. We analyzed clinical indices, histopathological features, and transplant-free survival in MZ individuals across Mayo Clinic sites in MN, WI, AZ, and FL.

Out of 30,869 individuals with defined phenotypes, 2259 had elastography data. MZ individuals (n = 132) showed higher median liver stiffness (7 kPa) compared to MM individuals (6 kPa, P = .026) and a higher proportion had advanced fibrosis (37% vs 28.4%, P = .035). In biopsies from 409 MZ individuals, periodic acid-Schiff positive diastase resistant (PAS-D) globules were present in 28%, correlating with advanced fibrosis and reduced transplant-free survival (617 vs 1289 days, P < .001). Multivariable analysis identified PAS-D globules, age, and advanced fibrosis as independent predictors of decreased transplant-free survival.

MZ individuals exhibit higher baseline liver stiffness and advanced fibrosis. The presence of PAS-D globules in liver biopsies is associated with more advanced disease and shorter transplant-free survival, highlighting the potential need for targeted therapies in this population.