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

Area of Science:

• Genetics
• Hepatology
• Pathology

Background:

• Alpha 1 antitrypsin deficiency (AATD) is a genetic disorder linked to SERPINA1 gene mutations.
• AATD can lead to significant liver disease, with varying severity based on genetic Z allele presence.

Purpose of the Study:

• To investigate the impact of heterozygous Pi*Z (MZ) alleles on liver disease progression in AATD.
• To identify histopathologic features associated with liver disease severity and outcomes in MZ individuals.

Main Methods:

• Utilized data from the Mayo Data Explorer, including elastography and pathology reports.
• Analyzed clinical data, histopathological findings (PAS-D globules), and transplant-free survival in MZ individuals.

Main Results:

• MZ individuals exhibited higher liver stiffness and advanced fibrosis compared to MM individuals.
• Periodic acid-Schiff positive diastase resistant (PAS-D) globules were found in 28% of MZ biopsies, correlating with advanced fibrosis.
• PAS-D globules, age, and advanced fibrosis independently predicted decreased transplant-free survival.

Conclusions:

• Heterozygous MZ alleles are associated with increased liver stiffness and fibrosis.
• The presence of PAS-D globules in liver biopsies is a significant predictor of poorer outcomes in AATD patients.
• Findings suggest a need for targeted therapies for MZ individuals with AATD-related liver disease.