Pavel Strnad, MD: The Underlying Molecular Mechanisms of PI*ZZ AATD Liver Disease

A recent study has identified a conserved serum proteomics signature between patients with the Pi*ZZ genotype of alpha-1 antitrypsin deficiency (AATD) and patients with chronic liver diseases due to other etiologies.

The research was presented at The Liver Meeting 2024 from the American Association for the Study of Liver Diseases (AASLD) in San Diego, California, by Pavel Strnad, MD, a full professor and senior physician at University Hospital Rheinisch–Westfälisch Technische Hochschule Aachen in Germany, and has the potential to aid the diagnosis, treatment response, and monitoring of AATD-associated liver disease.

“Classic alpha-1 antitrypsin deficiency is caused by a homozygous mutation called Pi*ZZ mutation, also known as Pi*ZZ genotype. This genotype leads to a retention of alpha-1 antitrypsin in the liver, and this retention leads to a gain of function liver injury,” Strnad explained to HCPLive.

Citing a lack of understanding of the underlying molecular mechanisms of AATD-liver disease, Strnad and colleagues leveraged population-level data from the UK Biobank project to identify a Pi*ZZ genotype-associated proteomic profile and compare it with signatures associated with chronic liver diseases. Specifically, the UK Biobank Pharma Proteomics Project includes plasma samples from 54,219 participants and 2923 proteins profiled by the Olink platform. Existing genotype array data were used to identify subjects with the Z (rs28929474) allele.

Using logistic regression, investigators identified differentially expressed proteins (DEPs) among genotypes and between subjects with versus without a disease diagnosis. DEPs were then integrated with single nucleus RNAseq data to map potential source cells in the liver.

Overall, 17/141 subjects with the Pi*ZZ genotype had proteomic data and were analyzed. Comparison of the Pi*ZZ and reference (Pi*MM; n = 39,265) genotypes resulted in the identification of 97 DEPs, and enrichment for lysosome and elastin fiber formation pathways.

Investigators noted these DEPs primarily mapped to hepatocytes, cholangiocytes, immune cells, endothelial cells, and mesenchymal cells, with many mesenchymal cell-enriched DEPs being extracellular matrix components associated with hepatic stellate cell activation and liver damage. The Pi*ZZ signature was most similar to liver disease diagnosis code signatures in the UK Biobank dataset and showed high similarity to cirrhosis.

“Basically, this proteomic analysis nicely depicts the processes which we know are occurring in this disease and that can potentially serve as a source of biomarkers,” Strnad explained. “Part of the work was to compare the signature that we see in the ZZ patients to the changes which we see with investigational compounds, where you can take a drug which is in development and see what this drug does in the serum or in the plasma and compare to what we see the disease itself is doing. If you can reverse most of the disease-related changes you see in this publicly available database by an investigational compound, this gives you an additional hint that this compound is helping the patients.”

Reference

^{Strnad P, Smith E, Hou R, et al. The plasma proteomic profile of subjects with the SERPINA1 Pi*ZZ genotype correlates with liver disease signatures: an analysis of population-level data from the UK Biobank Proteomics Project. Paper presented at: AASLD’s The Liver Meeting 2024. San Diego, California. November 15-19, 2024.}