ArticleChronic obstructive pulmonary diseases (Miami, Fla.)2020
The Alpha-1 Antitrypsin Polymer Load Correlates With Hepatocyte Senescence, Fibrosis Stage and Liver-Related Mortality.
Article in Chronic obstructive pulmonary diseases (Miami, Fla.), 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 20 citations in OpenAlex.
- Dual SORT LNPs for multi-organ base editing.Nature biotechnology · 2026Article
- From Birth to Midlife-Liver Function, Fibrosis and Mortality in Individuals with Severe Alpha-1-Antitrypsin Deficiency Identified by Neonatal Screening.Journal of clinical medicine · 2026Article
- Characterization of alpha-1 antitrypsin in a Pi∗ZZ patient with emphysema: a case report.Respiratory medicine case reports · 2025Article
- Transient growth factor expression via mRNA in lipid nanoparticles promotes hepatocyte cell therapy in mice.Nature communications · 2024Article
- NAFLD and AATD Are Two Diseases with Unbalanced Lipid Metabolism: Similarities and Differences.Biomedicines · 2023Review
- Role of Hepatocyte Senescence in the Activation of Hepatic Stellate Cells and Liver Fibrosis Progression.Cells · 2022Article
- The emerging role of proteases in αERJ open research · 2021Review
- Association between circulating alpha-1 antitrypsin polymers and lung and liver disease.Respiratory research · 2021Article
- Utility of Transient Elastography for the Screening of Liver Disease in Patients with Alpha1-Antitrypsin Deficiency.Journal of clinical medicine · 2021Article
- Serum Levels of Glutamate-Pyruvate Transaminase, Glutamate-Oxaloacetate Transaminase and Gamma-Glutamyl Transferase in 1494 Patients with Various Genotypes for the Alpha-1 Antitrypsin Gene.Journal of clinical medicine · 2020Article
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Authors and funding
7 authors at 6 institutions in 3 countries.
Funding
Abstract
backgroundAlpha-1 antitrypsin deficiency (AATD) is an important, inherited cause of chronic liver disease. Marked variation in fibrosis stages in patients with homozygous deficiency and those factors that determine whether heterozygous carriers develop liver fibrosis, remain unexplained. Murine studies implicate polymerized alpha-1 antitrypsin (AAT) within hepatocytes as pathogenic. AIMS AND
methodsThe relationship between the quantity of polymerized AAT within hepatocytes (polymer load), stage of hepatic fibrosis and liver-related clinical outcomes (death, evolution to hepatocellular carcinoma, or need for liver transplantation) were investigated using liver tissue from 92 patients at first presentation with either homozygous or heterozygous AATD. Further tissue-based studies were undertaken to determine if polymerized AAT was associated with failure of cell cycle progression, accelerated aging or hepatocyte senescence by immunohistochemical analysis.
resultsThe AAT polymer load correlated closely with hepatic fibrosis stage and long-term clinical outcome, independent of homozygous or heterozygous status. AAT polymers within hepatocytes correlated closely with failure of cell cycle progression assessed using cell cycle phase markers, accelerated aging manifest as shortened telomeres and other markers consistent with hepatocyte senescence manifest as the presence of nuclear p21 expression and enlarged nuclei. The proportion of p21 positive hepatocytes or hepatocytes with enlarged nuclei correlated with hepatic fibrosis stage and the long-term clinical outcome.
conclusionThese data suggest that accumulation of AAT polymers within hepatocytes drives senescence. Quantitation of both the AAT polymer load or hepatocyte senescence markers correlated with hepatic fibrosis stage and the long-term clinical outcome. Either or both could be considered markers of disease severity and treatment response in clinical trials.
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