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PERSPECTIVE ARTICLE

Alpha 1-antitrypsin deficiency and chronic liver disease in adults: Molecular basis and clinical aspects

Amedeo Lonardo1* ,  Ralf Weiskirchen2*
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1 Department of Internal Medicine, Azienda Ospedaliero-Universitaria of Modena, Modena, Italy
2 Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, Aachen, Germany
GPD, 025220041 https://doi.org/10.36922/GPD025220041
Received: 26 May 2025 | Revised: 27 July 2025 | Accepted: 29 August 2025 | Published online: 22 September 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Alpha 1-antitrypsin deficiency (A1ATD) is a codominant genetic disorder primarily caused by PiZ mutations in the serpin family A member 1 (SERPINA1) gene. A1ATD is typically associated with the early-onset lung emphysema. However, the misfolding and accumulation of alpha 1-antitrypsin (A1AT) in hepatocytes can also lead to chronic liver disease (CLD). This perspective paper discusses the genetic and molecular factors, the epidemiological features, and clinico-pathological spectrum of A1ATD-related CLD in adults. Emphasis is given to steatosis, cirrhosis, and primary liver cancer, the risks of which critically depend on the PiZ genotype. We discuss the diagnostic strategy, including non-invasive assessment of liver fibrosis. While augmentation therapy plays a role in treating the pulmonary manifestations of A1ATD, this approach carries no benefit for the liver, and early detection is critical to slow the progression of CLD. New approaches comprise gene-editing, innovative pharmacological chaperones, and personalized medicine that target the underlying protein misfolding defect. Enhancing early diagnosis and refining precision treatment strategies promise to significantly improve clinical outcomes.

Graphical abstract
Keywords
Cirrhosis
Fibrosis
Gene defect
Genetic disease
Liver
Lung
Steatosis
Primary liver cancer
Funding
None.
Conflict of interest
The authors declare that they have no competing interests.
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