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.
Lonardo et al. (Mon,) studied this question.