Review article: New developments in biomarkers and clinical drug development in alpha‐1 antitrypsin deficiency‐related liver disease

作者：Rohit Loomba, Ginger Clark, Jeffrey Teckman, Veeral Ajmera, Cynthia Behling, Mark Brantly, David A. Brenner, Jeanine D’Armiento, Michael Fried, Janani Iyer, Mattias Mandorfer, Don C. Rockey, Monica A. Tincopa, Raj Vuppalanchi, Zobair M. Younossi, Aleksander Krag, Alice Turner, Pavel Strnad · 发表于：Alimentary Pharmacology & Therapeutics · 年份：2024 · DOI：10.1111/apt.17967 · 被引用次数：11 · 研究领域：Protease and Inhibitor Mechanisms、Rheumatoid Arthritis Research and Therapies、Alkaline Phosphatase Research Studies

BACKGROUND: Alpha-1 antitrypsin liver disease (AATLD) occurs in a subset of patients with alpha-1 antitrypsin deficiency. Risk factors for disease progression and specific pathophysiologic features are not well known and validated non-invasive assessments for disease severity are lacking. Currently, there are no approved treatments for AATLD. AIMS: To outline existing understanding of AATLD and to identify knowledge gaps critical to improving clinical trial design and development of new treatments. METHODS: This report was developed following a multi-stakeholder forum organised by the Alpha-1 Antitrypsin Deficiency Related Liver Disease Expert Panel in which experts presented an overview of the available literature on this topic. RESULTS: AATLD results from a 'gain of toxic function' and primarily manifests in those with the homozygous Pi*ZZ genotype. Accumulation of misfolded 'Z' AAT protein in liver cells triggers intracellular hepatocyte injury which may ultimately lead to hepatic fibrosis. Male gender, age over 50 years, persistently elevated liver tests, concomitant hepatitis B or C virus infection, and metabolic syndrome, including obesity and type 2 diabetes mellitus, are known risk factors for adult AATLD. While the gold standard for assessing AATLD disease activity is liver histology, less invasive measures with low intra- and inter-observer variability are needed. Measurement of liver stiffness shows promise; validated thresholds for staging AATLD are in development...