Author information

¹Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Diego, San Diego, California, USA.

²Department of Medicine, University of Florida, Gainesville, Florida, USA.

³Pediatrics and Biochemistry, St. Louis University School of Medicine, Saint Louis, Missouri, USA.

⁴Pacific Rim Pathology Lab, San Diego, California, USA.

⁵Division of Pulmonary, Critical Care & Sleep Medicine, University of Florida College of Medicine, Gainesville, Florida, USA.

⁶Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.

⁷Department of Medicine, Columbia University Medical Center, New York, New York, USA.

⁸Target RWE, Durham, North Carolina, USA.

⁹PathAI Inc, Boston, Massachusetts, USA.

¹⁰Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.

¹¹Medical University of South Carolina, Charleston, South Carolina, USA.

¹²University of California San Diego, San Diego, California, USA.

¹³Indiana University School of Medicine, Indianapolis, Indiana, USA.

¹⁴Inova Liver Disease Services, Fairfax, Virginia, USA.

¹⁵University of Southern Denmark, Odense, Denmark.

¹⁶University of Birmingham, Birmingham, UK.

¹⁷University Hospital RWTH Aachen, Healthcare Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Aachen, Germany.

Abstract

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. Such advances will help patients by enabling risk stratification and personalised surveillance, along with streamlining the development process for novel therapies.

Conclusions: This inaugural forum generated a list of recommendations to address unmet needs in the field of AATLD.