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

Rohit Loomba ¹, Ginger Clark ², Jeff Teckman ³

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.

⁰Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Diego, San Diego, California, USA.

Alimentary Pharmacology & Therapeutics +

|

March 22, 2024

View abstract on PubMed

Summary

Alpha-1 antitrypsin liver disease (AATLD) lacks approved treatments and validated non-invasive assessments. Research is needed to understand risk factors and improve clinical trial design for this condition.

Area Of Science

Hepatology
Genetics
Internal Medicine

Background

Alpha-1 antitrypsin liver disease (AATLD) affects a subset of individuals with alpha-1 antitrypsin deficiency.
Current understanding of AATLD progression and pathophysiology is limited.
There are no approved treatments for AATLD, highlighting an unmet clinical need.

Purpose Of The Study

To review current knowledge of AATLD.
To identify critical knowledge gaps for improving clinical trial design.
To facilitate the development of novel therapeutic strategies for AATLD.

Main Methods

A multi-stakeholder expert forum was convened.
A comprehensive literature review on AATLD was presented.
Key unmet needs and research priorities were discussed.

Main Results

AATLD arises from a 'gain of toxic function' due to misfolded Z AAT protein accumulation in hepatocytes.
Risk factors include male gender, age >50, elevated liver tests, viral hepatitis, and metabolic syndrome.
Liver histology is the gold standard for assessment, but less invasive methods like liver stiffness measurement are under development.

Conclusions

The expert forum identified critical unmet needs in AATLD research.
Recommendations were generated to address these gaps.
Advancing non-invasive assessments and understanding risk factors are crucial for patient care and drug development.