Biomarker, Treatment Development Could Help Address Unmet Need in AATD-Related Liver Disease

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Using available literature, the review assesses our current understanding of AATD, emerging biomarkers, and the future of drug development.

A recent review article is providing clinicians with an overview of the latest advancements in biomarkers and clinical drug development in the context of alpha-1 antitrypsin deficiency (AATD)-related liver disease.1

Developed following a multi-stakeholder forum organized by the Alpha-1 Antitrypsin Deficiency Related Liver Disease Expert Panel, the review used available literature to examine the current understanding of the disease, highlight emerging biomarkers, and explore strategies for clinical drug development.1

“As the field gathers momentum, forums such as this will galvanise the community in its drive to improving the lives of people with AATLD around the world,” Rohit Loomba, MD, MHSc, chief of the division of gastroenterology and hepatology at the University of California at San Diego, and colleagues wrote.1

AATD occurs most frequently in individuals of Northern or Central European descent, affecting about 100,000 people in the US. However, most patients with AATD go unrecognized due to the fact that the disorder is highly underdiagnosed, with estimates suggesting that just 10% of the estimated 100,000 cases have received a diagnosis.2

AATD-related liver disease is a manifestation of the ‘gain of abnormal function’ that results from the accumulation of Z-AAT in liver cells, triggering intracellular injury that may lead to fibrosis, cirrhosis, liver transplant, and death. The Pi*ZZ genotype predisposes patients to advanced liver disease, while the Pi*MZ genotype is primarily disease-modifying, linked to increased disease severity and a more progressive course in patients with other liver illnesses.1

Compared to AATD-related lung disease, timely diagnosis of AATD-related liver disease is even less likely, potentially leading to poorer outcomes for these patients. Investigators described factors potentially contributing to this delay in the diagnosis of AATD liver disease, including low disease awareness, poor adherence to testing recommendations, the minimal signs and symptoms associated with mild and moderate liver disease, and the need for biopsy for a definitive diagnosis of AATLD.1

Identifying Pi*ZZ individuals who are at risk for developing AATD liver disease is an ongoing process, hindered by the lack of a clear and consistent definition of what constitutes AATD liver disease. Studies have consistently identified male gender, age over 50 years, repeated elevated liver function tests, hepatitis virus infection, obesity, metabolic syndrome, and diabetes as factors associated with an increased risk of developing AATD-associated liver disease in adulthood. However, further characterization of individuals at risk for developing adult AATD liver disease and early identification of patients at risk or showing features associated with disease progression are needed to facilitate targeted use of diagnostic tests.1

Available tests to screen for and assess the progression of AATD liver disease are limited. Although it is widely regarded as the gold standard, liver histology is invasive, associated with well-known risks, and expensive. Investigators also pointed out the scoring of liver biopsies is often subject to individual pathologist interpretation of scoring guidelines, leading to high rates of pathologist variability.1

The review highlights the use of automated image analysis for quantifiable features as a potential future avenue for research, noting AI-powered image analysis algorithms may allow for precise, reproducible detection and quantitation of clinically important features of AATD liver disease. Such advances could improve the sensitivity and reproducibility of histological assessment, reducing the impact of pathologist scoring variability on measurements of intervention efficacy, and enabling statistical analysis planning and power calculations for clinical trials. However, these methods have not yet been approved by regulatory agencies.1

Alternative blood-based biomarkers are also an active area of research. Investigators highlighted liver stiffness measurement as “the most promising” of the recent advances in the noninvasive assessment of AATD liver disease. Specifically, they pointed to the lack of safety concerns, reasonable reproducibility, and high correlation between the technologies.1

Currently, the standard treatment for AATD-related lung disease is augmentation therapy with AAT derived from the plasma of healthy human donors. However, it has no proven effect on the ‘gain of toxic function’ responsible for AATD liver disease.1

Other treatments are in development, but investigators noted that like many other rare diseases, AATD liver disease faces numerous challenges with drug development, including a lack of precedent, poor understanding of the natural history of the disease, and small populations restricting study design and replication. Nonetheless, investigators pointed out the importance of learning from other liver diseases to identify efficiencies in the clinical development process that may be applied to emerging therapies in AATD liver disease.1


  1. Loomba R, Clark G, Teckman J, et al. Review article: New developments in biomarkers and clinical drug development in alpha-1 antitrypsin deficiency-related liver disease. Aliment Pharmacol Ther. 2024;59(10):1183-1195. doi:10.1111/apt.17967.
  2. NORD. Alpha-1 antitrypsin deficiency - symptoms, causes, treatment: Nord. National Organization for Rare Disorders. March 22, 2024. Accessed May 31, 2024.