Alpha-1 antitrypsin deficiency: an update on clinical aspects of diagnosis and management

Abstract

Clinical heterogeneity has been demonstrated in alpha-1 antitrypsin deficiency (AATD), such that clinical suspicion plays an important role in its diagnosis. The PiZZ genotype is the most common severe deficiency genotype and so tends to result in the worst clinical presentation, hence it has been the major focus of research. However, milder genotypes, especially PiSZ and PiMZ, are also linked to the development of lung and liver disease, mainly when unhealthy behaviors are present, such as smoking and alcohol use. Monitoring and managing AATD patients remains an area of active research. Lung function tests or computed tomography (CT) densitometry may allow physicians to identify progressive disease during follow up of patients, with a view to decision making about AATD-specific therapy, like augmentation therapy, or eventually surgical procedures such as lung volume reduction or transplant. Different types of biological markers have been suggested for disease monitoring and therapy selection, although most need further investigation. Intravenous augmentation therapy reduces the progression of emphysema in PiZZ patients and is available in many European countries, but its effect in milder deficiency is less certain. AATD has also been suggested to represent a risk factor and trigger for pulmonary infections, like those induced by mycobacteria. We summarize the last 5–10 years’ key findings in AATD diagnosis, assessment, and management, with a focus on milder deficiency variants.

A Review of Alpha-1 Antitrypsin Binding Partners for Immune Regulation and Potential Therapeutic Application

“…Interim results from the AROAAT2002 study (NCT03946449) demonstrated that ARO-AAT was not only well tolerated but also capable of inhibiting Z-AAT expression, reducing intrahepatic Z-AAT accumulation to allow the clearance of Z-AAT polymers and improving liver fibrosis. Phase II trials of AROAAT2001 (SEQUOIA) is underway to evaluate the safety, efficacy and tolerability of multiple doses of the investigational product, ARO-AAT, administered subcutaneously to participants with AATD (NCT03945292) [ 110 ]. As of December 2021, the ESTRELLA trial is in the recruitment phase to investigate an alternative RNAi drug named Belcesiran or DCR-A1AT in patients with AATD-associated liver disease (NCT04764448).…”

Predicting Clinical Outcomes of Alpha-1 Antitrypsin Deficiency-Associated Liver Disease Using a Stacking Ensemble Machine Learning Model Based on UK Biobank Data

“…1 The PiZZ genotype is known as the most common de ciency genotype and tends to result in the worst clinical presentation. 4 Data from real-world clinical practice has shown that over 90% of AATD is due to the PiZZ genotype. 5 The milder genotypes such as PiSZ and PiMZ are also linked to the development of lung and liver disease, mainly when unhealthy behaviors such as smoking or alcohol use are present.…”

“…5 The milder genotypes such as PiSZ and PiMZ are also linked to the development of lung and liver disease, mainly when unhealthy behaviors such as smoking or alcohol use are present. 4 Clinical research shows approximately 40% of adult AATD patients dying of all causes had cirrhosis at the time of death, 6 and approximately 15% of adult patients with AATD-associated liver disease (AATD-LD) required liver transplantation. 7 There is no approved therapy for AATD-LD.…”

A stacking ensemble machine learning model to predict alpha-1 antitrypsin deficiency-associated liver disease clinical outcomes based on UK Biobank data

“…If the AAT proteins are malformed or deficient, it may lead to predisposition for obstructive pulmonary disease and/or liver disease 1 . The PiZZ genotype is known as the most common deficiency genotype and tends to result in the worst clinical presentation 4 . Data from real-world clinical practice has shown that over 90% of AATD is due to the PiZZ genotype 5 .…”

“…Data from real-world clinical practice has shown that over 90% of AATD is due to the PiZZ genotype 5 . The milder genotypes such as PiSZ and PiMZ are also linked to the development of lung and liver disease, mainly when unhealthy behaviors such as smoking or alcohol use are present 4 . Clinical research shows approximately 40% of adult AATD patients dying of all causes had cirrhosis at the time of death 6 , and approximately 15% of adult patients with AATD-associated liver disease (AATD-LD) required liver transplantation 7 .…”