CHEST 2025: Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder that continues to remain widely underdiagnosed, despite its serious implications for lung and liver health. Individuals with AATD face an increased risk of developing chronic obstructive pulmonary disease (COPD), emphysema, and liver cirrhosis. The challenge in identifying affected individuals stems from the complexity of the SERPINA1 gene mutations and the variability of alpha-1 antitrypsin (AAT) protein levels in the blood. Consequently, many patients remain undetected until significant organ damage has already occurred.
The importance of early and accurate diagnosis cannot be overstated. Traditional methods for AATD diagnosis, including serum AAT level testing and phenotyping, often fail to capture all cases, particularly in patients with rare or novel mutations. Inconsistent serum levels and overlapping clinical presentations with other respiratory or hepatic conditions add to the diagnostic challenges. Recognizing this gap, researchers and clinicians have been actively seeking a more reliable, comprehensive testing strategy to improve patient outcomes.
In response to these limitations, a new diagnostic algorithm has emerged, combining serum AAT measurements, genotyping of pathogenic single nucleotide polymorphisms (SNPs), and functional activity assays. This multifaceted approach promises not only to detect previously unrecognized cases but also to provide a more accurate clinical assessment of disease severity and progression. The findings of this innovative methodology were highlighted at the CHEST Annual Meeting 2025, offering hope for improved detection and management of AATD worldwide.
Understanding Alpha-1 Antitrypsin Deficiency (AATD)
AATD is caused by mutations in the SERPINA1 gene, which encodes alpha-1 antitrypsin, a protein crucial for regulating inflammation and protecting tissues from enzymatic damage. The deficiency or dysfunction of AAT can lead to uncontrolled inflammation, particularly in the lungs and liver.
Challenges with Traditional Diagnostic Methods
- Serum AAT Levels: Measuring AAT levels alone can be misleading because levels vary due to inflammation, infection, or liver function.
- Phenotyping Limitations: Traditional phenotyping may miss rare or novel SERPINA1 mutations.
- Incomplete Detection: Some patients with seemingly normal AAT levels may still carry pathogenic mutations that affect protein function.
These limitations have driven the need for a more precise diagnostic strategy that integrates multiple testing modalities.
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The New AATD Testing Algorithm
The new diagnostic algorithm is a stepwise approach designed to capture the broad spectrum of SERPINA1 mutations and evaluate the functional capacity of AAT.
Step 1: Genotyping
- Targets 19 SNPs and the normal M allele to identify common and rare pathogenic variants.
- Serves as the first-tier testing, efficiently detecting the majority of known AATD-associated mutations.
Step 2: Next-Generation Sequencing (NGS)
- If genotyping does not identify a mutation, NGS of SERPINA1 exons or whole gene sequencing (WGS) is employed.
- Allows detection of rare, novel, or splicing mutations that traditional tests may miss.
Step 3: Functional Activity Assays
- Measures anti-neutrophil elastase (anti-NE) activity, which reflects the functional capacity of AAT.
- Provides clinical relevance beyond serum protein levels, especially for mutations that impair function without affecting concentration.
Findings of the New Algorithm
The study highlighted several important discoveries:
- Previously Undetected Mutations: WGS identified a potential splicing mutation in the 3’ UTR of SERPINA1 in four subjects, three of whom were genotyped as MM (normal) and one as MmaltonS.
- Functional Variability: While serum AAT levels were moderately low, only one subject showed reduced anti-NE activity, indicating that some mutations may not impact enzyme inhibition.
- Pathogenic Alleles Impact: Individuals with Z, S, or F alleles displayed reduced anti-NE activity even when serum levels appeared normal, emphasizing the need for functional testing.
These findings underscore that relying solely on serum AAT levels may lead to underdiagnosis and misclassification of disease severity.
Implications for Clinical Practice
The integration of genotyping, serum measurement, and functional testing represents a significant advancement in the diagnostic approach to AATD. Key implications include:
- Improved Detection: Identifies individuals who would otherwise be missed by traditional methods.
- Tailored Management: Functional activity assessment allows clinicians to better predict disease progression and personalize treatment.
- Enhanced Screening Programs: Broader adoption of the algorithm could lead to earlier interventions and better long-term outcomes for patients.
Conclusion
The new AATD testing algorithm presented at CHEST 2025 marks a pivotal advancement in the accurate diagnosis of alpha-1 antitrypsin deficiency. By combining genotyping, serum AAT levels, and functional activity assays, the algorithm addresses the gaps of traditional diagnostic methods, uncovering previously undetected cases and providing a clearer clinical picture.
This comprehensive approach not only improves detection rates but also enhances the understanding of the functional impact of various SERPINA1 mutations. For clinicians, it offers a practical roadmap to more informed decision-making, enabling earlier interventions that can prevent severe lung and liver complications.
Early adoption of this algorithm could revolutionize AATD screening programs, especially for high-risk populations or those with unexplained respiratory and hepatic symptoms. The study highlights the importance of integrating genetic and functional assessments in routine clinical practice.
As the full results of the study are shared during the CHEST Annual Meeting 2025, the medical community anticipates further insights into the clinical impact of this innovative diagnostic strategy. Ultimately, this advancement holds the potential to improve patient outcomes and reduce the burden of undiagnosed AATD worldwide.
FAQs about AATD and the New Diagnostic Algorithm
1. What is alpha-1 antitrypsin deficiency (AATD)?
AATD is a genetic disorder caused by mutations in the SERPINA1 gene, leading to reduced levels or dysfunctional alpha-1 antitrypsin (AAT) protein. This protein is vital for regulating inflammation in the lungs and liver. Deficiency can result in chronic lung diseases like emphysema and COPD, as well as liver damage including cirrhosis. Early detection is crucial for managing symptoms and preventing organ damage.
2. Why are traditional AATD diagnostic methods often insufficient?
Traditional testing primarily measures serum AAT levels or uses phenotyping. However, AAT levels can fluctuate due to inflammation or liver function, and some mutations do not affect protein concentration but impair function. Phenotyping may also miss rare or novel genetic mutations, leading to underdiagnosis and delayed treatment.
3. How does the new AATD testing algorithm work?
The algorithm integrates three key steps: genotyping for known pathogenic SNPs, next-generation sequencing (NGS) if no mutations are found, and functional assays measuring anti-neutrophil elastase activity. This stepwise approach ensures detection of both common and rare mutations while assessing the functional capacity of AAT, providing a more comprehensive clinical assessment.
4. What are the benefits of functional activity testing in AATD?
Functional testing, such as anti-neutrophil elastase (anti-NE) activity measurement, assesses whether AAT protein can inhibit harmful enzymes in the body. This is important because some mutations may not lower serum levels but still impair protein function. Functional testing helps identify patients at risk for organ damage even when AAT levels appear normal.
5. How will this new algorithm impact patient care?
The algorithm improves early detection, enabling timely intervention and personalized treatment strategies. By identifying previously undetected cases, it allows clinicians to monitor and manage disease progression more effectively, reduce complications, and improve long-term outcomes. Adoption of this comprehensive testing could reshape AATD screening programs globally.
