Alpha-1 Antitrypsin Testing: Purpose, Test Details & Results

Alpha-1 antitrypsin (AAT) deficiency is one of the most underrecognized hereditary disorders, despite its significant impact on lung and liver health. Accurate and timely testing for AAT deficiency can change lives—by not only guiding treatment plans for those affected, but also by identifying at-risk family members. In this article, we explore the purpose of AAT testing, the details of how testing is performed, and how to interpret and act upon the results.

Purpose of Alpha-1 Antitrypsin Testing

Understanding why alpha-1 antitrypsin testing is performed is the first step to recognizing its value in medical care. This test plays a crucial role in diagnosing a genetic disorder that often masquerades as more common lung or liver diseases.

The Clinical Need for Testing

Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder caused by mutations in the SERPINA1 gene, resulting in low levels of the AAT protein—an important protector of lung tissue and other organs. Because symptoms overlap with common conditions like chronic obstructive pulmonary disease (COPD), asthma, and liver disease, AATD can be easily missed or misdiagnosed. Testing is the only reliable way to confirm or exclude the diagnosis 1, 2, 7.

Who Should Be Tested?

Current guidelines strongly recommend testing in several scenarios:

• All adults with symptomatic fixed airflow obstruction: This includes anyone diagnosed with COPD or asthma that doesn’t respond as expected to conventional treatment 1, 2.
• Anyone with unexplained bronchiectasis or chronic liver disease: Especially when other causes have been ruled out 1.
• First-degree relatives of diagnosed individuals: Family screening is vital for early detection—many relatives may be asymptomatic carriers or have mild disease 1, 7.

Targeted testing (case-finding) is more cost-effective and clinically valuable than population-wide screening, which is not routinely recommended 7.

Impact of Early Diagnosis

Timely diagnosis of AATD enables:

• Initiation of disease-specific therapy, such as augmentation therapy for lung involvement 1, 7.
• Recommendations for lifestyle changes, like smoking cessation, which has a profound effect on disease progression 1.
• Genetic counseling for families 1.
• Prevention of unnecessary or potentially harmful treatments for misdiagnosed conditions 5, 7.

Alpha-1 Antitrypsin Testing Details

Alpha-1 antitrypsin testing has evolved significantly, blending classic laboratory techniques with the latest genomic technologies to improve both speed and accuracy. Understanding these methods can help patients and clinicians navigate the diagnostic journey with greater confidence.

How Is Alpha-1 Antitrypsin Testing Performed?

The diagnostic process typically follows a stepwise approach:

• Serum AAT Level Measurement:
  The first step involves measuring AAT levels in the blood, usually by immunologic methods such as nephelometry. Low levels suggest possible deficiency but are not conclusive on their own, as AAT is an acute-phase reactant and can be increased in inflammation or infection 2, 3, 10.

• Phenotyping (Isoelectric Focusing, IEF):
  This method analyzes the type of AAT protein present, distinguishing normal (M) from deficient (S, Z, and other) variants. IEF helps clarify ambiguous results and can detect abnormal protein forms that may not be picked up by routine genotyping 2, 3, 10.

• Genotyping:
  The most common AATD-causing mutations—S and Z alleles—can be rapidly identified using polymerase chain reaction (PCR) or newer multiplex methods. Recent advances, such as Luminex xMAP technology, allow simultaneous detection of multiple mutations, improving diagnostic speed and accuracy 2, 3.

• Full SERPINA1 Gene Sequencing:
  If serum levels are low but genotyping and phenotyping are inconclusive, full sequencing of the SERPINA1 gene may be necessary to identify rare or novel mutations. This is more costly and typically reserved for complex cases 2, 3, 10.

• Next-Generation Sequencing (NGS):
  NGS enables comprehensive analysis of the SERPINA1 gene and can identify rare and compound heterozygous variants. While currently more expensive, its use is expanding and may become standard in the future 2.

Evolving Technologies

Technological innovations are streamlining AAT testing:

• Multiplex genotyping platforms (e.g., Luminex xMAP) can detect a broader array of mutations in a single test, reducing the need for sequential assays 3.
• NGS protocols provide high-throughput, accurate, and potentially cost-effective analysis, which could improve diagnostic rates and reduce delays 2.
• Some laboratories use algorithms that integrate serum levels, phenotyping, and genotyping/sequencing to maximize detection of both common and rare variants 10.

Limitations and Pitfalls

• Serum AAT levels can be temporarily elevated during infection or inflammation, potentially masking deficiency 2.
• Some rare or novel mutations may not be detected by targeted genotyping and require sequencing for identification 2, 3, 10.
• Protocols and detection rates can vary between laboratories, affecting diagnostic comprehensiveness, especially regarding rare or undefined molecular variants 10.

Alpha-1 Antitrypsin Testing Results & Follow-Up

Receiving results from AAT testing is a critical moment—not only for diagnosis, but also for planning the next steps in management and family care.

Understanding Your Results

Test outcomes fall into several broad categories:

• Normal:
  Normal AAT levels and genotype indicate no deficiency—no further testing for AATD is necessary 1, 2.

• Intermediate Deficiency:
  Heterozygous carriers (e.g., MZ, MS) have moderately reduced AAT levels. While most remain asymptomatic, risk increases with environmental exposures (notably smoking). Counseling focuses on prevention and awareness 9, 11.

• Severe Deficiency:
  Homozygous or compound heterozygous genotypes (e.g., ZZ, SZ, or rare combinations) result in very low AAT levels and a high risk of lung or liver disease. These individuals benefit most from targeted interventions, such as:

  • Referral to specialists (pulmonology, hepatology)
  • Consideration of intravenous augmentation therapy for lung involvement (where available and indicated)
  • Family screening for early detection in relatives 1, 7, 9

• Rare or Novel Variants:
  Some individuals have low AAT levels but genotypes that don’t match classic deficiency alleles. These cases may require full gene sequencing and specialist input, as clinical significance can vary and may be unclear 9, 10.

Follow-Up Actions

The next steps after receiving AAT test results are crucial for both patient health and family well-being:

• Medical Management:

  • Standard treatment for lung and liver disease, with added consideration for AAT-specific therapies in confirmed deficiency 1.
  • Lifestyle guidance (especially smoking cessation), vaccination, and avoidance of occupational exposures 1, 9.

• Family Counseling and Testing:
  Testing first-degree relatives is the most effective way to identify new cases early, offer preventive advice, and provide genetic counseling 1, 7.

• Long-Term Monitoring:
  Regular follow-up for those with deficiency, particularly to monitor disease progression and adjust treatment as needed 1, 9.

• Research and Registry Enrollment:
  Individuals with rare or novel mutations may be invited to join research registries to help advance understanding of AATD 9, 10.

Challenges and Ongoing Needs

Despite advances, AATD remains underdiagnosed, largely due to lack of awareness, inconsistent testing practices, and variable implementation of guidelines. Ongoing education for healthcare providers, improved testing algorithms, and patient empowerment are all critical for improving early detection and outcomes 5, 7, 11.

Conclusion

Alpha-1 antitrypsin testing is a vital tool—both for diagnosing a hidden genetic disease and for improving long-term outcomes in affected individuals and families. As testing technologies advance and awareness grows, more people stand to benefit from early, accurate diagnosis and tailored management.

Key Takeaways:

• Purpose: Alpha-1 antitrypsin testing helps diagnose a genetic deficiency with significant implications for lung and liver health, and guides therapies for affected patients and at-risk relatives 1, 2, 7.
• Testing Details: Modern AAT testing uses a combination of serum level measurement, phenotyping, genotyping, and, when needed, comprehensive gene sequencing—each with its own strengths and limitations 2, 3, 10.
• Results & Follow-Up: Accurate interpretation of results enables effective medical management, preventive counseling, family testing, and, when appropriate, consideration of specialized therapies 1, 9, 11.
• Ongoing Efforts: Addressing underdiagnosis requires better awareness, adherence to testing guidelines, and the integration of new technologies 5, 7, 11.

Early recognition and intervention in alpha-1 antitrypsin deficiency can transform lives—making testing not just a diagnostic step, but a pathway to improved health for individuals and families alike.