What is the role of fecal alpha 1 anti-trypsin (A1AT) testing in diagnosing gastrointestinal involvement in patients with alpha 1 anti-trypsin deficiency?

Role of Fecal Alpha-1 Antitrypsin Testing in Alpha-1 Antitrypsin Deficiency

Fecal alpha-1 antitrypsin (A1AT) testing has limited clinical utility in diagnosing gastrointestinal involvement in patients with alpha-1 antitrypsin deficiency and is not recommended as part of standard diagnostic protocols for this condition.

Diagnostic Approach for Alpha-1 Antitrypsin Deficiency

The current recommended diagnostic approach for alpha-1 antitrypsin deficiency focuses on two primary tests:

• Serum A1AT protein levels and DNA sequencing of the coding exons of SERPINA1 gene, which is considered the gold standard for diagnosis 1
• For patients with high clinical suspicion, both serum A1AT levels and genetic testing with DNA sequencing are recommended as the initial tests 1, 2

Testing Algorithm

1. High clinical suspicion cases (early-onset COPD, low tobacco exposure, panlobular emphysema, family history):

   • Initial measurement of serum A1AT levels AND genetic testing with DNA sequencing of SERPINA1 gene 1

2. Moderate clinical suspicion cases (COPD, adult-onset asthma with persistent airflow obstruction, unexplained bronchiectasis):

   • Serum A1AT level measurement first 1
   • If A1AT level is <23 mmol/L (<1.2 g/L), proceed to genetic testing 1
   • If A1AT level is ≥23 mmol/L (≥1.2 g/L), A1AT deficiency is generally ruled out 1, 3

Limitations of Serum A1AT Testing

• A1AT is an acute phase protein with levels that fluctuate over time, particularly increasing during inflammation 1
• Test-retest reproducibility is weak, making classification problematic in intermediate deficiency cases 1
• Some genetic variants have normal circulating levels but dysfunctional protein (e.g., Pi*F variant) 1, 2

Fecal A1AT Testing in Clinical Practice

Research on fecal A1AT in the context of A1AT deficiency is limited and outdated:

• Studies from the 1980s found that patients with A1AT deficiency had increased fecal clearance of A1AT compared to controls, but this was not considered a major cause of low serum levels 4
• Fecal A1AT testing has been primarily used to detect protein-losing enteropathies and gastrointestinal disorders rather than for diagnosing or monitoring A1AT deficiency 5, 6, 7
• Fecal A1AT has shown utility in monitoring intestinal protein loss in conditions like celiac disease 8, but not specifically for A1AT deficiency

Current Guidelines on A1AT Deficiency Diagnosis

Current guidelines from major respiratory societies do not include fecal A1AT testing in their recommended diagnostic protocols for A1AT deficiency:

• The American Thoracic Society and Canadian Thoracic Society recommend serum A1AT levels and genetic testing as the primary diagnostic methods 1, 3
• Diagnostic algorithms focus on serum testing and DNA sequencing rather than fecal testing 1, 2

Clinical Implications of A1AT Deficiency Diagnosis

Early and accurate diagnosis of A1AT deficiency is crucial because:

• Late diagnosis has been associated with reduced functional status, quality of life, and worse overall survival 1, 2
• Identification allows for consideration of specific augmentation therapy with purified A1AT protein 1
• Early diagnosis helps patients avoid high-risk environmental exposures and adopt healthier lifestyles 1
• It facilitates family screening to identify relatives who may be affected 1, 2

Conclusion

While fecal A1AT testing may have some historical research interest in A1AT deficiency, current diagnostic guidelines do not recommend it for diagnosing gastrointestinal involvement in these patients. The focus remains on serum A1AT levels and genetic testing, which provide more reliable and clinically relevant information for diagnosis and management.