What is alpha-1 antitrypsin (A1AT) deficiency?

From the Guidelines

Alpha-1 antitrypsin (A1AT) deficiency is a genetic disorder where the body doesn't produce enough alpha-1 antitrypsin protein, which protects the lungs and liver from damage, and the most recent and highest quality evidence recommends augmentation therapy with intravenous alpha-1 proteinase inhibitor for those with emphysema, as stated in the 2025 Canadian Thoracic Society meta-analysis and clinical practice guideline 1.

Key Points

• A1AT deficiency occurs due to mutations in the SERPINA1 gene, with the most common problematic variant being the Z allele, as noted in the 2025 study 1.
• People with two Z alleles (PiZZ) typically have the most severe deficiency, and the condition is diagnosed through blood tests measuring A1AT levels and genetic testing to identify specific mutations.
• Treatment focuses on managing symptoms and preventing complications, including augmentation therapy, avoiding lung irritants like cigarette smoke, receiving vaccinations against respiratory infections, using bronchodilators and other respiratory medications as needed, and monitoring liver function.
• The 2025 Canadian Thoracic Society meta-analysis and clinical practice guideline conditionally recommends A1AT augmentation therapy to preserve CT scan lung density and reduce mortality in patients with COPD and documented A1AT deficiency, as outlined in the study 1.

Management

• Augmentation therapy with intravenous alpha-1 proteinase inhibitor is recommended for those with emphysema, typically at a dose of 60 mg/kg body weight weekly, as stated in the example answer.
• Additional management includes avoiding lung irritants, receiving vaccinations, using bronchodilators and other respiratory medications as needed, and monitoring liver function.
• Lung and liver transplantation may be considered in advanced cases, and early diagnosis is crucial as lifestyle modifications can significantly slow disease progression, as noted in the example answer.

Diagnosis

• The condition is diagnosed through blood tests measuring A1AT levels and genetic testing to identify specific mutations, as stated in the example answer.
• The 2003 American Thoracic Society/European Respiratory Society statement provides a summary evidence table for augmentation therapy for A1AT deficiency, including indication and performance, as outlined in the study 1.

From the Research

Definition and Overview of Alpha-1 Antitrypsin Deficiency

• Alpha-1 antitrypsin (AAT) deficiency is a genetic disorder characterized by low levels of the protein alpha-1 antitrypsin, which protects the lungs from damage caused by an enzyme called neutrophil elastase 2.
• This deficiency can lead to lung disease, including emphysema and chronic obstructive pulmonary disease (COPD), as well as liver disease 3, 2.

Prevalence and Demographics

• AAT deficiency is estimated to affect approximately 1 in 2750 to 1 in 4500 individuals, although it is considered to be underrecognized and underdiagnosed 2, 4.
• A survey of patients with AAT deficiency found that the majority of participants reported COPD symptoms, including asthma, chronic bronchitis, and emphysema, and that lung or liver transplantation was reported by 9% of respondents 4.

Pathophysiology

• The loss of AAT disrupts the protease-antiprotease balance in the lungs, allowing proteases to destroy lung matrix and alveolar structures, leading to an increased risk of developing emphysema and COPD 5.
• The destruction of lung structures is exacerbated by smoking and other environmental factors.

Diagnosis and Treatment

• Diagnosis of AAT deficiency can be attained using qualitative or quantitative laboratory testing 5.
• Augmentation therapy, which involves intravenous infusion of AAT, is the only FDA-approved treatment for AAT deficiency and has been shown to slow the progression of lung disease 6.
• Other treatments, such as lung transplantation, may be necessary in severe cases of lung disease 3, 4.