What is Alpha-1 Antitrypsin (A1AT) deficiency disorder?

From the Guidelines

Augmentation therapy with intravenous alpha-1 antitrypsin (AAT) is recommended for patients with alpha-1 antitrypsin deficiency and obstructive lung disease, as indicated by a forced expiratory volume (FEV1) between 30 and 65% predicted, with the goal of slowing disease progression and improving quality of life. The treatment should be initiated regardless of the phenotype, with dosing and frequency guided by serum AAT levels and lung function tests 1.

Key Considerations

• Laboratory testing should include alpha-1 antitrypsin serum level measurements, with a threshold of 11.0 μmol/L 1.
• Lung function testing, including FEV1 postbronchodilation, is crucial for assessing disease severity and monitoring response to treatment 1.
• The indication for treatment is independent of the phenotype and based on the level and presence of obstructive lung disease 1.
• Patients with normal or nearly normal pulmonary function can be treated if they experience a rapid decline in lung function (FEV1 ≥ 120 ml/yr) 1.

Treatment Approach

• Augmentation therapy involves monthly infusion of AAT, with a recommended dose of 250 mg/kg 1.
• Active treatment has shown a trend towards reducing the decline in lung density by CT, although larger studies are needed to confirm efficacy 1.
• Adverse reactions to AAT concentrate are rare, with mild reactions (fever, chills, dyspnea) reported in some patients, and anaphylactic reactions being extremely rare 1.

Additional Recommendations

• Patients with alpha-1 antitrypsin deficiency should avoid smoking completely to prevent accelerated lung damage.
• Bronchodilators, inhaled steroids, and oxygen therapy may be prescribed based on symptom severity.
• Pulmonary rehabilitation is beneficial for patients with breathing difficulties.
• Vaccination against pneumococcal pneumonia and annual flu shots are essential preventive measures.

From the FDA Drug Label

Alpha1-PI deficiency is a chronic, autosomal, co-dominant hereditary disorder characterized by reduced levels of Alpha1-PI in the blood and lungs1, 2 Approximately 95% of identified Alpha1-PI deficient individuals have the PiZZ variant, typically characterized by Alpha1-PI serum levels < 35% of normal. Individuals with the lack of, or low, endogenous serum levels of Alpha1-PI, i. e., below 11 μM, manifest a significantly increased risk for development of emphysema above the general population background risk4, 5.

Alpha one antitrypsin disorder is a chronic, hereditary condition characterized by reduced levels of Alpha1-PI in the blood and lungs. The most common variant is PiZZ, which is typically associated with Alpha1-PI serum levels < 35% of normal. Individuals with low endogenous serum levels of Alpha1-PI (< 11 μM) are at a significantly increased risk of developing emphysema 2. Key points include:

• Autosomal, co-dominant hereditary disorder
• Reduced levels of Alpha1-PI in blood and lungs
• PiZZ variant: Alpha1-PI serum levels < 35% of normal
• Low endogenous serum levels of Alpha1-PI (< 11 μM): increased risk of emphysema 2

From the Research

Alpha-1 Antitrypsin Disorder Overview

• Alpha-1 antitrypsin (AAT) deficiency is a hereditary condition characterized by low levels of AAT in plasma, leading to an imbalance between proteases and antiproteases in the presence of environmental triggers 3.
• The condition can cause panacinar emphysema, and if left untreated, may develop into severe obstructive lung disease 3.
• Avoidance of environmental triggers, such as cigarette smoking, is a critical component of AAT deficiency treatment 3.

Treatment Options

• Intravenous augmentation therapy is the only specific therapy for AAT deficiency that has been approved by the US Food and Drug Administration (FDA) 3.
• Augmentation therapy has been associated with effective elevations of A1AT levels and function in serum and lung epithelial fluid, and may lead to attenuation in lung function decline 4.
• The optimal dose of augmentation therapy is being revised, and there is a need for more individualized assessment of who needs this therapy 5.

Controversies and Uncertainties

• There are several areas of controversy regarding the use of AAT augmentation therapy, including indications for treatment, selection of specific AAT augmentation therapy, and cost effectiveness 3.
• The indication for augmentation therapy must be personalized in expert reference centers after in-depth discussion of the pros and cons of augmentation with the patient 6.
• There is uncertainty about the clinical effect of augmentation therapy with intravenous alpha-1 antitrypsin, and it is not recommended due to sparse data and uncertainty about possible harms 7.

Key Findings

• Augmentation therapy may slow the rate of progression of emphysema and improve survival in selected individuals with severe AAT deficiency 3.
• Lung density measured by computer tomography (CT) scan deteriorated significantly less in the treatment group than in the placebo group 7.
• There is a need for further research to address the controversies and uncertainties surrounding AAT augmentation therapy 6.