What is alpha-1 (Alpha-1 Antitrypsin) deficiency in a pulmonary setting?

From the Guidelines

Alpha-1 antitrypsin deficiency is a genetic disorder that causes low levels or abnormal function of the alpha-1 antitrypsin protein, primarily affecting the lungs, and the cornerstone of specific treatment is augmentation therapy with intravenous alpha-1 antitrypsin for patients with severe deficiency and evidence of emphysema, as it can reduce mortality and slow disease progress, as shown in the most recent and highest quality study 1.

Key Points

• Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder that affects the lungs, causing progressive lung damage, particularly emphysema, which often develops in the third to fourth decade of life, especially in smokers.
• The condition is characterized by shortness of breath, wheezing, chronic cough, recurrent respiratory infections, and decreased exercise tolerance.
• Diagnosis involves blood tests measuring AAT levels and genetic testing to identify specific mutations, with the ZZ genotype being most severe.
• Management includes smoking cessation, bronchodilators, corticosteroids, supplemental oxygen when needed, and pulmonary rehabilitation.
• Augmentation therapy with intravenous alpha-1 antitrypsin is the specific treatment for patients with severe deficiency and evidence of emphysema, as recommended by the Canadian Thoracic Society 1.

Treatment

• Augmentation therapy with intravenous alpha-1 antitrypsin (typically 60 mg/kg weekly) is the cornerstone of specific treatment for patients with severe alpha-1 antitrypsin deficiency and evidence of emphysema, as it can reduce mortality and slow disease progress, as shown in the most recent and highest quality study 1.
• Smoking cessation, bronchodilators, corticosteroids, supplemental oxygen when needed, and pulmonary rehabilitation are also important components of management.

Importance of Early Detection

• Early detection is crucial as preventive measures can significantly slow disease progression, and genetic counseling should be offered to affected individuals and their families due to the hereditary nature of the condition.
• The Canadian Thoracic Society recommends targeted testing and augmentation therapy for patients with respiratory conditions associated with AATD, including COPD with emphysema, adult-onset asthma with persistent airflow obstruction, and unexplained bronchiectasis 1.

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 lungs 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 risk Individuals with severe Alpha1-PI deficiency have been shown to have increased neutrophil and neutrophil elastase concentrations in lung epithelial lining fluid compared to normal PiMM individuals

Alpha-1 deficiency in a pulmonary setting refers to a condition where there are reduced levels of Alpha1-PI in the blood and lungs, leading to an increased risk of developing emphysema.

• Key characteristics of Alpha1-PI deficiency include:
  • Reduced levels of Alpha1-PI in the blood and lungs
  • Increased risk of developing emphysema, particularly in individuals with severe deficiency (PiZZ variant)
  • Increased neutrophil and neutrophil elastase concentrations in lung epithelial lining fluid
• Risk factors for developing emphysema in patients with Alpha1-PI deficiency include:
  • Smoking
  • Severe genetic variants of Alpha1-PI deficiency (AAT deficiency)
  • Low endogenous serum levels of Alpha1-PI (below 11 μM) 2

From the Research

Definition and Pathogenesis

• Alpha-1 antitrypsin deficiency is a hereditary condition characterized by low alpha 1 proteinase inhibitor (also known as alpha 1 antitrypsin [AAT]) serum levels 3, 4, 5, 6.
• Reduced levels of AAT allow abnormal degradation of lung tissue, which may ultimately lead to the development of early-onset emphysema 3, 5.

Clinical Presentation

• The typical pulmonary manifestation is chronic obstructive pulmonary disease and emphysema 5.
• Severe chronic obstructive pulmonary disease may occur in young adulthood, and terminal respiratory insufficiency causes premature death in many patients 5.
• In the liver, alpha-1 antitrypsin deficiency may manifest as benign neonatal hepatitis syndrome; a small percentage of adults develop liver fibrosis, with progression to cirrhosis and hepatocellular carcinoma 5, 7.

Diagnosis and Treatment

• Diagnosis of alpha-1 antitrypsin deficiency can be established by measurement of the serum alpha-1 antitrypsin concentration or by genetic analysis 5.
• Treatment is similar to the usual treatment for patients with chronic obstructive pulmonary disease 5.
• A further option is substitution therapy with human alpha-1 antitrypsin, which can delay the progression of emphysema 3, 4, 6.
• Alternative strategies such as gene therapy, induced pluripotent stem cells, and prevention of AAT polymerization inside hepatocytes are being investigated 4, 6.