Current Status in the Issue of Alpha-1-Antitrypsin Deficiency

Alpha-1-Antitrypsin Deficiency

Alpha-1-antitrypsin deficiency (AATD) is a congenital disorder associated with the risk of developing liver and lung diseases, especially pulmonary emphysema and chronic obstructive pulmonary disease (COPD), asthma, and bronchiectasis. AAT is a significant antiprotease with anti-inflammatory effects. It modulates inflammation caused by host and microbial factors. It may play a significant role in protecting the lungs from damage caused by proteases and inflammation.

AAT is encoded by the SERPINA1 gene. Its pathological variants lead either to deficiency or complete absence of AAT. The common M variant, found in 95% of the Caucasian population, is associated with a normal AAT level of 1.02–2.54 g/l. Other common variants are S and Z, and possible phenotypes, including MM, MS, MZ, SS, SZ, and ZZ, occur in > 99% of the population. Lung damage is a risk with variants associated with AAT levels < 0.57 g/l.

Diagnosis of AATD

Diagnosis of AATD requires measuring the AAT level in the serum and determining the allelic variant through phenotyping or genotyping. In confirmed cases, testing the patient's relatives should be considered after appropriate consultation. Patients are recommended to have an initial and then annual examination of lung function, including the forced expiratory volume in one second (FEV₁) after bronchodilator administration and an assessment of gas exchange in the lungs, which provides information on the progression of lung damage.

Measuring lung tissue density via CT is performed in clinical studies because it is the most sensitive indicator of the progression of pulmonary emphysema. In the long term, the reduction in lung tissue density correlates with the decline in FEV₁ and the deterioration of the patient's overall condition. However, in routine practice, lung CT is not yet used to monitor patients.

According to the World Health Organization (WHO), the AAT level should be measured in all adults who develop asthma.

Therapeutic Options

Current therapeutic options for patients with AATD include lifestyle modification (quitting smoking, avoiding hazardous environments, monitoring nutritional status), pulmonary rehabilitation and exercise, pharmacological treatment of asthma and COPD (which includes inhaled bronchodilators and corticosteroids, antibiotics, oral corticosteroids), oxygen therapy, and vaccination against influenza and pneumococcus. 

The only approved specific treatment for AATD is the administration of exogenous purified AAT derived from human serum. It is administered in the PiZZ variant. It is not recommended for PiSZ, PiMZ variants, smokers, or patients with liver damage. Several clinical studies have shown that AAT augmentation therapy slows the progression of emphysema according to CT imaging. In these studies, AAT doses were based on the patients' body weight.

For selected patients, surgical treatments such as pulmonary volume reduction surgery, bronchial valve implantation, or lung transplantation can also be considered. Therapeutic decisions should be made by a multidisciplinary team. Lung transplantation improves the quality of life for patients, but there is no data on its impact on survival. The role of augmentation therapy after transplantation has not yet been assessed.

Ongoing Research

Current ongoing research is moving in several directions, aiming to improve the diagnosis of AATD, assess treatment response, and find other potential therapies – genetic, regenerative, etc.

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Source: Cazzola M., Stolz D., Rogliani P., Matera M. G. α₁-antitrypsin deficiency and chronic respiratory disorders. Eur Respir Rev 2020; 29 (155): 190073, doi: 10.1183/16000617.0073-2019.