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Review
. 2021 Mar 23;21(1):99.
doi: 10.1186/s12890-021-01466-x.

Alpha-1 antitrypsin (AAT) augmentation therapy in individuals with the PI*MZ genotype: a pro/con debate on a working hypothesis

Igor Barjaktarevic  1 , Marc Miravitlles  2
Affiliations
Review

Alpha-1 antitrypsin (AAT) augmentation therapy in individuals with the PI*MZ genotype: a pro/con debate on a working hypothesis

Igor Barjaktarevic et al. BMC Pulm Med. .

Abstract

Alpha-1 antitrypsin deficiency (AATD) is a significantly under-diagnosed genetic condition caused by reduced levels and/or functionality of alpha-1 antitrypsin (AAT), predisposing individuals to lung, liver or other systemic diseases. The management of individuals with the PI*MZ genotype, characterized by mild or moderate AAT deficiency, is less clear than of those with the most common severe deficiency genotype (PI*ZZ). Recent genetic data suggest that the PI*MZ genotype may be significantly more prevalent than currently thought. The only specific treatment for lung disease associated with severe AATD is the intravenous infusion of AAT augmentation therapy, which has been shown to slow disease progression in PI*ZZ individuals. There is no specific evidence for the clinical benefit of AAT therapy in PI*MZ individuals, and the risk of emphysema development in this group remains controversial. As such, current guidelines do not support the use of AAT augmentation in PI*MZ individuals. Here, we discuss the limited data on the PI*MZ genotype and offer pro and con perspectives on pursuing an AAT-specific therapeutic strategy in PI*MZ individuals with lung disease. Ultimately, further research to demonstrate the safety, risk/benefit balance and efficacy of AAT therapy in PI*MZ individuals is needed.

Keywords: Alpha-1 antitrypsin deficiency; Chronic obstructive pulmonary disease; Genotype; PI*MZ; Pulmonary disease.

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Conflict of interest statement

IB has received consulting fees from Astra Zeneca, Boehringer Ingelheim, CSL Behring, Grifols, Verona Pharma, GE Healthcare, Mylan, Theravance, GSK and has received research grants from AMGEN, GE Healthcare, Theravance and Mylan. MM has received speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Menarini, Rovi, Bial, Sandoz, Zambon, CSL Behring, Grifols and Novartis, consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Bial, Gebro Pharma, Kamada, CSL Behring, Laboratorios Esteve, Ferrer, Mereo Biopharma, Verona Pharma, TEVA, Spin Therapeutics, pH Pharma, Novartis, Sanofi and Grifols and research grants from GlaxoSmithKline and Grifols.

Figures

Fig. 1
Fig. 1
Potential mechanism for increased disease risk in individuals with the PI*MZ genotype. Left panel: In MM non-smokers, a normal protease/antiprotease balance exists with normal alveoli. Central panel: MZ non-smokers have a slight imbalance of AAT and neutrophil elastase, IL-8 levels may increase in the lungs causing neutrophil activation and inflammation and progressive damage in the lungs in some patients. Right panel: MZ smokers have a greater imbalance between AAT and neutrophil elastase as a result of reactive oxygen species in cigarette smoke inactivating AAT. Additional factors such as Z polymers and IL-8 inflammatory markers cause greater production of neutrophil elastase in the lung, causing irreversible damage. Figure adapted from Carroll et al. 2014; https://doi.org/10.5772/58602 [23] under the Creative Commons Attribution 3.0 License. AAT alpha-1 antitrypsin, IL interleukin
Fig. 2
Fig. 2
Predicted FEV1 curves according to smoking status (a) and duration of smoking cessation (b) [48]. Figure reproduced with permission from Oelsner et al. Lancet Respir Med 2020;8:34–44, Copyright Elsevier 2020. FEV1 forced expiratory volume in 1 s
See this image and copyright information in PMC

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