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

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.

Opinions and Attitudes of Pulmonologists About Augmentation Therapy in Patients with Alpha-1 Antitrypsin Deficiency. A Survey of the EARCO Group

“…28,29 More surprising is the indication of AT in almost 10% of cases with Pi*MZ genotypein this case, age <45 years, a DLCO (%) <50% and being symptomatic were the most relevant variables to decide the initiation of AT. It is of note that AT in Pi*MZ patients is off label, there is no evidence of efficacy of AT in Pi*MZ individuals 30,31 and, therefore, it is not recommended by guidelines. [7][8][9] Since the introduction of AT in the late 80s the same regimen of 60 mg/Kg weekly has been recommended for patients with severe AATD and lung disease based on biochemical efficacy restoring serum AAT levels above the protective threshold, 4,5 irrespective of the severity and phenotype of the respiratory disease.…”

“… 28 , 29 More surprising is the indication of AT in almost 10% of cases with Pi*MZ genotypein this case, age <45 years, a DLCO (%) <50% and being symptomatic were the most relevant variables to decide the initiation of AT. It is of note that AT in Pi*MZ patients is off label, there is no evidence of efficacy of AT in Pi*MZ individuals 30 , 31 and, therefore, it is not recommended by guidelines. 7–9…”

Estimated Prevalence and Number of PiMZ Genotypes of Alpha-1 Antitrypsin in Seventy-Four Countries Worldwide

“…Previous studies have found that among patients diagnosed with COPD the prevalence of the PiMZ genotype ranges from 1% to 22%. 1 , 27 , 42 According to these percentages of genetic penetrance, up to one-fifth of the estimated 35 million of the MZ carriers from the 74 selected countries (ie, approximately 7 million) will develop COPD.…”

“…Really, the “threshold” value represents a systemic concentration of AAT in serum rather than its level in the alveolar fluid, and thus does not accurately reflect the AAT functional activity into the lungs. 42 Another factor that may play a significant role in the development of lung emphysema is the gene expression of neutrophil elastase that could be increased in MZs, contributing to aggravate the AATD protease/antiprotease imbalance. 42 Lately, it has been reported that several “rare/M-like and Z” compound heterozygotes, correctly characterized by gene sequencing, initially were misdiagnosed as PiMZ.…”

“…42 Another factor that may play a significant role in the development of lung emphysema is the gene expression of neutrophil elastase that could be increased in MZs, contributing to aggravate the AATD protease/antiprotease imbalance. 42 Lately, it has been reported that several "rare/ M-like and Z" compound heterozygotes, correctly characterized by gene sequencing, initially were misdiagnosed as PiMZ. [56][57][58] For example, in 6 of 103 putative MZs from the Alpha-1 Foundation Research Registry, with serum levels around 15 µM, performing a gene sequencing with a nextgeneration sequencing (NGS) method showed that they were actually ZZ, SZ, FZ, ZSmunich, ZM2obernburg, and Z/c 0.922G> T genotypes.…”