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.
Highlights
BackgroundMost of the published evidence relating to the management of individuals with alpha-1 antitrypsin deficiency (AATD) is based on patients with the PI*ZZ or PI*Znull genotypes, who have a severe deficiency in alpha-1 antitrypsin (AAT), with plasma levels < 11 μM (< 52 mg/dL) compared with the normal range of 19–47 μM (102– 254 mg/dL) [1]
Pro: alpha-1 antitrypsin (AAT) treatment of PI*MZ patients could be an option Focus on AAT serum concentrations in PI*MZ can be misleading1) The relevance of the ‘protective threshold’ Systemic levels of AAT in PI*MZ individuals do not generally fall below 11 μM, a value historically used as a theoretical ‘protective threshold’ for AAT therapy provision; levels below this threshold are thought to be associated with a higher risk of developing emphysema [7]
Con: PI*MZ individuals should not be treated with AAT augmentation therapy Disease risk and severity in patients with the PI*MZ genotype It is well known that smoking is a key risk factor for the development of lung disease in patients with alpha-1 antitrypsin deficiency (AATD), and disease progression and survival are both significantly worse in smokers than never-smokers [3]
Summary
Most of the published evidence relating to the management of individuals with alpha-1 antitrypsin deficiency (AATD) is based on patients with the PI*ZZ or PI*Znull genotypes, who have a severe deficiency in alpha-1 antitrypsin (AAT), with plasma levels < 11 μM (< 52 mg/dL) compared with the normal range of 19–47 μM (102– 254 mg/dL) [1]. Z allele, such as those with the PI*MZ genotype, who have AAT serum levels of 11–28 μM (62–151 mg/dL), or approximately 60% of the normal range [1], may be at risk of developing lung and/or liver disease if they have other predisposing risk factors. Despite the understanding of the mechanisms responsible for pathologic changes in AAT-deficient individuals [5], and the fact that AAT augmentation therapy is the only disease-modifying therapeutic approach for patients with AATD-associated lung disease [6], current guidelines do not recommend the use of augmentation therapy in individuals with the PI*MZ genotype. We summarize the evidence supporting a potential AAT-specific therapeutic approach in individuals with the PI*MZ genotype, and discuss reasons why focus on this approach may not be warranted
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