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Unravelling the risk of (intermediate) antitrypsin deficiency
  1. Mark Quinn1,
  2. Alice Margaret Turner1,2,
  3. Ravi Mahadeva3
  1. 1IAHR, University of Birmingham, Birmingham, UK
  2. 2Respiratory Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
  3. 3Respiratory Medicine, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
  1. Correspondence to Dr Ravi Mahadeva, Respiratory Medicine, Cambridge University Hospitals NHS Foundation Trust, Cambridge, Cambridgeshire, UK; ravi.mahadeva{at}nhs.net

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The seminal observation of severe deficiency of alpha-1-antitrypsin (AAT) with premature emphysema over 50 years ago led to the elastase–antielastase hypothesis of lung disease. Subsequent research identified alpha-1-antitrypsin deficiency (AATD) as an inherited metabolic genetic condition caused by mutations on the SERPINA1 gene, resulting in a reduction in the serum concentration of AAT.1 The role of AAT is to act as an inhibitor to the enzyme neutrophil elastase, and it is crucial in the homeostasis of elastase–antielastase activity, with an imbalance in this activity causing lung disease via a cycle of inflammation and proteolytic damage leading to premature emphysema, disability and death. There are over 100 mutations of SERPINA1 described in the literature, some of which are associated with AATD. The normal genotype is designated PiMM; the most common genotype resulting in severe deficiency is designated PiZZ. AATD is an autosomal codominant condition so heterozygosity can also create in genotypes resulting in mild and intermediate deficiency, such as PiMZ and PiSZ. The prevalence of AATD worldwide is estimated between 0.02% and 0.05%. Normal AAT serum concentration would be in the range 20–53 µmol/L, while deficient genotypes express varying levels, from 55% for PiMZ to 40% for PiSZ and <15% for PiZZ. While the risk of developing premature emphysema in PiZZ is beyond doubt, there has been considerable debate regarding the risk of SZ genotype (intermediate deficiency) and emphysema severity.2

The study carried out by Franciosi et al3 in this journal is a welcome addition to the area aiming to further understand the PiSZ genotype and its effect on lung disease. Their results imply that …

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Footnotes

  • Contributors All authors were involved in reviewing the subject and planning the content and structure of the editorial. MQ was responsible for drafting the first and second versions with feedback and editing by AMT and RM. RM finalised the manuscript for submission.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests AMT has received research grants from CSL Behring (current) and Grifols (within the last 5 years) and consulting fees from CSL. RM has received consulting fees for educational activities and advisory boards between 2016 and 2020 sponsored by CSL Behring and Kamada.

  • Patient consent for publication Not required.

  • Provenance and peer review Commissioned; externally peer reviewed.

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