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Clarifying the role of the putative protective threshold ERJ final epub 2021.pdf (945.89 kB)

Alpha-1 antitrypsin deficiency: clarifying the role of the putative protective threshold

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posted on 2022-03-07, 11:18 authored by Alessandro Franciosi, Daniel Fraughen, Tomas CarrollTomas Carroll, Noel G McElvaneyNoel G McElvaney
Alpha-1 antitrypsin deficiency (AATD) is the only readily identifiable monogenic cause of COPD. To date the only condition-specific treatment for AATD-associated COPD is weekly administration of intravenous plasma-purified human alpha-1 antitrypsin (IV-AAT). Uncertainties regarding which AATD genotypes should benefit from IV-AAT persist. IV-AAT is costly and involves weekly administration of a plasma product. Much of the risk stratification has been centred around the long-accepted hypothesis of a "putative protective threshold" of 11 µM (0.57 g·L-1) AAT in serum. This hypothesis has become central to the paradigm of AATD care, although its derivation and accuracy for defining risk of disease remain unclear.We reviewed the literature and examined the association between the 11 µM threshold and clinical outcomes to provide context and insight into the issues surrounding this topic.We found no data demonstrating an increased risk of COPD dependent on the 11 µM threshold. Moreover, an abundance of recent clinical data examining this threshold refutes the hypothesis. Conversely, the use of 11 µM as a treatment target in appropriate ZZ individuals is supported by clinical evidence, although more refined dosing regimens are being explored.Continued use of the 11 µM threshold as a determinant of clinical risk is questionable, perpetuates inappropriate AAT-augmentation practices, may drive increased healthcare expenditure and should not be used as an indicator for commencing treatment.Genotype represents a more proven indicator of risk, with ZZ and rare ZZ-equivalent genotypes independently associated with COPD. New and better risk assessment models are needed to provide individuals diagnosed with AATD with reliable risk estimation and optimised treatment goals.



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Published Citation

Franciosi AN, Fraughen D, Carroll TP, McElvaney NG. Alpha-1 antitrypsin deficiency: clarifying the role of the putative protective threshold. Eur Respir J. 2022;59(2):2101410.

Publication Date

10 February 2022

PubMed ID



  • Medicine
  • Beaumont Hospital


European Respiratory Society


  • Accepted Version (Postprint)

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