Abstract
Alpha-1 Antitrypsin Deficiency (AATD), characterised by reduced levels or functionality of Alpha-1 Antitrypsin (AAT), is a significantly under-diagnosed genetic condition that predisposes individuals to lung and liver disease. Most of the available data on AATD is based on the most common, severe deficiency genotype (PI*ZZ); therefore, treatment and monitoring requirements for individuals with the PI*SZ genotype, which is associated with a less severe AAT deficiency, are not as clear. Recent genetic data suggest the PI*SZ genotype may be significantly more prevalent than currently thought, due in part to less frequent identification in the clinic and less frequent reporting in registries. Intravenous AAT therapy, the only specific treatment for patients with AATD, has been shown to slow disease progression in PI*ZZ individuals; however, there is no specific evidence for AAT therapy in PI*SZ individuals, and it remains unclear whether AAT therapy should be considered in these patients. The present narrative review evaluates the available data on the PI*SZ genotype, including genetic prevalence, the age of diagnosis and development of respiratory symptoms compared with PI*ZZ individuals, and the impact of factors such as index versus non-index identification and smoking history. The relevance of the putative 11 µM “protective threshold” for AAT therapy and the risk of liver disease in PI*SZ individuals is also explored. The purpose of this review is to identify open research questions in this area, with the aim of optimising the future identification and management of PI*SZ individuals.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: Dr. McElvaney reports personal fees from CSL Behring, grants and personal fees from Grifols, personal fees from Vertex, outside the submitted work.
Conflict of interest: Dr. Sandhaus reports personal fees from CSL Behring, during the conduct of the study. Dr. Sandhaus reports personal fees from CSL Behring, during the conduct of the study; non-financial support from Grifols, personal fees from AstraZeneca, outside the submitted work.
Conflict of interest: Dr. Miravitlles reports personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Menarini, Rovi, Bial, Zambon, CSL Behring, Grifols and Novartis, personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Bial, Gebro Pharma, CSL Behring, Laboratorios Esteve, Ferrer, Mereo Biopharma, Verona Pharma, TEVA, pH Pharma, Novartis and Grifols, grants from GlaxoSmithKline and Grifols, outside the submitted work.
Conflict of interest: Dr. Turino has nothing to disclose.
Conflict of interest: Dr. Seersholm has nothing to disclose.
Conflict of interest: Dr. Wencker reports personal fees from CSL Behring, during the conduct of the study.
Conflict of interest: Dr. Stockley reports personal fees from AstraZeneca, personal fees from Nycomed, personal fees from Boehringer Ingelheim, personal fees from CSL Behring, personal fees from Shire, personal fees from Chiesi, personal fees from Polyphor, personal fees from GlaxoSmithKline, personal fees from Mereo BioPharma, personal fees from Vertex Pharmaceuticals Inc, personal fees from Akari Therapeutics plc, outside the submitted work.
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- Received December 16, 2019.
- Accepted February 24, 2020.
- Copyright ©ERS 2020
