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Alpha-1 antitrypsin deficiency: outstanding questions and future directions
María Torres-Durán1,2, José Luis Lopez-Campos3,4, Miriam Barrecheguren4,5
1Pulmonary Department, Hospital Álvaro Cunqueiro EOXI, Vigo, Spain.
Insights
Alpha-1 antitrypsin deficiency (AATD) is underdiagnosed, with over 90% of severe cases undiagnosed. Research is needed for early detection and improved treatments for this genetic lung and liver disease.
Area of Science:
- Genetics and Medicine
- Pulmonology
- Hepatology
Background:
- Alpha-1 antitrypsin deficiency (AATD) is a rare genetic disorder causing low alpha-1 antitrypsin (AAT) levels.
- AATD significantly elevates the risk of severe lung and liver diseases in affected individuals.
- Key aspects of AATD pathogenesis and clinical presentation require further elucidation.
Purpose of the Study:
- To review and update current knowledge on Alpha-1 antitrypsin deficiency.
- To identify and discuss controversial areas within AATD research.
- To formulate critical questions for future research directions in AATD.
Main Methods:
- Comprehensive literature review and synthesis of existing data on AATD.
- Analysis of diagnostic challenges and underdiagnosis rates.
- Evaluation of current and emerging therapeutic strategies for AATD.
Main Results:
- Alpha-1 antitrypsin deficiency (AATD) is significantly underdiagnosed, with over 90% of an estimated 120,000+ severe European cases remaining undetected.
- Critical knowledge gaps persist regarding the clinical and etiological facets of AATD.
- Augmentation therapy is the sole approved treatment for emphysema progression, though its reimbursement is hindered by a lack of extensive clinical trial data.
Conclusions:
- Urgent need for improved early detection strategies and predictive biomarkers to mitigate AATD-related morbidity and mortality.
- Augmentation therapy's efficacy is established, but broader access is impeded by trial data requirements.
- Investigational therapies include gene therapy, induced pluripotent stem cells, and strategies to inhibit AAT polymerization in hepatocytes.
Background:
Alpha-1 antitrypsin deficiency (AATD) is a rare hereditary condition that leads to decreased circulating alpha-1 antitrypsin (AAT) levels, significantly increasing the risk of serious lung and/or liver disease in children and adults, in which some aspects remain unresolved.
Methods:
In this review, we summarise and update current knowledge on alpha-1 antitrypsin deficiency in order to identify and discuss areas of controversy and formulate questions that need further research.
Results:
1) AATD is a highly underdiagnosed condition. Over 120,000 European individuals are estimated to have severe AATD and more than 90% of them are underdiagnosed.
Conclusions:
2) Several clinical and etiological aspects of the disease are yet to be resolved. New strategies for early detection and biomarkers for patient outcome prediction are needed to reduce morbidity and mortality in these patients; 3) Augmentation therapy is the only specific approved therapy that has shown clinical efficacy in delaying the progression of emphysema. Regrettably, some countries reject registration and reimbursement for this treatment because of the lack of larger randomised, placebo-controlled trials. 4) Alternative strategies are currently being investigated, including the use of gene therapy or induced pluripotent stem cells, and non-augmentation strategies to prevent AAT polymerisation inside hepatocytes.
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