Alpha-1 antitrypsin (AAT) deficiency is a genetic disorder with an autosomal inheritance pattern and codominant expression of alleles.
Allele mutations cause ineffective activity of alpha-1 antitrypsin, the enzyme responsible for neutralizing neutrophil elastase.
Pulmonary and hepatic manifestations include emphysema, COPD, bronchiectasis, and cirrhosis.
Granulomatosis with polyangiitis (formerly known as Wegener granulomatosis) and necrotizing panniculitis are infrequent complications but can prompt diagnosis.
Plasma AAT levels, protein phenotyping (called PI-typing), and genotyping may be necessary for diagnosis. Rare alleles may require gene sequencing.
Intravenous AAT augmentation therapy benefits some patients.
Alpha-1 antitrypsin (AAT) deficiency is an autosomal codominant genetic disorder (i.e., 1 allele is inherited from each parent and each allele is expressed equally). It results from allele mutations in the SERPINA1 gene at the protease inhibitor (PI) locus.
The PI locus is highly polymorphic. Different protein variants have different charges because of amino acid alterations. The charge affects the speed of protein migration on serum electrophoresis. Alleles are assigned a letter from A to Z depending on their relative speed of migration, with A being the fastest and Z the slowest. The allele most widely associated with clinical AAT deficiency is allele Z. The pattern of protein migration observed on serum electrophoresis is called the PI phenotype, which is written in form PI*[allele A][allele B].
PI* allele mutations cause ineffective activity of the specific protease inhibitor AAT, the enzyme responsible for neutralizing neutrophil elastase and preventing inflammatory tissue damage in the lungs. Variants of the enzyme may also polymerize and accumulate in the liver, resulting in hepatic failure in some patients.
AAT is also known as alpha-1 proteinase inhibitor.
History and exam
Key diagnostic factors
- productive cough
- shortness of breath on exertion
- current cigarette smoker
- exposure to gas, fumes, and/or dust
Other diagnostic factors
- age 32-41
- male sex
- chest hyperinflation
- scleral icterus/jaundice
- family history of AAT deficiency
1st investigations to order
- plasma AAT level
- pulmonary function testing
- chest x-ray
- chest CT
Investigations to consider
- gene sequencing
- exercise testing with ABG analysis
- liver ultrasound
- abdominal CT
low plasma AAT
D. Kyle Hogarth, MD, FCCP
Pulmonary and Critical Care
University of Chicago
DKH has given lectures for Grifols and Takeda, makers of alpha-1 antitrypsin related products. He serves on the data safety and monitoring board for a study conducted by InhibRx and is the principal investigator for studies sponsored by Vertex and Takeda. DKH is an author of a number of references cited in this topic.
Dr D. Kyle Hogarth would like to gratefully acknowledge Dr Paul J. Hutchison, a previous contributor to this topic.
PJH declares that he has no competing interests.
Jane Deng, MD
Assistant Professor of Medicine
David Geffen School of Medicine at UCLA
JD declares that she has no competing interests.
Franck Rahaghi, MD
Chair of Quality
Pulmonary Hypertension Clinic
Pulmonary Education and Rehabilitation
Department of Pulmonary, Allergy and Critical Care
Cleveland Clinic Florida
FR has been a consultant and speaker and has received funding from Baxter Healthcare and CSL Behring.
Graeme P. Currie, MD, FRCP
Consultant Chest Physician
Aberdeen Royal Infirmary
GPC declares that he has no competing interests.
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