Alpha-1 antitrypsin deficiency

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Last reviewed: 19 Jun 2025

Last updated: 15 Apr 2025

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 AAT, 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.

Definition

Alpha-1 antitrypsin (AAT) deficiency is an autosomal codominant genetic disorder (i.e., one 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.[1]

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.[2] 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].[3]

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.[4][5] 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.

História e exame físico

Principais fatores diagnósticos

productive cough
shortness of breath on exertion
current cigarette smoker
exposure to gas, fumes, and/or dust
hepatomegaly
ascites
confusion

Detalhes completos

Outros fatores diagnósticos

ages 32-41 years
male sex
wheezing
chest hyperinflation
scleral icterus/jaundice
asterixis

Detalhes completos

Fatores de risco

family history of AAT deficiency

Detalhes completos

Investigações diagnósticas

Primeiras investigações a serem solicitadas

plasma AAT level
pulmonary function testing
chest x-ray
chest CT
LFTs

Detalhes completos

Investigações a serem consideradas

phenotyping
genotyping
gene sequencing
exercise testing with ABG analysis
alpha-fetoprotein
liver ultrasound
abdominal CT
abdominal MRI
liver biopsy

Detalhes completos

Algoritmo de tratamento

CONTÍNUA

low plasma AAT

Colaboradores

Autores

D. Kyle Hogarth, MD, FCCP

Professor

Pulmonary and Critical Care

University of Chicago

Chicago

Disclosures

DKH is a consultant for Grifols, Takeda, and Wave Life Sciences, and gives lectures for Takeda; Grifols and Takeda are both makers of alpha-1 antitrypsin related products. DKH serves on the MASEK committee for the Alpha One Foundation, and is part of the A1BC study sponsored by the National Institutes of Health and the Alpha One Foundation. DKH is an author of a number of references cited in this topic.

Acknowledgements

Dr D. Kyle Hogarth would like to gratefully acknowledge Dr Paul J. Hutchison, a previous contributor to this topic.

Disclosures

PJH declares that he has no competing interests.

Peer reviewers

Jane Deng, MD

Assistant Professor of Medicine

David Geffen School of Medicine at UCLA

Los Angeles

Disclosures

JD declares that she has no competing interests.

Franck Rahaghi, MD

Chair of Quality

Director

Pulmonary Hypertension Clinic

Head

Pulmonary Education and Rehabilitation

Department of Pulmonary, Allergy and Critical Care

Cleveland Clinic Florida

Weston

Disclosures

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

Aberdeen

Disclosures

GPC declares that he has no competing interests.

References

Our in-house evidence and editorial teams collaborate with international expert contributors and peer reviewers to ensure that we provide access to the most clinically relevant information possible.

Key articles

American Thoracic Society/European Respiratory Society Statement. Standards for the diagnosis and management of individuals with alpha 1-antitrypsin deficiency. Am J Respir Crit Care Med. 2003 Oct 1;168(7):818-900.Full text Abstract

Sandhaus RA, Turino G, Brantly ML, et al. The diagnosis and management of alpha-1 antitrypsin deficiency in the adult. Chronic Obstr Pulm Dis (Miami). 2016 Jun 6;3(3):668-82.Full text Abstract

Marciniuk DD, Hernandez P, Balter M, et al. Alpha-1 antitrypsin deficiency targeted testing and augmentation therapy: a Canadian Thoracic Society clinical practice guideline. Can Respir J. 2012 Mar-Apr;19(2):109-16.Full text Abstract

Hill AT, Sullivan AL, Chalmers JD, et al. British Thoracic Society Guideline for bronchiectasis in adults. Thorax. 2019 Jan;74(suppl 1):1-69.Full text Abstract

Fraughen DD, Ghosh AJ, Hobbs BD, et al. Augmentation therapy for severe alpha-1 antitrypsin deficiency improves survival and is decoupled from spirometric decline-A multinational registry analysis. Am J Respir Crit Care Med. 2023 Nov 1;208(9):964-74.Full text Abstract

Reference articles

A full list of sources referenced in this topic is available to users with access to all of BMJ Best Practice.

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- Asthma
- COPD
- Bronchiectasis
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Guidelines
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Alpha-1 antitrypsin deficiency

Summary

Definition

História e exame físico

Principais fatores diagnósticos

Outros fatores diagnósticos

Fatores de risco

Investigações diagnósticas

Primeiras investigações a serem solicitadas

Investigações a serem consideradas

Algoritmo de tratamento

low plasma AAT

Colaboradores

Autores

D. Kyle Hogarth, MD, FCCP

Disclosures

Acknowledgements

Disclosures

Peer reviewers

Jane Deng, MD

Disclosures

Franck Rahaghi, MD

Disclosures

Graeme P. Currie, MD, FRCP

Disclosures

References

Key articles

Reference articles

A full list of sources referenced in this topic is available to users with access to all of BMJ Best Practice.

Differentials

Guidelines

Patient information

Log in or subscribe to access all of BMJ Best Practice

Log in or subscribe to access all of BMJ Best Practice

Log in to access all of BMJ Best Practice