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Alpha-1 antitrypsin deficiency

What's new

The Canadian Thoracic Society (CTS) has updated its guidelines for the evaluation and management of alpha-1 antitrypsin (A1AT) deficiency. The revised guidelines suggest testing for A1AT deficiency at COPD diagnosis, in adult-onset asthma with persistent airway obstruction, and in unexplained bronchiectasis. Initial testing includes serum A1AT levels and SERPINA1 genetic testing in high clinical suspicion, and serum A1AT levels followed by genetic testing if levels are elevated in moderate clinical suspicion. Augmentation therapy can be offered to patients with COPD who meet all of the following criteria: never-smoker or ex-smoker, FEV1 <80% predicted, emphysema, A1AT deficiency-associated SERPINA1 genotype, severely reduced functional A1AT level, and receiving optimal pharmacological and nonpharmacological COPD treatment. .

Background

Overview

Definition
AATD is an inherited disorder caused by mutations in the SERPINA1 gene, leading to a deficiency or dysfunction of the α-1 antitrypsin protein.
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Pathophysiology
The pathophysiology of α-1 antitrypsin deficiency involves a deficiency in the α-1 antitrypsin protein. The imbalance of proteases and antiproteases leads to unopposed neutrophil elastase activity and subsequent tissue damage in the lungs.
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Epidemiology
The prevalence of α-1 antitrypsin deficiency in Europe is estimated at 20 per 100,000 population.
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Risk factors
The primary risk factor for α-1 antitrypsin deficiency is a genetic predisposition, as the condition is inherited in an autosomal co-dominant manner. Individuals of Northern European descent are particularly susceptible due to a higher likelihood of carrying the defective gene.
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Disease course
Clinically, patients with α-1 antitrypsin deficiency often present with symptoms such as dyspnea, chronic cough, and recurrent respiratory infections. In some cases, the disease may also manifest as unexplained bronchiectasis. In rare cases, it can also lead to liver disease, including chronic hepatitis, cirrhosis, and HCC.
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Prognosis and risk of recurrence
The prognosis can vary widely among patients. The disease is generally progressive, with the potential for significant lung damage over time.
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Guidelines

Key sources

The following summarized guidelines for the evaluation and management of alpha-1 antitrypsin deficiency are prepared by our editorial team based on guidelines from the Canadian Thoracic Society (CTS 2025), the Global Initiative for Chronic Obstructive Lung Disease (GOLD 2025), the European Association for the Study of the Liver (EASL 2024), the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP ...
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Screening and diagnosis

Clinical presentation
As per ERS 2017 guidelines:
Recognize that lung disease in α-1 antitrypsin deficiency generally presents at a younger age than usual COPD and may be misdiagnosed as asthma.
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Recognize that patients with α-1 antitrypsin deficiency are more likely to have basal emphysema than patients with usual COPD.
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  • Screening of family relatives

  • Indications for testing (lung disease)

  • Indications for testing (liver disease)

  • Indications for testing (vasculitis)

  • Indications for testing (panniculitis)

Diagnostic investigations

AAT levels
As per CTS 2025 guidelines:
Consider obtaining initial measurement of serum α-1 antitrypsin levels and genetic testing in patients with high clinical suspicion of α-1 antitrypsin deficiency.
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Consider obtaining initial measurement of serum α-1 antitrypsin levels, followed by genetic testing if α-1 antitrypsin level is < 23 mcmol/L (< 1.2 g/L), in patients with moderate clinical suspicion of α-1 antitrypsin deficiency.
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  • Protein electrophoresis

  • Genetic testing

  • Pulmonary function testing

  • Chest imaging

  • Liver testing

Medical management

Setting of care: as per ERS 2017 guidelines, manage patients with α-1 antitrypsin deficiency in supervision by reference centers of excellence at a national or regional level.
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  • Augmentation therapy

  • UDCA

Nonpharmacologic interventions

Lifestyle modifications: as per EASL 2024 guidelines, provide lifestyle counseling as smoking, obesity, and alcohol consumption have negative effects on the health of patients with α-1 antitrypsin deficiency.
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Surgical interventions

Lung volume reduction surgery: as per ERS 2017 guidelines, consider performing surgical volume reduction and endobronchial valve placement in selected patients with α-1 antitrypsin deficiency, with a careful appraisal of risks and benefits assessed by a multidisciplinary team experienced in lung volume reduction and α-1 antitrypsin deficiency.
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  • Lung transplantation

  • Liver transplantation

  • Liver donation

Follow-up and surveillance

Surveillance for lung disease: as per ERS 2017 guidelines, obtain annual pulmonary function testing including post-bronchodilator FEV1 and gas transfer to monitor for disease progression.
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  • Surveillance for liver disease

  • Surveillance for HCC