17th February 2025

Alpha-1 antitrypsin deficiency

AAT deficiency is an inherited condition which causes reduced levels of alpha-1 antitrypsin, a protease inhibitor that inhibits elastase, an enzyme that causes inflammatory damage to the lungs. It should be considered in younger non-smokers who present similarly to COPD.

Genetics of AAT deficiency

The inheritance for alpha-1 antitrypsin deficiency is co-dominant.

The affected gene is on chromosome 14. Many different alleles have been identified but the most common are the M allele (normal), S allele (partially defective) and Z allele (nearly fully defective).

• MM – normal phenotype
• MS/MZ – reduced levels of AAT (50-75% of normal) but if non-smoker, risk of developing COPD is low
• SS/SZ – increased risk of developing COPD compared to the general population
• ZZ – worst prognosis, with an almost 100% chance of developing COPD

Features of AAT deficiency

Pulmonary manifestations include COPD and bronchiectasis, which is worse in smokers. Hepatic manifestations include cirrhosis, increased risk of hepatocellular carcinoma and cholestasis. There are also skin manifestations such as panniculitis and vasculitis (particularly ANCA-positive disease).

Management of AAT deficiency

Smoking cessation is crucial. Other treatments include bronchodilator therapy, alpha-1 antitrypsin augmentation therapy and surgical management options (lung transplant or lung volume reduction surgery).

References

• National Institute for Health and Care Excellence. Chronic obstructive pulmonary disease in over 16s: diagnosis and management [Internet]. 2018 [cited 2022 Jan 31] Available from: https://www.nice.org.uk/guidance/ng115/resources/chronic-obstructive-pulmonary-disease-in-over-16s-diagnosis-and-management-pdf-66141600098245 
• The National Institute for Health and Care Excellence. Oxygen [Internet]. NICE; 2019 [cited 2022 March 28] Available from: https://bnf.nice.org.uk/treatment-summary/oxygen.html
• Sethi S. Bacteria in Exacerbations of Chronic Obstructive Pulmonary Disease: Phenomenon or Epiphenomenon? Proceedings of the American Thoracic Society. 2004 Apr 1;1(2):109–14
• Davidson AC, Banham S, Elliott M, Kennedy D, Gelder C, Glossop A, et al. BTS/ICS guideline for the ventilatory management of acute hypercapnic respiratory failure in adults. Thorax. 2016 Mar 14;71(Suppl 2):ii1–35
• Chapman S. Oxford handbook of respiratory medicine. Oxford; New York: Oxford University Press; 2005