Alpha-1 Antitrypsin Deficiency

The clinical effects of alpha-1 antitrypsin deficiency (AATD) are highly variable and are dependent on genotype, phenotype and exposure to risk factors such as smoking and pollution.1,2

AATD is a genetic condition associated with low protein levels of functional alpha-1 proteinase inhibitor (A1PI).2,3

The main clinical manifestations involve the lungs, leading to emphysema, and the liver, but it can also be associated with other skin and cardiovascular disorders.3,4,5

Pathophysiology

AATD is caused by a mutation in the SERPINA1 gene on chromosome 14 encoding for A1PI.6 Each person has two alleles (variants) of the gene, one inherited from each parent where the most common ones are:5

  • M allele— results in normal levels of functional A1PI6,7
  • S allele—  expresses approximately 50 to 60% normal A1PI where the variant is unstable and easily degrades8,9
  • Z allele—  expresses approximately 10 to 20% of normal A1PI due to much of the A1PI accumulating in the liver8,9


A1PI is primarily synthesized in the liver and secreted into the bloodstream where it diffuses into the lungs and other tissues.2,8,10  The main role of A1PI is to inhibit neutrophil elastase (NE) and keep its activity in check.2,10 NE is a proteinase responsible for the breakdown of a variety of proteins involved in modulating inflammation and therefore plays a key role in tissue repair and protection from infections.11 Therefore, a deficiency in functional A1PI results in excessive NE activity and leads to the degradation of lung tissue and blood vessels.12

Epidemiology

The prevalence of AATD varies by genotype with an estimated 3.4 million people living with the disease worldwide (protease inhibitor [Pi] SS, PiSZ, PiZZ) and 116 million carriers (PiMS, PiMZ).2,13 In the U.S., it’s estimated that more than 500,000 people have deficient PiSS and PiSZ allele combinations, and 60,000 have the PiZZ genotype which is associated with severe deficiency, while more than 24 million people are carriers (PiMS, PiMZ).8

Diagnosis

Variability in clinical presentations results in delayed and misdiagnosis, which means the majority of cases remain undiagnosed (>90%).1,14,15,16 A confirmed AATD diagnosis should involve both quantitative and qualitative laboratory determinations:10,17,18,19

  • Quantitative determination of serum A1PI levels
  • Confirmatory qualitative assessment of genotyping/phenotyping
  • DNA sequencing may be necessary to identify rarer mutations

Navigating AATD

The primary manifestations of AATD are lung disease and liver involvement, which are irreversible and progressive.20 Therefore, the consequences of delayed or misdiagnosis can be fatal in those patients with severe AATD; most commonly due to respiratory failure (58% of deaths), including pneumonia and pneumothorax; and liver diseases (12% of deaths), including liver failure and primary carcinoma.21 This leads to a high disease burden, associated with increased mortality, morbidity, quality of life impairment and cost.21,22,23,24,25,26 Nonpharmacological approaches are crucial to managing AATD and include smoking cessation, maintaining a healthy diet and moderate exercise, staying up to date with recommended immunization and pulmonary rehabilitation.17 Currently, augmentation therapy is the only A1P1 pharmacological option available and can be part of the strategy in the management of patients with AATD-related emphysema.10,27,28 It is administered by intravenous infusion and aims to increase serum A1PI levels.2 However, the manufacturing process is complex and expensive to produce as it needs to be purified from large volumes of human plasma.29

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  28. Global Initiative for Chronic Obstructive Lung Disease, 2020 report. Available from https://goldcopd.org/wp-content/uploads/2019/12/GOLD-2020-FINAL-ver1.2-03Dec19_WMV.pdf. Accessed February 1, 2023.
  29. National Institute for Health and Care Excellence. Highly specialized technology evaluation. Human alpha 1-proteinase inhibitor for treating emphysema. Available at: https://www.nice.org.uk/guidance/gid-hst10017/documents/scope-consultation-comments-and-responses. Accessed February 1, 2023.