Diagnosis and augmentation therapy for alpha-1 antitrypsin deficiency: current knowledge and future potential

Abstract

The underdiagnosis of alpha-1 antitrypsin (AAT) deficiency (AATD) has been recognized for many years, yet little progress has been made in treatment of the disease. In this review, we summarize the AATD disease process as well as its diagnosis and treatment by AAT augmentation therapy. AATD is a rare autosomal disease that primarily affects the lungs and liver. AATD is associated with an increased susceptibility to developing pulmonary emphysema. The specific pharmacological treatment for AATD is intravenous administration of exogenous AAT. Augmentation therapy with AAT increases serum and pulmonary epithelial AAT levels, restores anti-elastase capacity, and decreases inflammatory mediators in the lung. Augmentation therapy reduces the loss of lung density over time, thus slowing progression of the disease. The effects of augmentation therapy on outcomes, such as frequency/duration of flare-ups, quality of life, lung function decline and mortality, are assessed. Wider testing for AATD, potentially through primary care physicians, could result in earlier treatment and better outcomes for individuals with AATD-induced lung respiratory disease.

Keywords: alpha-1 antitrypsin; alpha-1 antitrypsin deficiency; augmentation therapy; computed tomography densitometry; forced expiration volume in 1 s; lung density.

Figure 1

3D structure of the alpha-1 antitrypsin molecule. The polypeptide chain is composed of three β-sheets (yellow, green and red strips) and nine α-helices (in yellow, blue, orange and red coils). The active site loop mediates inhibitory specificity. Adapted from a generic image of the free-use protein.

Figure 2

Individuals who have inherited at least one abnormal alpha-1 antitrypsin gene (S, Z) are referred to as heterozygotes for PiMZ or PiMS gene variants or carriers. Most prevalent severe deficiency is associated with individuals who are homozygous for Pi*ZZ.

Figure 3

Protective and confirmatory testing thresholds in the context of the ranges of serum alpha-1 antitrypsin (AAT) concentrations for genetic variants. Created with data taken from ref.