Review
α-1-Antitrypsin deficiency: clinical variability, assessment, and treatment

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Highlights

  • α-1-Antitrypsin deficiency predisposes to several clinical manifestations.

  • The detailed mechanisms for the range of clinical variation remain unknown, but include genetic, epigenetic, and environmental factors.

  • Augmentation or gene therapy may prevent or cure disease manifestations.

  • Identifying who needs treatment and how it is given remains to be elucidated.

The recognition of α-1-antitrypsin deficiency, its function, and its role in predisposition to the development of severe emphysema was a watershed in our understanding of the pathophysiology of the condition. This led to the concept and development of intravenous replacement therapy used worldwide to protect against lung damage induced by neutrophil elastase. Nevertheless, much remained unknown about the deficiency and its impact, although in recent years the genetic and clinical variations in manifestation have provided new insights into assessing impact, efficacy of therapy, and development of new therapeutic strategies, including gene therapy, and outcome measures, such as biomarkers and computed tomography. The current article reviews this progress over the preceding 50 years.

Section snippets

Fifty years of exploring the implications of α-1-antitrypsin deficiency

The original observation of a missing α1 protein based on paper electrophoresis of blood samples resulted in the first description of the clinical features of α-1-antitrypsin-deficient (AATD) subjects [1]. The subsequent 20–25 years consolidated an association of basal panacinar emphysema (see Glossary) with AATD, the identification of neutrophil elastase (NE) as its cognate proteinase with the ability to cause emphysema in animal models [2], and the logical development of α-1-antitrypsin (AAT)

α-1-Antitrypsin

AAT is a 52-kDa glycoprotein predominantly synthesised in hepatocytes from two alleles located on chromosome 14, although a small amount of protein is also made by monocytes/macrophages and airway epithelial cells that may have some local implications in the lung. AATD is the result of any of a variety of abnormalities in the AAT gene, including single point mutations, insertions and deletions, and even gene deletion. The majority of these variations have been covered in other reviews (e.g., [3]

Clinical variation

The initial patients described were young smokers with early onset basal panacinar emphysema. This has remained the ‘classical’ clinical phenotype and led to a testing policy confined to young COPD patients with a dominance of basal emphysema rather than the apical centrilobular emphysema of patients with COPD and normal AAT. Selective testing thus reinforced this as the clinical phenotype. However, significant variations in the ‘classical’ clinical phenotype have now become recognised (Figure 1

Other conditions

The other major morbidity in AATD due to homozygosity of the common Z variant gene relates to the liver. The Z gene variant protein product polymerises in the hepatocyte and accumulates within the endoplasmic reticulum [3]. This accumulated protein produces the classic Periodic acid–Schiff (PAS) positive inclusion bodies seen histologically [5]. The protein which accumulates in the hepatocyte enters the physiological degradation pathway; however, this is overloaded, and the end result is tissue

Epigenetics and genetic modifiers

Data suggest that although AATD predisposes to several clinical conditions the outcome is highly variable, indicating that other genetic or environmental factors may play a role (Table 1). Epigenetics refers to changes in the switching on/off of gene expression by factors other than DNA sequence; this might include environmental or lifestyle factors. Methylation is probably the best studied form of epigenetic change, in terms of predisposition to disease. DNA methylation in individuals with

Augmentation therapy

The susceptibility of AATD patients to the development of emphysema and the ability of neutrophil serine proteinases to produce many of the features of lung disease in experimental animals suggested cause and effect 2, 6, 7. For this reason, the logic of replenishing plasma (and hence lung) AAT was both sensible and subsequently shown to be feasible [62]. The infused half-life of AAT suggested that a reasonable regimen would be weekly infusions to restore AAT protection. However, it was

Biomarkers

Although lung physiology and radiological density are, by definition, biomarkers of lung damage in AATD, the term is commonly used in the context of a biochemical marker or relevant metabolite of the disease process or activity. Identification of biomarkers has enormous potential in the management of chronic lung diseases in general and, specifically, AATD. Markers specific for the presence and extent of the tissue damage leading to progressive lung and liver disease would enable clinicians to

Gene therapy

The classical form of gene therapy inserts normal genes into cells of patients with a genetic mutation. Studies of AAT gene therapy in animals have used retroviral [91], adenoviral 92, 93, 94, 95, 96, adeno-associated viral 97, 98, 99, and liposomal 100, 101 vectors to transfect cells. Recombinant adeno-associated viral vectors (rAAVs) containing the AAT gene have proven capable of achieving higher therapeutic levels of AAT 97, 98, and were less likely to induce an inflammatory response than

Concluding remarks

Although much has been learnt about AATD over the decades, and augmentation therapy has become widely available, much remains unknown. The true natural history of the condition in smokers and never smokers has yet to be determined, and may help explain why some individuals are particularly susceptible to the development of lung disease, fulminant hepatic failure, panniculitis, and Wegener's granulomatosis, whereas others are not. In addition, the reasons for and variations in the type and

Disclaimer statement

Professor R.A. Stockley has served on advisory boards for Grifols, Kamada, CSL Behring, and Baxter and has received fees for lecturing for Grifols and non-commercial grant funding from Grifols.

Glossary

α-1-Antitrypsin deficiency (AATD)
low circulating levels of α-1-antitrypsin.
Apical centrilobular emphysema
typical pattern of emphysema seen in COPD unrelated to AATD, where emphysema occurs in the upper zones and is most marked in the centre of pulmonary lobules.
Asthma
a condition in which intermittent airflow obstruction due to bronchospasm occurs; hallmarks include bronchodilator responsiveness (an increase in FEV1 of over 400 ml, or 12% of baseline value) and variability of peak expiratory flow

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      Patients with AATD can also progress into COPD, which is often triggered by interactions between environmental and genetic factors [61]. Currently, the intravenous infusion of purified human AAT protein is the gold standard of therapeutic option for the prevention of emphysema patients with AATD [62–64]. The protective action of augmentation therapy is very effective in improving wild-type AAT circulating levels, and lung function can be further improved via weekly or biweekly intravenous infusion of AAT protein [64].

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