Current (and Future) Possibilities for Diagnosing Alpha-1-Antitrypsin Deficiency

AAT Deficiency as an Underdiagnosed Disease

Alpha-1-antitrypsin is among the serine protease inhibitors. In its congenital deficiency, proteolysis of the alveolar walls occurs, leading to the development of COPD with emphysema. It may also manifest as liver damage among other symptoms. It is estimated that this autosomal co-dominant inherited disease is undiagnosed in up to 90% of patients.

According to data from an American survey of nearly 400 patients with AAT deficiency, the average interval between the first respiratory difficulties and diagnosis was on average 7.2 years. By that time, 43.7% of patients had seen at least 3 doctors — only 25.1% of cases were diagnosed by the first doctor they saw.

The progression of emphysema can be slowed by augmentation therapy with exogenous AAT. Therefore, it is important to actively seek these patients and start treatment as soon as possible. Genetic counseling also allows the identification of potential carriers or other patients in affected families.

What Are the Current Possibilities for Diagnosing AAT Deficiency?

It is estimated that around 3.4 million patients worldwide are affected by AAT deficiency. There are another 116 million carriers. In our population, the most common alleles are M (normal), S (medium AAT deficiency in serum), and Z (severe deficiency) of the SERPINA1 gene.

Genotyping with allele identification of this gene should be performed in all patients with COPD. If a defective allele is found, serum AAT level determination follows. One study included a total of 515,480 such patients. Of them, 14.4% had a different genotype than MM — the Z allele was identified in 5.9% of patients, and in 0.4% in homozygous form (ZZ). The average age of subjects with the ZZ genotype was 53.7 years, compared to 58.4 years for patients with the MM genotype, slightly higher.

In recent years, a kit for genotyping the SERPINA1 gene using hybridization and PCR has been developed. After DNA extraction from the patient's blood or a buccal swab, 14 of the most common mutations associated with AAT deficiency are tested, focusing on the F, I, S, and Z alleles. Results should be available in about 7 days.

Newborn Screening

Opinions vary on whether to expand newborn screening to include AAT deficiency detection. Some argue that lung and liver diseases are relatively rare in childhood with this genetic defect. In an American study, 32 samples with a dysfunctional allele were identified among 107,038 newborns: 21 homozygous ZZ or ZNull and 11 heterozygous MZ or SZ. The prevalence of severe AAT deficiency was thus estimated at 1:5097. Combined with data from a large Swedish population study, the estimated prevalence was 1:4455. Early detection of AAT deficiency may, however, be beneficial for educating about risk behaviors associated with smoking (not only) in adolescence or in career selection.

Primary Care Registries and Physician Education

Another considered option is active screening of non-smokers with COPD in primary care registers. However, this would require improvements in the diagnosis of chronic obstructive pulmonary disease itself.

In a study at the Miami Veterans Affairs Medical Center (VAMC) in the USA, for example, 13.3% of people over 40 years old were evaluated as at risk for developing COPD. In this group, the use of automatically generated reminders for attending physicians saw an increase in spirometric examinations in at-risk patients from 24.4% to 83%. In the group with known COPD, the increase was from 58% to 84.2%. In 43% of at-risk individuals, COPD was newly diagnosed, while in 33% of patients with