How and What the National AATD Register Benefits Experts and Patients
Given that alpha-1-antitrypsin deficiency (AATD) is still not receiving enough attention, it is necessary to raise professional awareness of this hereditary disease by all means. This is also one of the goals of the National AATD Register, which collects patient data to monitor the progression of the disease, identify the most suitable prognostic markers, and monitor the presence or progression of other organ impairments in these patients.
Alpha1-Antitrypsin Deficiency
Alpha1-antitrypsin deficiency (AATD) is a hereditary disease first described by Laurell and Eriksson in 1963. The discovery of the disease was related to the development of pulmonary emphysema at a young age. It results from a defect in the AAT gene, which is located on the chromosomal segment 14q31-32.3. Today, more than 100 variants of this gene are observed, and the combination of alleles results in various homozygous and heterozygous constitutions. The specific disorder and combination of alleles determine the risk of organ impairment.
Diagnosis, Detection, and Prevalence
The exact number of individuals with AATD is unknown. It is estimated that there are about 3.5 million people worldwide with this condition. Since routine screening is not recommended nowadays, the detection rate of affected individuals is very low. Testing is mainly done in younger people diagnosed with chronic obstructive pulmonary disease (COPD). Approximately 1% of all COPD patients have their disease conditioned (in part) by AATD. AATD identification is based on the serum concentration of alpha1-antitrypsin, with normal levels ranging from 1.0 to 2.0 g/l. If levels drop below the lower limit of normal, it is considered AATD. The threshold between mild and severe deficiency is set at 0.5 g/l.
Clinical Manifestations
COPD is the primary organ manifestation of alpha1-antitrypsin deficiency. Individuals with severe deficiency may show COPD symptoms as early as the third decade of life and are typically diagnosed a decade later. However, severe deficiency does not necessarily lead to lung impairment, as both internal and external factors, especially cigarette smoking, play a significant role.
The liver is another commonly affected organ. The specific defect determines the outcome, as some variants of AATD do not cause liver impairment (e.g., when AAT protein is not produced at all), while others may lead to accumulation of defective AAT protein polymers and subsequent hepatocyte apoptosis, potentially resulting in liver cirrhosis, with about a third of patients being at risk. Rarely, other organs such as the skin (panniculitis), intestines, or others may be affected.
Treatment Options
Upon diagnosis of AATD, patients are advised to quit smoking. Being a non-smoker is one of the criteria for augmentation therapy, which is currently the only disease-modifying approach. It involves intravenous infusion of purified AAT obtained from the plasma of healthy donors, typically administered once a week.
Since the establishment of the National AATD Register, the criteria for augmentation therapy have been revised. Based on new findings, patients with milder impairment have been eligible for this therapy since 2019, aiming to provide treatment early and slow the progression of the disease. Augmentation therapy is not recommended for patients with liver impairment, who are treated similarly to other liver diseases not related to AATD.
National AATD Register
The National AATD Register is a non-interventional retrospective-prospective longitudinal study involving patients with alpha1-antitrypsin deficiency. Since AATD does not receive much attention, one of the main goals is to raise professional awareness of this hereditary disease. The register collects data from patients with severe or rare AATD, regardless of the type of organ impairment and age, to track lung impairment progression, establish the most suitable monitoring parameters to characterize lung impairment progression and predict the disease prognosis, as well as to monitor the presence or progression of other organ impairments.
The register collects data from AATD patients who have consented to participate in the study. By July 2021, 135 patients were registered, with 66.7% being men. The register is initiated by the guarantor of the diagnostic and treatment center for alpha1-antitrypsin deficiency at the Department of Pulmonary Medicine, First Faculty of Medicine, Charles University, and Thomayer Hospital in Prague, Dr. Jan Chlumský, Ph.D.
System Functioning
Data is collected using electronic forms within the CLADE-IS system developed by the Institute of Biostatistics and Analyses, Ltd., for data collection and management in clinical studies. CLADE-IS (Clinical Data Warehouse – Information System) is one of the most modern electronic data collection systems. It provides an efficient alternative to traditional data collection using paper forms, which required transcription into a relational database.
The system allows physicians to enter and verify data in real-time, and online validation rules ensure data quality during entry. The system can be used across various devices and works on most available web browsers, so no additional software installation is required. Only authorized individuals with unique usernames and passwords can access the system interface. Each patient/case is assigned a unique ID, ensuring that data in the system is anonymized (preventing specific patient identification). This complies with applicable data protection regulations.
Institute of Biostatistics and Analyses (IBA)
The Institute of Biostatistics and Analyses, Ltd. (IBA) is a spin-off company of Masaryk University in Brno, operational since 2014. It primarily focuses on clinical research project management, real-world evidence (RWE) projects, organization and management of clinical studies (especially non-interventional studies and medical registries). This main activity is complemented by other offered and provided services such as market access support, cost-effectiveness analyses, pharmacovigilance, clinical data analyses, development of proprietary software products, and graphic design.
Dr. Jan Chlumský, Ph.D.
Department of Pulmonary Medicine, First Faculty of Medicine, Charles University and Thomayer Hospital, Prague
Ing. Kateřina Kusalová
Institute of Biostatistics and Analyses, Ltd., Brno
Sources:
1. Laurell C. B., Eriksson S. The electrophoretic α1-globulin pattern of serum in α1-antitrypsin deficiency. 1963. COPD 2013; 10 (Suppl. 1): 3–8, doi: 10.3109/15412555.2013.771956.
2. Chlumský J., Kusalová K. COPD and alpha1-antitrypsin deficiency: What do the data from the national register say? Acta medicinae 2020; 8: 58–60.
3. Chlumský J. Augmentation therapy for COPD based on alpha1-antitrypsin deficiency. Remedia 2016; 26 (6); 500–502.
4. Chronic obstructive pulmonary disease based on alpha-1 antitrypsin deficiency. Thomayer Hospital, 2021. Available at: https://alfa1.cz/index.php
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