National Alpha-1 Antitrypsin Deficiency Targeted Detection Programme

June 25, 2014 Alpha1 Admin Comments Off

Alpha-1 antitrypsin (AAT) is an antiprotease produced chiefly by the liver. Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder characterised by low serum levels of AAT and is associated with lung and liver disease.
In May 2004 a national targeted detection programme for alpha-1 antitrypsin deficiency was established in Beaumont Hospital. Funded directly by the Irish Government’s Department of Health, the screening programme provides free testing to patients with chronic obstructive pulmonary disease (COPD), non-responsive asthma, cryptogenic liver disease and to relatives of AATD patients.

A range of methods are used to diagnose AATD including phenotyping by isoelectric focussing and genotyping by RT-PCR. Upon diagnosis the Alpha One Foundation also provides a range of ancillary services to patients including counselling, expert advice, information packs and leaflets, and opportunities to enrol in clinical trials and to join the Alpha-1 patient support group. Alpha-1 antitrypsin (AAT) is a 52kDa glycosylated protein. Produced in the liver and secreted into the blood, AAT diffuses into the lungs where it functions as an antiprotease. Antiproteases regulate and inactivate protein-splitting enzymes such as neutrophil elastase, an enzyme capable of destroying alveolar wall connective tissue. AAT is the most abundant antiprotease in the lung and therefore plays a major role in maintaining a healthy, functioning lung. Alpha-1 antitrypsin deficiency (AATD) is a hereditary autosomal codominant disorder caused by mutations in the AAT gene located on chromosome 14. Genetic variants of the AAT gene are characterised by their electrophoretic mobilities as medium (M), slow (S) or very slow (Z). The most common variants associated with disease are the S (Glu264Val) and Z (Glu342Lys) mutations, caused by a single amino acid replacement of glutamic acid at positions 264 and 342 of the polypeptide respectively. Both mutations result in decreased levels of circulating AAT due to retention of the aberrantly folded protein in the liver, and classically result in liver disease in children, and early onset emphysema or occasionally liver disease in adults. Moreover, the small amount of AAT that reaches the lung in AATD patients is inactivated by cigarette smoke. Smoking is the single biggest risk factor for the development of emphysema in AATD patients, and individuals with AATD who smoke develop severe, early-onset emphysema. The most commonly observed genotypes are MM (normal), MS, MZ (heterozygotes), SZ (compound heterozygote) and SS or ZZ (homozygotes). It is unclear, as yet, whether the carrier status (MS or MZ) confers an increased risk of disease.

AATD is under-diagnosed with prolonged delays in diagnosis common. In addition, the majority of AATD individuals with emphysema are misdiagnosed as COPD patients. A recent US study showed it takes an average 5.6 years from the time symptoms first appear to accurate diagnosis. Increased awareness and understanding of AATD is therefore vital to prevent the continuing under-diagnosis of this condition. To this end, we have launched a national registry of AATD patients and a website ( providing a resource for doctors, patients, and the general public. All patients diagnosed through our targeted detection programme are offered a variety of services including counselling, expert advice, information packs/leaflets, and opportunities to enrol in clinical trials and to join the Alpha-1 patient support group. Based on studies in other European countries it is estimated that 1,200 Irish citizens have AATD and up to 200,000 Irish citizens are carriers, yet only 110 individuals with AATD have been identified in Ireland to date. A research project recently undertaken in our laboratory screened 1,000 anonymised DNA samples provided by the Trinity College Biobank for the presence of the S and Z mutations. This investigation of a sample Irish population revealed a gene frequency of 0.05 for the S mutation and 0.022 for the Z mutation, which is higher than anticipated based on studies in other European populations.

  Phenotype AAT (%) What does it mean?
Normal  MM  100  No altered AAT gene so no risk of disease 
Carrier  MS  80  Carries altered AAT gene but evidence suggests no increased risk of disease
Carrier  MZ  60  Carries altered AAT gene & may develop disease (particularly if smoking)
Mild Deficiency SS 60 Carries two altered AAT genes but evidence suggests no increased risk of disease
Severe Deficiency SZ/ZZ 10 – 30 Carries two altered AAT genes and will probably develop disease (particularly if smoking)

Table 1: Explanation of the various AAT phenotypes and their clinical consequences.

In summary, AATD is more prevalent in Ireland than previously thought, even allowing for the targeted, symptomatic population investigated in this programme. The advantages of early and accurate diagnosis of AATD are manifold and include (1) closer observation and management of affected individuals, especially regarding pulmonary and liver health, (2) family member testing, at least some of whom may have lung or liver complications, (3) aggressive smoking cessation efforts, which have been associated with lower rates of smoking among AAT-deficient individuals, and (4) consideration of occupational hazards and environment as exposures to some occupational dusts and vapours can accelerate pulmonary decline. Once identified, AATD patients have the opportunity to enrol in clinical trials currently taking place in Beaumont Hospital, such as the AAT augmentation therapy clinical trial for ZZ individuals, and the MZ family study which is attempting to fully clarify the risk of COPD in MZ individuals. To conclude, the importance of an early diagnosis of AATD cannot be over-emphasised as the resulting appropriate medical follow-up and lifestyle changes can help prevent or at least postpone the development of AATD-related lung and liver disease.