Clinical FeaturesOncology

Alpha-1 Antitrypsin Deficiency (AATD) – Precision Medicine for COPD?

Authors: Tomás P. Carroll1,2, Ronan C. Heeney1,2, Geraldine Kelly2, Gerry McElvaney1

Author Affiliations: 1Irish Centre for Genetic Lung Disease, RCSI Education and Research Centre, Beaumont Hospital, Dublin 9. 2Alpha-1 Foundation Ireland.


What is Alpha-1 Antitrypsin Deficiency?

Alpha-1 antitrypsin (AAT) is a protein produced primarily by the liver that is responsible for inhibiting neutrophil elastase (NE) as well as several other proteases. AAT provides a protective screen for the lungs against proteases released by cigarette smoke and other inhaled irritants. These proteases can damage lung tissue if left uncontrolled. AAT is an acute-phase protein and rises during infection and inflammation, a clue to its additional immuno-modulatory properties.

Alpha-1 antitrypsin deficiency (AATD) is a genetic condition that causes low serum levels of AAT. Deficiency allows proteases such as NE to cause irreversible damage to fragile lung tissue, a process dramatically accelerated by cigarette smoke. The lung tissue destruction manifests as emphysema or chronic obstructive pulmonary disease (COPD)(Figure 1).


Figure 1. The role of alpha-1 antitrypsin (AAT) in normal and AAT deficient individuals.

AAT protein production is controlled by the SERPINA1 gene. Every individual has 2 copies (also called alleles) of the SERPINA1 gene. Each allele is equally responsible (co-dominant) for producing its share of AAT protein. The normal SERPINA1 allele is called M and produces fully functional M AAT protein. If a person inherits 2 normal SERPINA1 alleles, they produce enough AAT protein to protect their lungs and are referred to as having the “MM” phenotype.

More than 200 alleles of the SERPINA1 gene exist resulting in a large variety of abnormal variants of AAT. These mutations can impair the quantity or quality of the protein produced, or sometimes both. Common mutations include “I”, “S” and “Z”. A person can have many different allele combinations resulting in various phenotypes such as MM, MS, MZ, SZ, IZ, and ZZ. This gives rise to a spectrum of deficiency from moderate (MZ and SZ) to severe (ZZ)(Figure 2).

Figure 2. Average serum AAT concentrations (g/L) between the different AAT phenotypes (data from the Irish National Targeted Detection Programme for AATD). Normal range for AAT is 1.0 – 2.0 g/L (red dotted lines on graph).

AAT phenotypes are confirmed in the laboratory by the technique of isoelectric focusing where the AAT variants are separated on agarose gel by an electrical current. Where the protein stops on the gel and the resulting banding pattern it produces reveals a specific protein “phenotype” unique to each combination of alleles (Figure 3).

Figure 3. Isoelectric focusing technique used to diagnose AATD. The 6 major AAT phenotypes are shown with ZZ the most severe AATD phenotype (serum AAT reduced by 80-85%).

Further genetic analysis is sometimes required to determine the precise mutation caused a deficiency (genotype), but this usually applies to rare or novel mutations. The further genetic testing takes the form of allele-specific genotyping for known mutations, or gene sequencing for novel mutations. The full range of diagnostic techniques used to investigate AATD at the National Centre of Expertise for AATD at Beaumont Hospital are presented in Figure 4. Through the national targeted detection programme for AATD, several ultra-rare mutations have been found to exist in the Irish population that produce no detectable AAT in blood. These are called “Q0” or “null” mutations.  These mutations are named after the place of birth of the index or first case, examples include the novel Q0dublin and Q0cork mutations.

Figure 4. The various diagnostic approaches used on the path to a diagnosis of AATD.

Clinical Manifestations of AATD

The risk of disease in AATD is influenced by the type of AATD (severe or moderate) in combination with lifestyle and occupational exposures (e.g. smoking)(Figure 5). Nevertheless, the organs most commonly affected by AATD are the lungs and the liver. The progression to significant airflow obstruction in the form of COPD and emphysema is greatly accelerated in smokers. Patients with AATD also have bronchial hyper-responsiveness, which can mimic asthma. Patients can also present with bronchiectasis, which may manifest itself as recurrent respiratory tract infections. Given the wide variety of different phenotypes that exist; it should be noted that clinical expression is highly variable, even within individuals with the same phenotype. Lung symptoms can be as simple as a persistent cough or mild shortness of breath even in the absence of airflow obstruction and some may be minimally affected or asymptomatic. With regard smokers who have yet to develop significant respiratory disease, we would encourage testing for AATD given the high prevalence in the Irish population and the potential for significant risk factor modification in the form of rapid smoking cessation in affected individuals.

While AATD causes lung disease through its absence (loss of function); it causes liver disease through the gain of a toxic function. The Z mutation causes the AAT protein to misfold and adopt an abnormal shape, which results in hepatocyte accumulation. This can result in the development of hepatic steatosis, cirrhosis and hepatocellular carcinoma. This may ultimately progress to liver transplantation or death. The progression to cirrhosis is also accelerated by lifestyle factors such as alcohol consumption and is another reason for testing in order to guide lifestyle modification.

Figure 5. Key facts about the three most common forms of AATD found in Ireland (MZ, SZ, and ZZ).

Rarer manifestations of AATD include a skin condition called panniculitis, which presents as inflammation of the subcutaneous fat. Erythema nodosum is a form of panniculitis and as such AATD should be screened for in patients presenting with erythema nodosum, especially necrotising erythema nodosum as it can be effectively treated with intravenous purified AAT. In fact, the contribution of AATD to panniculitis continues to be under-recognised. Panniculitis can be fatal and often occurs suddenly in otherwise healthy individuals. Importantly, AATD-related panniculitis can be effectively treated with intravenous infusions of plasma-purified AAT protein, and in some cases represents a treatment that is life-saving (Franciosi et al, 2015) when first-line treatment with dapsone fails.AATD is also linked to ANCA-associated vasculitis, likely due to the imbalance between the anti-protease effects of AAT and neutrophil-derived proteases. Patients presenting with ANCA-associated vasculitis should be screened for AATD.


The Prevalence of AATD in Ireland

It is known that 1 in 25 individuals carry the Z mutation and that ~265,000 people have a clinically relevant phenotype of some description. Currently, over 22,000 people have been screened for AATD on the island of Ireland in a national targeted detection programme and approximately 5,000 have been found to carry an abnormal phenotype. Our screening efforts have identified over 450 out of the estimated 3,000 ZZ (most severely affected) AATD individuals who live with the condition on the island of Ireland (Figure 6). This is the tip of the iceberg, as there are an estimated 85% of individuals with ZZ AATD yet to be diagnosed. We rely on each individual physician’s clinical acumen to consider AATD part of the differential for diseases such as COPD, refractory asthma, liver fibrosis and liver cirrhosis, erythema nodosa and the vasculitides.

Figure 6. The geographical distribution of severe AATD in Ireland to date.


So Who Should be Tested and How?
The criteria for screening in Ireland follow WHO and ATS/ERS recommendations2 which suggest the following groups be screened:

  • Adults with emphysema or COPD (regardless of age/smoking status).
  • Adults with asthma and airflow obstruction that is incompletely reversed by treatment.
  • Asymptomatic individuals with airflow obstruction on lung function testing.
  • Adults with panniculitis.
  • Siblings of those with AATD.
  • Individuals with unexplained liver disease, including neonates and the elderly.
  • Individuals with ANCA-associated vasculitis.

More information for healthcare professionals can be found on the Alpha-1 Foundation Ireland website ( Getting tested for AATD is very simple and requires a single standard 3ml serum/plasma blood bottle. The sample is sent to the Alpha-1 Foundation Ireland laboratory at the RCSI Education and Research Centre at Beaumont Hospital. Testing is free as part of the HSE-funded national targeted detection programme. Of note, severe AATD can also be picked up by a common laboratory test called serum protein electrophoresis (or SPE). For a person with severe AATD, the alpha-1 globulin fraction will be visibly reduced and marked as abnormal.

If a patient is found to have low levels of AAT on screening (or by SPE); then their sample is usually be automatically referred for confirmatory AAT phenotyping. Once the test is completed, a comprehensive report is sent back to the healthcare provider. The report explains the patient’s AAT level and AAT phenotype and details what disease that individual is likely to suffer in the presence/absence of risk factors (smoke/alcohol). Typically, the turnaround time for phenotyping is approximately 14 to 20 days and can be done sooner if there is a clinical urgency.

National Centre of Expertise for AATD

If the patient is agreeable, they can be referred to the National Centre of Expertise for AATD at Beaumont Hospital. Here, patient investigations are tailored to look for diseases associated with AATD and patients are provided with education about their condition and their particular phenotype. Investigations include spirometry, oscillometry, and CT thorax to evaluate lung disease, in addition to abdominal ultrasound and transient elastography to evaluate liver disease. Patients may also be invited to take part in clinical trials investigating new treatments for both lung and liver disease.

Due to the genetic nature of the condition patients often enquire about what it means to have AATD, and the implications for family planning/children and first-degree relatives. At the national centre, we can provide a more tailored discussion around these topics and explain the inheritance patterns of the condition. The centre is headed by Professor Gerry McElvaney, an international leader in the field of AATD. It should be noted that we accept patient referrals from anywhere in the island of Ireland with many patients travelling from northern Ireland. More details can be found on

Are There Positives to a Diagnosis?

There are notable positive aspects to a diagnosis of AATD. These cannot be overstated, and most notably, individuals can avail of expert specialist care at the national AATD centre at Beaumont Hospital. Knowing the degree of AATD can be a useful motivator for smoking cessation or avoidance, for consideration of workplace gases, fumes and dusts, and for other health promotion measures such as flu vaccination.

We have recently shown that people with AATD are highly motivated to quit smoking. Our study of participants on the national AATD registry found that parental smoking was significantly associated with smoking and having a higher pack year history than AATD individuals without a parental smoking history. Therefore, individuals with AATD whose parents smoke are primed for a “double hit” increasing their risk of COPD due to inheritance of both genetic and social factors (increased likelihood of smoking)(Figure 7). This highlights the importance of targeted smoking cessation efforts in people with AATD, not only to reduce lung disease risk in the individual, but to also reduce the likelihood of their children ever smoking and thereby mitigating the future burden of COPD. While numerous AATD registries report a low percentage of ZZ active smokers, this was the first study of its kind to specifically evaluate smoking cessation in an AATD cohort and further highlights the behaviour modification benefits of intervening in this cohort.

Figure 7. The concept of a “double-hit” in AATD families related to genetic and social risks.

Equally important is the knowledge of AATD acquired by the wider family when a member is diagnosed. Family screening is strongly recommended as it can identify additional at risk relatives who may also benefit from expert care and rapid smoking cessation (see Figure 8).

Figure 8. Typical AATD family tree. ZZ (severe AATD), MZ (moderate AATD), and MM (unaffected) phenotypes are shown.

A national Alpha-1 patient conference is usually held each year that provides patients an invaluable insight into their condition through meeting other people affected by the condition. It gives patients an overview of what can be expected from living with the condition as well as learning coping strategies and receiving peer to peer support. The conference also covers exciting new research and new treatment prospects in the field of AATD. Giving patients who live with AATD a better understanding of their condition and the supports available empowers them to make informed decisions about their health.

The National AATD Registry

When patients are seen in our national centre for expertise in Beaumont Hospital, they are given the opportunity to take part in the national AATD registry ( This confidential registry seeks to improve the care of patients living with AATD and allows doctors involved in the care of patients with AATD an easy and rapid method of determining if a patient might benefit from taking part in new clinical trials testing new treatments. The registry allows the consolidation of relevant key results and parameters for patients with AATD in order to effectively track a patient’s clinical status. The registry has proved its value generating several important publications which have deepened our knowledge around AATD4,5.

Alpha-1 Foundation Ireland Resources

The Alpha-1 Foundation Ireland website ( has been a source of information for patients seeking guidance on their condition and was particularly valuable during the COVID-19 pandemic with a huge increase in site visitors. The website is hosted by Alpha-1 Foundation Ireland team members, Ms. Geraldine Kelly, Ronan Heeney, and Dr. Tomás Carroll. The site contains a wealth of knowledge about AATD in general as well as upcoming events of interest to the AATD community. Of note, the global Alpha-1 conference will take place in April 2023 in Dublin. This is a great opportunity for patients and healthcare providers to learn more about AATD from leading researchers in the field.

Figure 9. Alpha-1 Foundation Ireland core activities and services.


The Future

In 2023, the only specific treatment for severe AATD-related emphysema continues to be intravenous purified AAT. Unfortunately, this therapy is not widely available in Ireland and is not reimbursed by the government. Historically, the absence of a treatment has been an obstacle to more widespread testing for AATD. However, there are ongoing clinical trials taking place at the National Centre of Expertise for AATD. The trials are testing new medications that attempt to correct the misfolded AAT protein and allow it to be secreted from the liver to reach and protect the lungs. Patients who know their AATD status could be entitled to take part in trials of new medications that may one day treat or potentially cure their condition. A recent ground-breaking study published in the New England Journal of Medicine described the first effective treatment for liver disease caused by severe AATD (Strnad et al, 2022). It is an exciting time with many other potential treatments for AATD in development.

In the future it is envisaged that AATD screening could potentially be included in the new-born screening programme, which would equip affected individuals with a much earlier diagnosis, better knowledge, and more control over their own condition through risk factor avoidance. Ultimately, it is only through increasing public and professional awareness that we can hope to improve the lives of those living with AATD. People who are found to have AATD have a wealth of resources and opportunities available to them, but this only applies to the lucky minority who are correctly diagnosed. More work is needed to increase the detection of this common, yet rarely diagnosed condition with a modifiable outcome in terms of COPD risk.


  1. Carroll TP, O’Connor CA, Floyd O, McPartlin J, Kelleher DP, O’Brien G, Dimitrov BD, Morris VB, Taggart CC, McElvaney NG. The prevalence of alpha-1 antitrypsin deficiency in Ireland. Respiratory research. 2011 Dec 1;12(1):91.
  2. American Thoracic Society. European Respiratory Society. American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2003 Oct 1;168(7):818-900.
  3. Franciosi AN, Carroll TP, McElvaney NG. Pitfalls and caveats in α1-antitrypsin deficiency testing: a guide for clinicians. Lancet Respir Med. 2019 Dec;7(12):1059-1067.
  4. Franciosi AN, Hobbs BD, McElvaney OJ, Molloy K, Hersh C, Clarke L, Gunaratnam C, Silverman EK, Carroll TP, McElvaney NG. Clarifying the Risk of Lung Disease in SZ Alpha-1 Antitrypsin Deficiency. Am J Respir Crit Care Med. 2020 Jul 1;202(1):73-82.
  5. Franciosi AN, Carroll TP, McElvaney NG. SZ alpha-1 antitrypsin deficiency and pulmonary disease: more like MZ, not like ZZ. Thorax. 2020 Sep 11:thoraxjnl-2020-215250.
  6. Franciosiz AN, McCarthy C, Carroll TP, McElvaney NG. Unusual Acute Sequelae of α1-Antitrypsin Deficiency: A Myriad of Symptoms With One Common Cure. Chest. 2015 Nov;148(5):e136-e138.
  7. Franciosi AN, Alkhunaizi MA, Woodsmith A, Aldaihani L, Alkandari H, Lee SE, Fee LT, McElvaney NG & Carroll TP. Alpha-1 Antitrypsin Deficiency and Tobacco Smoking: Exploring Risk Factors and Smoking Cessation in a Registry Population. COPD. 2021 Feb;18(1):76-82.
  8. Strnad P, Mandorfer M, Choudhury G, Griffiths W, Trautwein C, Loomba R, Schluep T, Chang T, Yi M, Given BD, Hamilton JC, San Martin J, Teckman JH. Fazirsiran for Liver Disease Associated with Alpha1-Antitrypsin Deficiency. N Engl J Med. 2022 Aug 11;387(6):514-524.

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