ALPHA-1 ANTITRYPSIN DEFICIENCY By Michael K Mitchell BSRS RT(R)(CT) A thesis submitted to the School of Radiologic Sciences in collaboration with a research agenda team In partial fulfillment of the requirements for the degree of MASTER OF SCIENCE IN RADIOLOGIC SCIENCES (MSRS) WEBER STATE UNIVERSITY Ogden, Utah December 15, 2023 ii THE WEBER STATE UNIVERSITY GRADUATE SCHOOL SUPERVISORY COMMITTEE APPROVAL of a thesis submitted by Michael K Mitchell BSRS RT(R)(CT) This thesis has been read by each member of the following supervisory committee and by majority vote found to be satisfactory. ______________________________ Dr. Robert Walker, PhD Chair, School of Radiologic Sciences ______________________________ Dr. Laurie Coburn, EdD Director of MSRS RA ______________________________ Dr. Tanya Nolan, EdD Director of MSRS ______________________________ Christopher Steelman, MS Director of MSRS Cardiac Specialist iii Abstract Alpha-1 Antitrypsin Deficiency is a genetic disease affecting liver and pulmonary function. This condition is mistaken for asthma in younger patients and can further develop into COPD in older patients, without genetic testing. Without genetic testing, AATD, can be misdiagnosed and mistreated, leading to exacerbation and death. Treatments include similar treatments for asthma and COPD until exacerbation, however, can progress to augmentation therapy and transplantation of either the lungs or liver. Chapter 1: Introduction Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder that may result in lung disease or liver disease (4). This may result in shortness of breath, wheezing, or an increased risk of lung infections. Complications may include COPD, cirrhosis, neonatal jaundice, or panniculitis. Symptoms include Shortness of breath, Excessive cough with phlegm/sputum production, Wheezing (Usually diagnosed as asthma first), Decrease in exercise capacity and a persistent low energy state or tiredness, and Chest pain that increases when breathing in. Symptoms typically appear between the ages of 20 and 50. Some people can develop COPD, especially those with a history of smoking. In rare cases: demyelinating peripheral neuropathy can develop. Some people who have AAT deficiency may also have liver damage. Background Since AATD is a condition that doesn’t present until well into adulthood, it is important for early detection. Misdiagnosis is common, however genetic testing can be the key to its detection. Genetic testing during childhood, including testing of the subject’s family, can greatly increase and shape treatment. Early detection has also been seen to deter many from smoking during their lifetime, which increases chances of those with AATD to develop COPD. Statement of the Problem It is estimated that about 3.5 million people have AATD, however due to misdiagnosis and practitioners that feel further genetic testing recommendations are unfounded, it can be missed. AATD might be interpreted as a common mechanism with 2 different clinical manifestations and frequent overlap among chronic respiratory disorders. Proper genetic testing, early, can lead to correct diagnosis and preemptive treatment. It is unacceptable to just treat the symptoms or the diseases that AATD hides behind. Can early genetic testing lead to a better quality of life in the patient, even though there is no cure for AATD? The focus group of this thesis will be patients between the ages of 20 and 50. This is not a direct case study, but a gathering of research on past patient treatment and testing worldwide. Alpha-1 antitrypsin deficiency is a genetic disorder that may result in lung disease or liver disease, which can be combatted but not cured. I believe that the best way to combat AATD successfully is through early genetic testing. The purpose of this thesis is to provide insight on whether or not early genetic testing can lead to better treatment and thus increase the quality of life for patients suffering with AATD. Purpose of the Study The purpose of this quantitative study is to derive an understanding of different treatments and preventative measures in dealing with Alpha-1 Antitrypsin Deficiency. Several sources were reviewed to come to a consensus on the treatment of AATD. The sources were hand picked to identify differences in long-term treatment. 3 Research Questions Q1. Can genetic testing aid in prevention and treatment of Alpha-1 Antitrypsin Deficiency? Q2. Should genetic testing be a requirement for all children as a way to combat Alpha-1 Antitrypsin Deficiency? Nature of the Study The purpose of this quantitative study is to derive an understanding of different treatments and preventative measures in dealing with Alpha-1 Antitrypsin Deficiency. Several sources were reviewed to come to a consensus in the treatment of AATD. The sources were hand-picked to identify differences in long term treatment. A systematic review of the respiratory literature in New Zealand/Australia was interpreted, which led to several proposed guidelines for treatment (5). A qualitative review of clinical trials in Spain interprets a paradigm shift in treatment methods (10). A review of the American Lung Association website provides an overview of AATD, and treatments currently offered (12), as well as a website providing those afflicted with AATD, advice and support (1). Gramegna et. al. provide arguments on three main topics will be addressed, including 1) the limitation of the current definition of AATD lung disease; 2) the need of broader testing and improvement of AATD awareness among physicians taking care of chronic respiratory diseases; 3) new paradigm and perspectives in AATD future research (6). Case studies provided by radiopaedia.org were reviewed for epidemiological, pathological and treatment options (2)(3). A review of the U.S. Department of Health and Human Service’s website was also performed to provide 4 background on AATD and its treatment options (12). Future goals of AATD treatment, as explained by Kalfopoulos et al., are to use gene therapy using vector systems to produce therapeutic levels of AAT in the lungs without causing a systemic inflammatory response (8). A literature review, addressing the methods developed for the purification of alpha1antitrypsin (AAT) from the 1950s to the present, was studied as well (14). A survey of 63 experts was reviewed to become familiar with the professional opinion of augmentation therapy (7). Full lung transplantation requirements are discussed and reviewed through the European Respiratory Review (15). Acta Med Portuguesa looked into the management of AATD in neonates and patients’ quality of life (4). Significance of the Study The significance of this study is to examine the benefit genetic testing, earlier in life can have on patients’ quality of life compared to waiting until later in life, once symptoms are presenting. Genetic testing at any point can aid in the cessation of smoking, which can then lessen chances of developing Chronic Obstructive Pulmonary Disease (COPD) later in life (5). Summary Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder that may result in lung disease or liver disease. This may result in shortness of breath, wheezing, or an increased risk of lung infections (4). Complications may include COPD, cirrhosis, neonatal jaundice, or panniculitis. Symptoms include Shortness of breath, Excessive cough with phlegm/sputum production, Wheezing (Usually diagnosed as asthma first), 5 Decrease in exercise capacity and a persistent low energy state or tiredness, and Chest pain that increases when breathing in. Symptoms typically appear between the ages of 20 and 50. Some people can develop COPD, especially those with a history of smoking. In rare cases: demyelinating peripheral neuropathy can develop. Some people who have AAT deficiency may also have liver damage. Since AATD is a condition that doesn’t present until well into adulthood, it is important for early detection. Misdiagnosis is common, however genetic testing can be the key to its detection. Genetic testing during childhood, including testing of the subject’s family, can greatly increase and shape treatment. Early detection has also been seen to deter many from smoking during their lifetime, which increases chances of those with AATD to develop COPD. It is estimated that about 3.5 million people have AATD, however due to misdiagnosis and practitioners that feel further genetic testing recommendations are unfounded, it can be missed. AATD might be interpreted as a common mechanism with different clinical manifestations and frequent overlap among chronic respiratory disorders. Proper genetic testing, early, can lead to correct diagnosis and preemptive treatment. It is unacceptable to just treat the symptoms or the diseases that AATD hides behind. Can early genetic testing lead to a better quality of life in the patient, even though there is no cure for AATD? The focus of this thesis will be patients between the ages of 20 and 50. This is not a direct case study, but a gathering of research on past patient treatment and testing worldwide. Alpha-1 antitrypsin deficiency is a genetic disorder that may result in lung disease or liver disease, which can be combatted but not cured. I believe that the best way to combat AATD successfully is through early genetic testing. The purpose of this thesis is to provide insight on whether early genetic testing can lead to better treatment and thus increase the 6 quality of life for patients suffering with AATD. The purpose of this quantitative study is to derive an understanding of different treatments and preventative measures in dealing with Alpha-1 Antitrypsin Deficiency. Several sources were reviewed to come to a consensus on the treatment of AATD. The sources were hand-picked to identify differences in long term treatment (5). Chapter 2: Clinical Background Introduction Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder that can lead to lung or liver disease, causing symptoms such as shortness of breath, wheezing, and an elevated risk of lung infections (4). Possible complications encompass COPD, cirrhosis, neonatal jaundice, and panniculitis. Indications of AATD involve shortness of breath, persistent cough with phlegm/sputum production, wheezing initially diagnosed as asthma, reduced exercise capacity, chronic fatigue, and chest pain intensified during inhalation. Manifestations typically emerge between ages 20 and 50, with some individuals developing COPD, particularly those with a smoking history. In rare instances, demyelinating peripheral neuropathy may occur, and liver damage is also possible. Since AATD manifests in adulthood, early detection is crucial. Misdiagnosis is prevalent, but genetic testing is pivotal for accurate identification. Conducting genetic tests in childhood, including testing family members, significantly enhances and customizes treatment. Early detection has proven effective in dissuading individuals from smoking, thereby reducing the likelihood of AATD patients developing COPD. Approximately 3.5 million people are estimated to have AATD, yet due to misdiagnosis and reluctance among practitioners to recommend further genetic testing, cases may go unnoticed. 7 AATD could be perceived as a common mechanism with diverse clinical manifestations, often overlapping with chronic respiratory disorders (5). Etiology Alpha-1 Antitrypsin Deficiency is a hereditary metabolic disorder and is the most common genetic cause of emphysema and metabolic liver disease in children. It results in the unopposed action of neutrophil elastase and subsequent severe basal pan lobular emphysema and respiratory symptoms. Accumulation of altered alpha-1antitrypsin in hepatocytes incites an inflammatory response and chronic liver disease (11). Epidemiology Estimated prevalence of AATD is thought to be around 1 in 1,500 to 3,500 individuals with European ancestry. It is reported to be uncommon in people of Asian descent (11). Because AATD is an inherited disease, meaning it runs in families, it cannot be prevented. It can happen to anyone of any race or ethnicity. However, it is more common in white people of Northern European backgrounds, as stated above (13). Pathophysiology Alpha-1-antitrypsin (A1AT) is a protein that prevents enzymes such as elastase from degrading normal host tissue. Over 90% of the alpha-1-antitrypsin protein is produced in hepatocytes by codominant expression of the SERPINA1 gene on chromosome 14. The common alleles of this gene are designated M, Z, or S, prefixed by PI (standing for protease inhibitor). Normal individuals have two copies of the M allele so are designated 'PIMM'. The most common abnormal allele is Z, and individuals 8 homozygous for this (i.e. 'PIZZ') have severe alpha-1-antitrypsin deficiency (AATD). Heterozygous individuals (i.e. 'PIMZ') are usually asymptomatic. The S allele confers a partially functional alpha-1-antitrypsin protein, and only usually causes symptoms when combined with the Z allele (i.e. 'PISZ') (11). The alpha-1-antitrypsin protein inhibits neutrophil elastase. In patients with severe deficiency, the neutrophil elastase acts unopposed resulting in damage to the lower respiratory tract. This damage is predominantly basal because of the gravitational distribution of pulmonary blood flow (11). History and Physical Patients with AATD most often present with dyspnea and to a lesser extent cough and wheeze. Lung disease in AATD is characteristically premature (<45 years), pan‐lobular emphysema with lower zone predominance; however, upper zone predominance of emphysema and bronchiectasis and partially reversible airflow obstruction are also well recognized. The World Health Organization (WHO) recommendations, which are supported by the European and North American guidelines for AATD management, are that all adults with chronic airflow obstruction or assumed diagnosis of adult‐onset asthma be screened for AATD, although local and international asthma guidelines do not make a similar recommendation. We suggest that AATD testing should be considered in patients with asthma when clinically relevant, particularly in patients with persistent airflow limitation, emphysema disproportionate to the smoking history or in the presence of liver or skin disease (5). 9 Evaluation Plain radiograph and Computed tomography (CT) lung scans help define the pattern and extent of disease in AATD even in those with normal lung function. CT lung densitometry is currently a valuable research tool in quantitating emphysema in AATD studies but its role in patient management remains unclear (5). The appearance of pan lobar emphysema, bronchiectasis, bronchial wall thickening, and hepatopulmonary syndrome can suggest further investigation into AATD (11). Treatment / Management Options Emphysema and cirrhosis are typically the most common causes of death. Survival is substantially worse for smokers, resulting in a 20-year decrease in longevity compared to non-smokers. Studies have shown, the overall median survival time was ~55 years. Alpha-1-antitrypsin replacement therapy, also known as augmentation therapy, most often a weekly intravenous infusion of alpha-1-antitrypsin purified from human plasma, has been used in some situations to partially correct the biochemical defect. Other management strategies include cessation of smoking and other risk factors for cirrhosis. Lung and liver transplants are generally reserved for those with end stage disease (11). Complications Complications of cirrhosis with increased risk of hepatocellular carcinoma although carriers of the deficient gene are generally asymptomatic and do not suffer significant pulmonary or hepatic complications, they are at 70-100% increased risk of lung cancer (11). 10 Summary Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder that can lead to lung or liver disease, resulting in symptoms such as shortness of breath, wheezing, and an increased susceptibility to lung infections. Complications may include COPD, cirrhosis, neonatal jaundice, or panniculitis. Recognizable symptoms encompass shortness of breath, excessive cough with phlegm/sputum production, initially diagnosed as asthma, reduced exercise capacity, persistent fatigue, and chest pain exacerbated during inhalation. Typically appearing between ages 20 and 50, some individuals, especially those with a smoking history, may develop COPD. In rare instances, demyelinating peripheral neuropathy may arise, and liver damage is also a potential concern. Early detection of AATD, which manifests in adulthood, is crucial, although misdiagnosis is common. Genetic testing serves as a key tool for accurate identification, with testing during childhood and family members contributing to shaping treatment. Early detection has proven effective in deterring smoking, reducing the risk of AATD patients developing COPD. Approximately 3.5 million people are estimated to have AATD, but misdiagnosis and practitioner reluctance to recommend further genetic testing can lead to overlooked cases. AATD might be perceived as a common mechanism with diverse clinical manifestations, frequently overlapping with chronic respiratory disorders. Proper early genetic testing can lead to a correct diagnosis and preemptive treatment. It is inadequate to merely address the symptoms, or the diseases associated with AATD. Can early genetic testing enhance the quality of life for patients, even though there is no cure for AATD? This thesis focuses on patients aged 20 to 50, presenting a compilation of 11 global research on past patient treatment and testing rather than a direct case study. Alpha-1 antitrypsin deficiency, while incurable, can be effectively managed. The thesis argues that early genetic testing is the optimal approach to combat AATD successfully. The objective is to explore whether early genetic testing can improve treatment outcomes and elevate the quality of life for AATD patients. This quantitative study aims to gain insights into various treatments and preventative measures for dealing with Alpha-1 Antitrypsin Deficiency, drawing from carefully selected sources to identify differences in long-term treatment approaches. Documentation The documentation strategy used in this review was a thorough search on google, radiopaedia and the Stewart library. Searches included Alpha-1 Antitrypsin Deficiency, Alpha-1 Antitrypsin Deficiency treatments, Alpha-1 Antitrypsin Deficiency support groups. General Literature Review The documentation strategy used in this review was a thorough search on google, radiopaedia and the Stewart library. Searches included Alpha-1 Antitrypsin Deficiency, Alpha-1 Antitrypsin Deficiency treatments, Alpha-1 Antitrypsin Deficiency support groups. The sub search included treatment, augmentation therapy, transplantations, neonatal genetics, family genetics and COPD/Asthma treatments. 12 Literature Review A study out of Australia and New Zealand takes an in depth look at AATD and its treatment, making several suggestions on guidelines. Recommendations of AATD testing to be performed on patients with chronic airflow obstruction and asthma patients with airflow limitations and emphysema in the absence of a history of smoking. Also recommending testing to be done on those with liver disease. The study further suggests that genetic testing can help determine which patients require further treatment and follow up. Furthermore, it recommends augmentation therapy not be used on those with a history of smoking. Lung volume reduction therapy was briefly reviewed and found to require more research. Lung transplantation is recommended for AATD patients with severe emphysema. Recommendation further suggests that management include cessation of smoking, non-invasive monitoring of the liver, an interdisciplinary team that includes hepatologists and respiratory physicians, and genetic counseling and testing for the patient and family (5). A study from Spain acknowledges the rarity of AATD and goes further in analyzing the relevance of current testing measures. Its analysis augmentation therapy in comparison to lung transplantation as the major treatments, recommending further research, multi-nationally to come to a consensus (10). The American Lung Association gives a breath overview of AATD, recommending augmentation therapy as a long-term treatment. Recommendations of smoking and alcohol cessation are also made. Which is repeated by the Alpha-1 Foundation, based in Florida, with the addition of a healthy diet and exercise. The foundation also recommends the utilization of a support group (12). 13 A publication out of Europe, focusing on Italy, recommends deeper evaluation of clinical, radiological, microbiological and functional variables is, therefore, needed in order to investigate different phenotypes in AATD patients (6). In addition, a new line of translational research in AATD might focus on the development of personalized therapeutic regimens considering the patient clinical profile and needs (6). Another publication by Kafapolous, Wetmore, and Almallah touches on the factors of under recognition and diagnostic delay. And identify them as inadequate awareness of the disease by healthcare providers, a failure to implement evidence-based recommendations and the belief that testing for AATD is not warranted because of the lack of effective and available therapies. They state that it is currently recommended for physicians to test for AATD if any of the following features are found in a patient: Emphysema in a patient 45 or younger, Emphysema in a nonsmoker or in the absence of a risk factor, Emphysema with prominent basilar changes on a chest x-ray, A family history of emphysema, bronchiectasis, liver disease or panniculitis, Clinical findings of panniculitis or unexplained liver disease, and Anti-proteinase 3-positive vasculitis(8). Another publication by Viglio and associates examined the need and progression of purification of AAT for augmentation therapy. As this publication does praise augmentation therapy, it doesn’t look into other options such as early genetic testing specifically in pediatric patients and neonates. Greulich and associates attempted a cross-sectional survey of 63 experts in AATD from 13 European countries about their opinions and attitudes of augmentation therapy (7). However, they concluded that the clinical trial size was inadequate and were not able to provide a successful analysis. 14 Research out of Portugal suggests that the early detection of AATD allows the implementation of preventive measures, namely avoidance of smoking and of environmental risks, compliance with vaccination, physical exercise, adequate follow-up and eventual treatment in the early stages of the disease, which are widely recognized as being of particular importance to prevent and/or avoid the progression of pulmonary disease (4). These findings are based on experts and the availability of noninvasive pre and neonatal genetic testing, as well as considering that both parents have been tested and are carriers of AATD. It further considers that some roadblocks would be cost and the limitations of accuracy. Summary Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder that may result in lung disease or liver disease. This may result in shortness of breath, wheezing, or an increased risk of lung infections. Complications may include COPD, cirrhosis, neonatal jaundice, or panniculitis. Symptoms include Shortness of breath, Excessive cough with phlegm/sputum production, Wheezing (Usually diagnosed as asthma first), Decrease in exercise capacity and a persistent low energy state or tiredness, and Chest pain that increases when breathing in. Symptoms typically appear between the ages of 20 and 50. Some people can develop COPD, especially those with a history of smoking. In rare cases: demyelinating peripheral neuropathy can develop. Some people who have AAT deficiency may also have liver damage. Since AATD is a condition that doesn’t present until well into adulthood, it is important for early detection. Misdiagnosis is common, however genetic testing can be the key to its detection. Genetic testing during childhood, 15 including testing of the subject’s family, can greatly increase and shape treatment. Early detection has also been seen to deter many from smoking during their lifetime, which increases chances of those with AATD to develop COPD. It is estimated that about 3.5 million people have AATD, however due to misdiagnosis and practitioners that feel further genetic testing recommendations are unfounded, it can be missed. AATD might be interpreted as a common mechanism with different clinical manifestations and frequent overlap among chronic respiratory disorders. Proper genetic testing, early, can lead to correct diagnosis and preemptive treatment. It is unacceptable to just treat the symptoms or the diseases that AATD hides behind. Can early genetic testing lead to a better quality of life in the patient, even though there is no cure for AATD? The focus of this thesis will be patients between the ages of 20 and 50. This is not a direct case study, but a gathering of research on past patient treatment and testing worldwide. Alpha-1 antitrypsin deficiency is a genetic disorder that may result in lung disease or liver disease, which can be combatted but not cured. I believe that the best way to combat AATD successfully is through early genetic testing. The purpose of this thesis is to provide insight on whether early genetic testing can lead to better treatment and thus increase the quality of life for patients suffering with AATD. The purpose of this quantitative study is to derive an understanding of different treatments and preventative measures in dealing with Alpha-1 Antitrypsin Deficiency. Several sources were reviewed to come to a consensus in the treatment of AATD. The sources were hand-picked to identify differences in long term treatment. Reviewing the literature led to more focus on augmentation therapy and less on preventative treatment, such as genetic testing. Where it is necessary to focus on 16 treatment, I also feel it necessary to provide genetic testing earlier in life for predisposed patients. Some patients will be asymptomatic and enjoy a better quality of life, however, research is needed to observe those that have been diagnosed as children and followed healthier lifestyle guidelines, such as avoidance of smoking and environmental hazards. Chapter 4: Research Method Alpha-1 antitrypsin deficiency (AATD) is a genetic condition that can lead to either lung or liver disease, potentially causing symptoms such as shortness of breath, wheezing, or an increased vulnerability to lung infections. Complications associated with AATD encompass COPD, cirrhosis, neonatal jaundice, or panniculitis. Manifestations include shortness of breath, excessive cough with phlegm/sputum production (often initially misdiagnosed as asthma), a reduction in exercise capacity, persistent low energy, and chest pain exacerbated during inhalation. These symptoms typically manifest between the ages of 20 and 50. Individuals, especially those with a smoking history, may develop COPD, and in rare cases, demyelinating peripheral neuropathy can occur. Additionally, some people with AAT deficiency may experience liver damage. Research Questions Q1. Can genetic testing aid in prevention and treatment of Alpha-1 Antitrypsin Deficiency? Q2. Should genetic testing be a requirement for all children as a way to combat Alpha-1 Antitrypsin Deficiency? 17 Research Methods and Design(s) 1. A case study review was chosen for this thesis. 2. A review of various sources from different countries with strong foundations in healthcare was chosen. 3. The design of this study was chosen so that it can be replicated and should be replicated as more information becomes available. A sufficient search of data throughout the world can be obtained and reviewed, especially as we adjust through the years post covid. Searches of treatment, therapies, guidelines and prevention should be considered. Population The population chosen was of broad range and set to include, not just those between 20 and 50 years of age, but all patients, as AATD can affect anyone. AATD is most common among Caucasians of European descent but is genetic and can be observed in all races. Summary Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder that may result in lung disease or liver disease. This may result in shortness of breath, wheezing, or an increased risk of lung infections. Complications may include COPD, cirrhosis, neonatal jaundice, or panniculitis. Symptoms include Shortness of breath, Excessive cough with phlegm/sputum production, Wheezing (Usually diagnosed as asthma first), Decrease in exercise capacity and a persistent low energy state or tiredness, and Chest pain that 18 increases when breathing in. Symptoms typically appear between the ages of 20 and 50. Some people can develop COPD, especially those with a history of smoking. In rare cases: demyelinating peripheral neuropathy can develop. Some people who have AAT deficiency may also have liver damage. A mixed method literature review was performed to answer the following questions: Q1. Can genetic testing aid in prevention and treatment of Alpha-1 Antitrypsin Deficiency? Q2. Should genetic testing be a requirement for all children as a way to combat Alpha-1 Antitrypsin Deficiency? More research will be needed to determine whether genetic testing will benefit the world population and quality of life for those afflicted with Alpha-1 Antitrypsin Deficiency. Conclusions Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder that may result in lung disease or liver disease. This may result in shortness of breath, wheezing, or an increased risk of lung infections. Complications may include COPD, cirrhosis, neonatal jaundice, or panniculitis. Symptoms include Shortness of breath, Excessive cough with phlegm/sputum production, Wheezing (Usually diagnosed as asthma first), Decrease in exercise capacity and a persistent low energy state or tiredness, and Chest pain that increases when breathing in. Symptoms typically appear between the ages of 20 and 50. 19 Some people can develop COPD, especially those with a history of smoking. In rare cases: demyelinating peripheral neuropathy can develop. Some people who have AAT deficiency may also have liver damage. A mixed method literature review was performed to answer the following questions: Q1. Can genetic testing aid in prevention and treatment of Alpha-1 Antitrypsin Deficiency? Q2. Should genetic testing be a requirement for all children as a way to combat Alpha-1 Antitrypsin Deficiency? More research and observation will be needed to determine whether genetic testing will benefit the world population and quality of life for those afflicted with Alpha1 Antitrypsin Deficiency. The sources reviewed were knowledgeable of AATD, however research is limited in expanding genetic testing to all prenatal and neonatal subjects. At this time, genetic testing remains a suggestion. My hope is that in the future affordability and accuracy of genetic testing will lead to normalization and awareness that contributes to practitioner and patient education. With genetic testing earlier in life, a better quality of life can be attained for those possibly facing the hereditary curse of Alpha-1 Antitrypsin Deficiency. 20 References 1. Alpha-1 Foundation. Healthy Lifestyle Choices. https://alpha1.org/healthy-lifestylechoices/. Accessed November 8, 2023. 2. Case courtesy of Dr Abdallah Alqudah, Radiopaedia.org. From the case rID: 50561. Link. 3. Case courtesy of Dr Andrew Dixon, Radiopaedia.org. From the case rID: 9674. Link. 4. Conde B, Costa F, Gomes J, Lopes AP, Mineiro MA, Rodrigues O, Santos C, Semedo L, Sucena M, Guimarães C. Expert Perspectives on the Management of Alpha 1Antitrypsin Deficiency. *Acta Med Port* [Internet]. 2022 Jul. 18 [cited 2023 Nov. 9];36(1):49-54. Available from: https://actamedicaportuguesa.com/revista/index.php/amp/article/view/18497. 5. Dummer J, Dobler CC, Holmes M, et al. Diagnosis and treatment of lung disease associated with alpha one-antitrypsin deficiency: A position statement from the Thoracic Society of Australia and New Zealand. *Respirology*. 2020;25(3):321335. doi:10.1111/resp.13774. 6. Gramegna A, Aliberti S, Confalonieri M, Corsico A, Richeldi L, Vancheri C, Blasi F. Alpha-1 antitrypsin deficiency as a common treatable mechanism in chronic respiratory disorders and for conditions different from pulmonary emphysema? A commentary on the new European Respiratory Society statement. *Multidisciplinary Respiratory Medicine*. 2017;13. https://doi.org/10.1186/s40248-018-0153-4. 7. Greulich T, Albert A, Cassel W, et al. Opinions and Attitudes of Pulmonologists About Augmentation Therapy in Patients with Alpha-1 Antitrypsin Deficiency. A Survey of the EARCO Group. *Int J Chron Obstruct Pulmon Dis*. 2022;17:5364. Published 2022 Jan 5. doi:10.2147/COPD.S346051. 8. Kalfopoulos M, Wetmore K, ElMallah MK. Pathophysiology of Alpha-1 Antitrypsin Lung Disease. *Methods Mol Biol*. 2017;1639:9-19. doi: 10.1007/978-1-49397163-3_2. PMID: 28752442. 9. Lebbe F. Alpha 1 antitrypsin deficiency; A case of demyelinating sensory-motor peripheral neuropathy in a Sri Lankan child. *Archives of Disease in Childhood*. 2022;107:A223. 10. López-Campos JL, Carrasco Hernandez L, Caballero Eraso C. Implications of a Change of Paradigm in Alpha1 Antitrypsin Deficiency Augmentation Therapy: From Biochemical to Clinical Efficacy. *Journal of Clinical Medicine*. 2020;9(8):2526. https://doi.org/10.3390/jcm9082526. 21 11. Radswiki T, Bell D. Alpha-1-antitrypsin deficiency. Reference article, Radiopaedia.org. Accessed on October 13, 2022. Link. 12. "Alpha-1 antitrypsin deficiency." *American Lung Association*. (n.d.). Retrieved October 13, 2022, from https://www.lung.org/lung-health-diseases/lung-diseaselookup/alpha-1-antitrypsin-deficiency. 13. U.S. Department of Health and Human Services. Alpha-1 antitrypsin deficiency. *National Heart Lung and Blood Institute*. (n.d.). Retrieved October 14, 2022, from https://www.nhlbi.nih.gov/health/alpha-1-antitrypsindeficiency#:~:text=Alpha%2D1%20antitrypsin%20(AAT),This%20can%20lead %20to%20COPD. 14. Viglio S, Iadarola P, D’Amato M, Stolk J. Methods of Purification and Application Procedures of Alpha1 Antitrypsin: A Long-Lasting History. *Molecules*. 2020;25(17):4014. https://doi.org/10.3390/molecules25174014. 15. Verleden GM, Gottlieb J. Lung transplantation for COPD/pulmonary emphysema. *Eur Respir Rev*. 2023;32(167):220116. Published 2023 Mar 22. doi:10.1183/16000617.0116-2022.