Alpha-1 deficiency in severe asthma patients.

Alpha-1 antitrypsin (AAT) deficiency, an autosomal co-dominant condition, decreases protein concentration and activity at both serum and tissue levels. Few studies investigated whether the type of SERPINA1 gene phenotype in patients with severe asthma can influence symptoms and disease control during follow-up.To assess whether the presence of a non-MM genotype of SERPINA1 in patients with severe asthma is associated with disease control, systemic and airway inflammation, lung function and comorbidities prevalence compared to severe asthma patients with a homozygous genotype (MM).Asthmatic patients belonging to Global Initiative for Asthma (GINA) step 5 were retrospectively analysed in an Italian reference asthma clinic. We collected clinical, biological and functional variables at baseline and for the three following years.Out of 73 patients enrolled, 14 (19.18%) were non-MM and 59 (80.8%) were MM. Asthmatics with non-MM genotype had lower serum AAT concentration (P = 0.004) and higher emphysema prevalence than the MM group (P = 0.003) at baseline. During follow up, only MM patients showed a significant improvement of both ACQ-6 score (P < 0.0001) and eosinophilic systemic inflammation (P < 0.0001).Our findings emphasise the importance of a screening for AAT deficiency in severe asthma, as alleles mutation may influence patient's follow-up..

Alpha-1 antitrypsin deficiency and pregnancy complications and birth outcomes: A population-based cohort study in Denmark.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is related to developing lung and liver disease, but no large-scale studies examine its association with birth outcomes. OBJECTIVE: We investigated the risk of pregnancy complications and adverse birth outcomes in mothers and children with AATD. METHODS: Using a large cohort data of Danish mothers and children with AATD from 1973 to 2013 (n = 2,027,229), with 559 cases (305 mothers and 254 children). We conducted Poisson regression to examine associations between alpha-1 antitrypsin deficiency, adverse birth outcomes, and pregnancy complications in mothers and children. RESULTS: AATD was related to term low birth weight [<2500g; Risk Ratio(RR) = 2.04, 95% confidence interval (CI): 1.50-2.79], lowest quartile of abdominal circumference at birth in children of non-smoking mothers (RR = 1.55, 95% CI: 1.14-2.11), delivery via Cesarean-section (RR = 1.59, 95% CI: 1.05-2.40), preterm birth (RR = 1.54, 95% CI: 1.19-2.00) and preeclampsia (RR = 2.64, 95% CI: 1.76-3.94). CONCLUSIONS: This emphasizes the need for mothers with AATD to be monitored closely during pregnancy to reduce the risk of adverse birth outcomes. Routine screening for alpha-1 antitrypsin in pregnancy may be considered among mothers with a pulmonary and liver disease history.

Prevalence of Cardiovascular Disease and Rate of Major Adverse Cardiovascular Events in Severe Alpha-1 Antitrypsin Deficiency COPD.

Aim: Alpha-1 antitrypsin deficiency is an autosomal co-dominant condition that predisposes individuals to early-onset emphysema. As with COPD, AATD-COPD is associated with pulmonary exacerbations, which impacts on overall mortality and quality of life. Though there is evidence that COPD is associated with a higher prevalence of cardiovascular disease and major adverse cardiovascular events (MACE), it is unclear if this is true for patients with AATD-COPD. Methods: Prevalence of cardiovascular disease was determined in two separate severe AATD cohorts: AlphaNet, USA and the Birmingham AATD registry, UK. All patients had preexisting lung disease. Cardiovascular disease was defined as presence of any of the following: heart failure, ischaemic heart disease, atrial fibrillation, stroke, and myocardial infarction. A Cox proportional hazards model was used to assess the impact of prior cardiovascular disease and frequent exacerbator phenotype on risk of future MACE. Results: Out of 3493 patients with severe AATD, 14.7% had prior cardiovascular disease, including stroke (2.3%), myocardial infarction (2.2%), and heart failure (2.5%). Frequent exacerbators were more likely to have preexisting cardiovascular disease compared with those with one or no exacerbations in the preceding year (63% vs 44.8%, p = 0.001). There was increased risk of future MACE in frequent exacerbators (HR 1.85, 95% CI 1.24 to 2.75), former and current smokers (HR 1.80, 95% CI 1.07 to 3.02, p = 0.026, and HR 4.04, 95% CI 1.44 to 11.32, p = 0.008, respectively), and those with prior cardiovascular disease (HR 3.81, 95% CI 2.60 to 5.58, p < 0.001). Conclusion: In severe AATD-COPD, MACE are associated with an increased exacerbation frequency, previous cardiovascular disease, and a history of smoking.

Alpha-1-antitrypsin-deficiency is associated with lower cardiovascular risk: an approach based on federated learning.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is an inflammatory multisystemic disease caused by environmental exposures and/or genetic factors. Inherited alpha-1-antitrypsin deficiency (AATD) is one of the best recognized genetic factors increasing the risk for an early onset COPD with emphysema. The aim of this study was to gain a better understanding of the associations between comorbidities and specific biomarkers in COPD patients with and without AATD to enable future investigations aimed, for example, at identifying risk factors or improving care. METHODS: We focused on cardiovascular comorbidities, blood high sensitivity troponin (hs-troponin) and lipid profiles in COPD patients with and without AATD. We used clinical data from six German University Medical Centres of the MIRACUM (Medical Informatics Initiative in Research and Medicine) consortium. The codes for the international classification of diseases (ICD) were used for COPD as a main diagnosis and for comorbidities and blood laboratory data were obtained. Data analyses were based on the DataSHIELD framework. RESULTS: Out of 112,852 visits complete information was available for 43,057 COPD patients. According to our findings, 746 patients with AATD (1.73%) showed significantly lower total blood cholesterol levels and less cardiovascular comorbidities than non-AATD COPD patients. Moreover, after adjusting for the confounder factors, such as age, gender, and nicotine abuse, we confirmed that hs-troponin is a suitable predictor of overall mortality in COPD patients. The comorbidities associated with AATD in the current study differ from other studies, which may reflect geographic and population-based differences as well as the heterogeneous characteristics of AATD. CONCLUSION: The concept of MIRACUM is suitable for the analysis of a large healthcare database. This study provided evidence that COPD patients with AATD have a lower cardiovascular risk and revealed that hs-troponin is a predictor for hospital mortality in individuals with COPD.

Alpha1-antitrypsin deficiency in Greece: Focus on rare variants.

PURPOSE: A1Antitrypsin deficiency (AATD) pathogenic mutations are expanding beyond the PI*Z and PI*S to a multitude of rare variants. AIM: to investigate genotype and clinical profile of Greeks with AATD. METHODS: Symptomatic adult-patients with early-emphysema defined by fixed airway obstruction and computerized-tomography scan and lower than normal serum AAT levels were enrolled from reference centers all over Greece. Samples were analyzed in the AAT Laboratory, University of Marburg-Germany. RESULTS: Included are 45 adults, 38 homozygous or compound heterozygous for pathogenic variants and 7 heterozygous. Homozygous were 57.9% male, 65.8% ever-smokers, median (IQR) age 49.0(42.5-58.5) years, AAT-levels 0.20(0.08-0.26) g/L, FEV1(%predicted) 41.5(28.8-64.5). PI*Z, PI*Q0, and rare deficient allele's frequency was 51.3%, 32.9%,15.8%, respectively. PI*ZZ genotype was 36.8%, PI*Q0Q0 21.1%, PI*MdeficientMdeficient 7.9%, PI*ZQ0 18.4%, PI*Q0Mdeficient 5.3% and PI*Zrare-deficient 10.5%. Genotyping by Luminex detected: p.(Pro393Leu) associated with MHeerlen (M1Ala/M1Val); p.(Leu65Pro) with MProcida; p.(Lys241Ter) with Q0Bellingham; p.(Leu377Phefs*24) with Q0Mattawa (M1Val) and Q0Ourem (M3); p.(Phe76del) with MMalton (M2), MPalermo (M1Val), MNichinan (V) and Q0LaPalma (S); p.(Asp280Val) with PLowell (M1Val); PDuarte (M4), YBarcelona (p.Pro39His). Gene-sequencing (46.7%) detected Q0GraniteFalls, Q0Saint-Etienne, Q0Amersfoort(M1Ala), MWürzburg, NHartfordcity and one novel-variant (c.1A>G) named Q0Attikon.Heterozygous included PI*MQ0Amersfoort(M1Ala), PI*MMProcida, PI*Mp.(Asp280Val), PI*MOFeyzin. AAT-levels were significantly different between genotypes (p = 0.002). CONCLUSION: Genotyping AATD in Greece, a multiplicity of rare variants and a diversity of rare combinations, including unique ones were observed in two thirds of patients, expanding knowledge regarding European geographical trend in rare variants. Gene sequencing was necessary for genetic diagnosis. In the future the detection of rare genotypes may add to personalize preventive and therapeutic measures.

An Alpha-1 Antitrypsin Deficiency Screening Study in Patients with Chronic Obstructive Pulmonary Disease, Bronchiectasis, or Asthma in Turkey.

Purpose: Alpha-1 antitrypsin deficiency (AATD) is a rare hereditary condition characterized by decreased serum alpha-1 antitrypsin (AAT) levels. We aim to identify AATD in patients with chronic obstructive pulmonary disease (COPD), bronchiectasis, or asthma and to report the frequency of AAT variants in Turkey. Patients and Methods: This non-interventional, multicenter, prospective study was conducted between October 2021 and June 2022. Adult patients with COPD, bronchiectasis, asthma, liver symptoms, or family members with AATD were included. Demographic and clinical characteristics, pulmonary diagnosis, respiratory symptoms, and AAT serum levels were assessed. Whole blood samples were collected as dried blood spots, and the most common AATD mutations were simultaneously tested by allele-specific genotyping. Results: A total of 1088 patients, mainly diagnosed with COPD (92.7%) and shortness of breath (78.7%), were assessed. Fifty-one (5%) were found to have AATD mutations. Fifteen (29.4%) patients had Pi*S or Pi*Z mutations, whereas 36 (70.6%) patients carried rare alleles Pi*M malton (n=18, 35.3% of mutations), Pi*I (n=8, 16%), Pi*P lowell (n=7, 14%), Pi*M heerlen (n=2, 4%), and Pi*S iiyama (n=1, 2%). The most common heterozygous combinations were Pi*M/Z (n=12, 24%), and Pi*M/M malton (n=11, 22%). Ten patients with severe AATD due to two deficiency alleles were identified, two with the Pi*Z/Z genotype, four with the genotype Pi*M malton/M malton, three with Pi*Z/M malton, and one with Pi*Z/M heerlen. Conclusion: Our results identified AATD mutations as a genetic-based contributor to lung disease in patients with COPD or bronchiectasis and assessed their frequency in a population of Turkish patients.

Neonatal cholestasis in children with Alpha-1-AT deficiency is a risk for earlier severe liver disease with male predominance.

BACKGROUND: Our objective was to better understand the natural history and disease modifiers of Alpha-1-antitrypsin deficiency (AATD), a common genetic liver disease causing hepatitis and cirrhosis in adults and children. The clinical course is highly variable. Some infants present with neonatal cholestasis, which can resolve spontaneously or progress to cirrhosis; others are well in infancy, only to develop portal hypertension later in childhood. METHODS: The Childhood Liver Disease Research Network has been enrolling AATD participants into longitudinal, observational studies at North American tertiary centers since 2004. We examined the clinical courses of 2 subgroups of participants from the several hundred enrolled; first, those presenting with neonatal cholestasis captured by a unique study, enrolled because of neonatal cholestasis but before specific diagnosis, then followed longitudinally (n=46); second, separately, all participants who progressed to liver transplant (n=119). RESULTS: We found male predominance for neonatal cholestasis in AATD (65% male, p=0.04), an association of neonatal gamma-glutamyl transpeptidase elevation to more severe disease, and a higher rate of neonatal cholestasis progression to portal hypertension than previously reported (41%) occurring at median age of 5 months. Participants with and without preceding neonatal cholestasis were at risk of progression to transplant. Participants who progressed to liver transplant following neonatal cholestasis were significantly younger at transplant than those without neonatal cholestasis (4.1 vs. 7.8 years, p=0.04, overall range 0.3-17 years). Neonatal cholestasis had a negative impact on growth parameters. Coagulopathy and varices were common before transplant, but gastrointestinal bleeding was not. CONCLUSIONS: Patients with AATD and neonatal cholestasis are at risk of early progression to severe liver disease, but the risk of severe disease extends throughout childhood. Careful attention to nutrition and growth is needed.

Initial alpha-1 antitrypsin screening in Turkish patients with chronic obstructive pulmonary disease.

BACKGROUND: Alpha-1 antitrypsin (AAT) deficiency is associated with several types of pathology, and the reported effects of mutations in the ATT-encoding gene vary worldwide. No Turkish study has yet appeared. We thus explored the AAT status of Turkish patients with chronic obstructive pulmonary disease (COPD). METHODS: This prospective cross-sectional study included outpatients and inpatients treated from June 2021 to June 2022. Serum AAT levels were checked, and dry blood samples were subjected to genetic analysis. RESULTS: : Genetic mutations were found in 21 (3.52%) of 596 patients with prior and new COPD diagnoses treated in our pneumonology outpatient department. The mean serum AAT level was 114.80 mg/dL (minimum 19, maximum 209; standard deviation 27.86 mg/dL). The most frequent mutation was M/Plowell (23.8%, n = 5), followed by M/S (23.8%, n = 5), M/I (19%, n = 4), M/Malton (14.3%, n = 3), Z/Z (9.5%, n = 2), M/Z (4.8%, n = 1), and Kayseri/Kayseri (4.8%, n = 1). Thoracic computed tomography revealed that 85.7% (n = 18) of all patients had emphysema, 28.5% (n = 6) had bronchiectasis, and 28.5% (n = 6) had mass lesions. Of the emphysema patients, 55% (n = 10) had only upper lobe emphysema, and 83.3% (n = 15) had emphysema in additional areas, but statistical significance was lacking (p > 0.05). DISCUSSION: In patients with emphysema and normal serum AAT levels, genetic analyses may reveal relevant heterozygous mutations, which are commonly ignored. Most clinicians focus on lower lobe emphysema. Evaluations of such patients might reveal AAT mutations that are presently overlooked because they are not considered to influence COPD status.

Impact of the COVID-19 pandemic on well-being and quality of life of patients with alpha-1-antitrypsin deficiency.

BACKGROUND: Alpha-1-antitrypsin deficiency (AATD) is a genetic disorder characterized by mutations in the SERPINA1 gene, primarily affecting the lungs and liver. The COVID-19 pandemic has raised questions about the susceptibility of individuals with AATD to COVID-19 and whether patients with rare lung disease might experience increased stress-related symptoms and mental health challenges. This study aims to investigate the impact of the COVID-19 pandemic on the quality of life of individuals living with AATD. METHODS: The study enrolled participants from the German registry for individuals with AATD. Questionnaires were sent to the 1250 participants, and a total of 358 patients were included in the analysis. The primary objective was to examine the influence of sociodemographic and disease-related factors on the occurrence of stress-related symptoms. This was accomplished through correlation and regression analyses. We also investigated the role of baseline quality of life (QoL), as measured by the St. George's Respiratory Questionnaire (SGRQ), as a mediator of this relationship. RESULTS: Stress-related symptoms were predicted by young age, female gender, psychological disorders, and a history of exacerbations of lung disease, as determined by multiple regression analysis. QoL as measured by the SGRQ mediated the relationship between poor lung function, stress, and a decline in overall well-being. CONCLUSION: The presented data demonstrate that the COVID-19 pandemic significantly affects the psychological well-being of patients with rare diseases, leading to increased levels of anxiety and stress. Disease-related factors can exacerbate stress manifestations, especially when compounded by sociodemographic and contextual factors. Thus, our study emphasizes the crucial role of taking these factors into account when managing individuals with AATD in pandemic situations.

Governmental Non-Pharmaceutical Interventions during the COVID-19 Pandemic and the COPD Exacerbation and Respiratory Infection Rate in Patients with Alpha-1 Antitrypsin Deficiency.

During the COVID-19 pandemic the number of hospital admissions due to chronic obstructive pulmonary disease (COPD) exacerbations was significantly reduced. The reason for this decline is not fully understood. Governmental non-pharmaceutical interventions (NPI's), an increase in community treated exacerbations, or healthcare avoidance by patients, are potential reasons. For the current study, the impact of Dutch governmental NPI's on the COPD exacerbations and respiratory infections rate in patients with severe alpha-1 antitrypsin deficiency (AATD) was analyzed. The patients participated in the NCT04204252 study, a randomized controlled trial evaluating the efficacy and safety of inhaled alpha-1 antitrypsin. Data collected in the time-period from March 2020 until February 2022 was analyzed. In this period the Dutch government imposed variable NPI's to contain the spread of SARS-CoV-2. Patients were required to document their daily symptoms in an electronic diary. The strictness of the governmental NPI's was measured by the COVID-19 Stringency Index. 19 patients participated in this study during the analysis period. A total of 40 respiratory infections and COPD exacerbations occurred. The Spearman's correlation coefficient of the monthly average COVID-19 Stringency Index and respiratory infections and COPD exacerbations rate was -0.316 (p = 0.132). When months known for a low respiratory infection rate were excluded, the correlation coefficient was -0.625 (p = 0.010). This study showed a significant negative correlation between the COPD exacerbations and respiratory infection rate and the COVID-19 Stringency Index in patients with AATD related COPD in the autumn-winter months.

The prevalence of bronchiectasis in patients with alpha-1 antitrypsin deficiency: initial report of EARCO.

BACKGROUND: Although bronchiectasis has been recognised as a feature of some patients with Alpha1-Antitrypsin deficiency the prevalence and characteristics are not widely known. We wished to determine the prevalence of bronchiectasis and patient characteristics. The first cohort of patients recruited to the EARCO (European Alpha1 Research Collaboration) International Registry data base by the end of 2021 was analysed for radiological evidence of both emphysema and bronchiectasis as well as baseline demographic features. RESULTS: Of the first 505 patients with the PiZZ genotype entered into the data base 418 (82.8%) had a reported CT scan. There were 77 (18.4%) with a normal scan and 38 (9.1%) with bronchiectasis alone. These 2 groups were predominantly female never smokers and had lung function in the normal range. The remaining 303 (72.5%) ZZ patients all had emphysema on the scan and 113 (27%) had additional evidence of bronchiectasis. CONCLUSIONS: The data indicates the bronchiectasis alone is a feature of 9.1% of patients with the PiZZ genotype of Alpha1-antitrypsin deficiency but although emphysema is the dominant lung pathology bronchiectasis is also present in 27% of emphysema cases and may require a different treatment strategy.

Testing Patterns and Disparities for Alpha-1 Antitrypsin Deficiency.

BACKGROUND: Alpha-1 antitrypsin deficiency is an under-recognized genetic cause of chronic lung and liver disease; it remains unclear what the testing frequency and disparities are for alpha-1 antitrypsin deficiency. METHODS: This is a retrospective cohort study of people with newly diagnosed chronic obstructive pulmonary disease and liver disease identified at the University of Florida between January 1, 2012 and December 31, 2021. We performed incidence and prevalence analysis for alpha-1 antitrypsin (AAT) testing and point-biserial correlation analysis for tobacco use and AAT testing. We evaluated characteristics with AAT testing using adjusted multivariable logistic regression. RESULTS: Among 75,810 subjects with newly diagnosed chronic obstructive pulmonary disease and liver disease between 2012 and 2021, 4248 (5.6%) were tested for AAT deficiency. All subjects had an AAT level performed, while 1654 (39%) had phenotype testing. Annual incidence of testing increased for subjects with newly diagnosed chronic obstructive pulmonary disease or liver disease from 2.8% and 5.4%, respectively, in 2012 to 4.1% and 11.3%, respectively, in 2021. Adjusted multivariable regression analysis showed factors favoring AAT testing were White race, and concomitant chronic obstructive pulmonary disease and liver disease. Increasing age, non-White race, current tobacco use, and being a male with chronic obstructive pulmonary disease had lower odds of AAT testing. CONCLUSION: Although slowly improving, testing for AAT deficiency continues to have a low uptake in the clinical setting despite guidelines recommending broader testing. Individuals of White race and those with concomitant chronic obstructive pulmonary disease and liver disease are more likely to be tested, while older subjects, individuals of non-White race, current tobacco use, and men with chronic obstructive pulmonary disease are less favored to be tested.

Estimated Worldwide Prevalence of the PI*ZZ Alpha-1 Antitrypsin Genotype in Subjects With Chronic Obstructive Pulmonary Disease

Introduction: The prevalence of α1-antitrypsin PI*ZZ genotypes in patients with COPD is only partially known. We aimed to estimate this prevalence worldwide. Method: A systematic review of the literature was conducted for studies investigating the prevalence of COPD and the prevalence of severe alpha-1-antitrypsin deficiency (AATD) PI*ZZ genotype. Results are shown in tables and on a whole world interpolation map. Results: Studies from 48 countries with available data (21 from Europe, 9 from the Americas, 5 from Africa, 11 from Asia and 2 from Australasia) were selected. About 235,000 individuals with PI*ZZ genotypes were accounted: 50% in Europe, 37% in America, 9% in Asia, 3% in Australasia and 1% in Africa. The estimated crude prevalence of COPD in adults older than 40 years was 12.45% in Europe, 13.51% in America, 13.22% in Africa, 11.70% in Asia and 11.86% in Australasia. The highest PI*ZZ weighted average prevalence among COPD subjects (expressed as 1/x [95% confidence intervals]) were found in Northern Europe (395 [252–576]) followed by Western (797 [538–1165]), Southern (944 [600–1475]) and Central Europe (1096 [687–1738]). Outside Europe, high values were found in Australia–New Zealand (1007 [684–1509]), Saudi Arabia (1276 [563–2961]), United States (1298 [1094–1540]), Canada (1482 [1057–2083]) and Thailand (1807 [717–4692]). In the rest of the world, prevalence was significantly lower, especially in vast regions of Asia and Africa where the PI*Z gene is practically non-existent. Conclusions: Severe AATD is associated with a significant number of cases of COPD, especially in Europe, USA, Canada, New Zealand and Australia. (AU)

Estimating the Prevalence of AATD Patients in the UK to Identify Underdiagnosis and Determine the Eligibility for Potential Augmentation Therapy.

Purpose: Alpha 1 antitrypsin deficiency (AATD) is a genetic risk factor for chronic obstructive pulmonary disease (COPD). Whilst testing for the condition is relatively simple, there is a disconnect in published literature between genetic epidemiology and numbers of patients known to specialists. This makes planning services for patients difficult. We aimed to estimate the number of patients likely to have lung disease eligible for specific AATD therapy within the UK. Patients and Methods: The THIN database was used to determine the prevalence of AATD and symptomatic COPD. This, and published rates of AATD were used to extrapolate THIN data to the population size of the UK to give an indicative population size for symptomatic AATD patients who have lung disease. The Birmingham AATD registry was used to describe age at diagnosis, rate of lung disease and symptomatic lung disease for patients with PiZZ (or equivalent) AATD, together with the time from symptom onset to diagnosis, in order to aid interpretation of the THIN data and improve modeling. Results: THIN data showed COPD prevalence of 3%, and AATD prevalence of 0.005-0.2%, depending on how stringently AATD diagnostic codes were applied. The majority of Birmingham AATD patients were diagnosed between the ages 46-55, whilst patients recorded in THIN tended to be older. The rate of COPD was similar in the THIN and Birmingham patients diagnosed with AATD. Modelling to the size of the UK demonstrated a likely symptomatic AATD population of between 3016 and 9866 people. Conclusion: AATD is likely to be under-diagnosed in the UK. Based on projected patient numbers an expansion to specialist services is desirable, in particular if specific therapy for AATD such as augmentation were to be introduced to the healthcare system.

Increased Prevalence of Alpha-1-Antitrypsin Deficiency in Patients with Biliary Tract Cancer and Its Associated Clinicopathological Features.

Alpha-1 antitrypsin deficiency (A1ATD) is underdiagnosed and associated with liver diseases. Here, we genotyped 130 patients with biliary tract cancer (BTC) scheduled for liver resection and found A1ATD in 10.8% of the patients. A1ATD was found in all BTC subtypes, and patients had similar clinical features as non-A1ATD BTC, not permitting their identification using clinical routine liver tests. In intrahepatic cholangiocarcinoma (iCCA), the abundance of A1AT protein was increased in the tumor and appeared to be influenced by the genomic alterations. On the one hand, BTC with A1ATD had lower perineural invasion at histopathology and displayed a longer survival, suggesting that a deficiency in this protein is associated with a less aggressive phenotype. On the other hand, iCCA with high A1AT expression had more advanced tumor staging and enriched pathways for complement system and extracellular matrix interactions, indicating that A1AT protein might contribute to a more aggressive phenotype. With increased awareness, screening, and basic studies, A1ATD could represent one more layer of stratification for future targeted therapies in BTC.

Prevalence of genetic mutations in alpha-1 antitrypsin deficiency (aatd) in patients with chronic obstructive pulmonary disease in Colombia.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is an underrecognized genetic disorder associated mainly with pulmonary emphysema and Chronic Obstructive Pulmonary Disease (COPD). All individuals with COPD regardless of age or ethnicity should be tested for AATD, but in Colombia its prevalence in unknown. MAIN OBJECTIVE: To determine the prevalence of the genetic mutations, present in AATD in adult patients with COPD in Colombia, using a genotyping test on cells from the oral mucosa. METHODS: This was a multicentre, observational, cross-sectional study which included adult patients attending seven COPD care centres in Colombia. Demographic data, medical history, including history of exposure to smoking and biomass smoke, most recent spirometry, pharmacological and non-pharmacological treatment received, serum AAT levels, and mutations detected by the genotyping test were recorded for all the recruited patients. For the comparison of variables between the groups with and without mutation, we used the X2 test for the qualitative variables and the Student's t-test or Mann-Whitney U test according to their distribution. MAIN FINDINGS: We collected a sample of 1,107 patients, the median age was 73.8 years (87.6-79.9). Mutations were documented in 144 patients (13.01%), the majority had the M/S mutation (78.50%), followed by M/Z (9.72%). One patient had a ZZ mutation and two patients had null alleles. In total, 23 patients had mutations associated with serum AAT deficiency (levels below 60 mg/dl). CONCLUSIONS: Genetic mutations were documented in 13.01% of patients with COPD in Colombia and 2.07% were AATD-related, showing that there is a significant number of underdiagnosed patients.

Meta-analysis: Prevalence of significant or advanced fibrosis in adults with alpha-1-antitrypsin deficiency.

BACKGROUND: The prevalence of liver fibrosis detected by non-invasive imaging in alpha-1-antitrypsin (AAT) deficiency has not been systematically assessed. AIMS: We conducted a systematic review and meta-analysis to determine the prevalence of significant fibrosis and advanced fibrosis in AAT deficiency based on non-invasive imaging. METHODS: Medline and Embase electronic databases were searched for studies from inception to 13 November 2022 that provided data for the prevalence of fibrosis in adults with AAT deficiency. A generalised linear mixed model with Clopper-Pearson intervals was used to pool single-arm outcomes. RESULTS: Of the 214 records identified, 8 studies were included. Five studies assessed fibrosis using vibration-controlled transient elastography. The prevalence of significant fibrosis (defined as ≥7.1 kPA) in Z homozygosity, Z heterozygosity and non-carrier status was 22.10% (five studies, 95% CI: 17.07-28.12), 9.24% (three studies, 95% CI: 4.68-17.45) and 5.38% (one study, 95% CI: 3.27-8.73), respectively, p < 0.0001, and the prevalence of advanced fibrosis (defined as ≥9.5 kPa) was 8.13% (five studies, 95% CI: 4.60-13.96), 2.96% (three studies, 95% CI: 1.49-5.81) and 1.08% (one study, 95% CI: 0.35-3.28), respectively, p = 0.003. There were limited data regarding the use of magnetic resonance elastography or acoustic radiation force impulse to assess for fibrosis. CONCLUSION: More than one in five adult individuals with AAT deficiency and Z homozygosity harbour significant fibrosis, and nearly 1 in 10 harbours advanced fibrosis. The risk of fibrosis increases incrementally with the frequency of Pi*Z mutations.

Estimated Worldwide Prevalence of the PI*ZZ Alpha-1 Antitrypsin Genotype in Subjects With Chronic Obstructive Pulmonary Disease.

INTRODUCTION: The prevalence of α1-antitrypsin PI*ZZ genotypes in patients with COPD is only partially known. We aimed to estimate this prevalence worldwide. METHOD: A systematic review of the literature was conducted for studies investigating the prevalence of COPD and the prevalence of severe alpha-1-antitrypsin deficiency (AATD) PI*ZZ genotype. Results are shown in tables and on a whole world interpolation map. RESULTS: Studies from 48 countries with available data (21 from Europe, 9 from the Americas, 5 from Africa, 11 from Asia and 2 from Australasia) were selected. About 235,000 individuals with PI*ZZ genotypes were accounted: 50% in Europe, 37% in America, 9% in Asia, 3% in Australasia and 1% in Africa. The estimated crude prevalence of COPD in adults older than 40 years was 12.45% in Europe, 13.51% in America, 13.22% in Africa, 11.70% in Asia and 11.86% in Australasia. The highest PI*ZZ weighted average prevalence among COPD subjects (expressed as 1/x [95% confidence intervals]) were found in Northern Europe (395 [252-576]) followed by Western (797 [538-1165]), Southern (944 [600-1475]) and Central Europe (1096 [687-1738]). Outside Europe, high values were found in Australia-New Zealand (1007 [684-1509]), Saudi Arabia (1276 [563-2961]), United States (1298 [1094-1540]), Canada (1482 [1057-2083]) and Thailand (1807 [717-4692]). In the rest of the world, prevalence was significantly lower, especially in vast regions of Asia and Africa where the PI*Z gene is practically non-existent. CONCLUSIONS: Severe AATD is associated with a significant number of cases of COPD, especially in Europe, USA, Canada, New Zealand and Australia.