Alpha-1 Antitrypsin Deficiency Research Articles

Case Report: When cystic fibrosis, elexacaftor/tezacaftor/ivacaftor therapy, and alpha1 antitrypsin deficiency get together

In the last 10 years, the care of patients with cystic fibrosis (CF) has been revolutionized with the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulator drugs, with a major impact on symptoms and life expectancy, especially considering the newest and highly effective elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) therapy. Conversely, adverse effects are relatively frequent, with some being life-threatening, such as severe hepatitis. Clinical trials on children starting CFTR modulators have reported transaminase elevations >3× upper limit of the norm in 10%–20% of patients, whereas real-life studies have reported discontinuation rates three times higher than those observed in phase 3 trials. We report the case of a 10-year-old boy with CF who developed severe acute hepatitis 2 weeks after starting ELX/TEZ/IVA therapy. An extensive screening for potential causes led to the identification of heterozygous alpha1-antitrypsin (AAT) deficiency with genotype MZ. The Z allele of SERPINA1 gene, encoding AAT, is known as a risk factor for CF liver disease. We hypothesized that it may act as a risk factor for drug-induced liver injury from CFTR modulators, notably ELX/TEZ/IVA. Therefore, checking AAT before starting CFTR modulator therapy can be suggested, in particular for children with previous, even transient, liver disease.

Genetic epidemiology of alpha-1 antitrypsin deficiency in Macaronesia.

The prevalence of alpha-1 antitrypsin deficiency (AATD) in Macaronesia (i.e., Azores, Madeira, Canary Islands and Cape Verde archipelagos) is poorly known. Our goal is to update it by selecting the most reliable available articles. Literature search using Medline, EMBASE (via Ovid) and Google Scholar, until December 2023, for studies on prevalence of AATD in the general population and in screenings, published in peer-reviewed journals. Three studies carried out in the general population of Madeira, La Palma and Cape Verde, and three screenings carried out in La Palma (2) and Gran Canaria (1) were selected. The frequencies of PI*S in the general population showed an ascending gradient, from South to North, with values (per thousand) of 35 in Cape Verde, 82 in La Palma and 180 in Madeira. The PI*Z frequencies showed this same gradient, with values of 2 x1,000 in Cape Verde, 21 in La Palma and 25 in Madeira. Screenings detected high percentages of defective alleles, including several rare and null alleles, some unique to these islands. The frequencies of PI*S and PI*Z in Madeira are comparable to the highest in the world. Those of the Canary Islands are similar to those of the peninsular population of Spain, and contrast with the low rates of Cape Verde. Screenings detected high numbers of deficient alleles. These results support the systematic investigation of AATD in clinically suspected patients and in relatives of index cases, to reduce underdiagnosis and apply early preventive and therapeutic measures in those affected.

Abstract CT278: [DREAM] Double lung transplant registry aimed for lung-limited malignancies - a prospective registry study for medically refractory cancers

Abstract BackgroundAdenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) are listed as ‘special circumstances’ for lung transplantation according to a consensus document from the International Society for Heart and Lung Transplantation (ISHLT) (Weill D et al., 2015). Five studies have reported on lung transplantation in carefully selected subsets of patients with multifocal lung adenocarcinoma (Raemdonck DV et al., 2016; Glanville AR et al., 2018). The 5-year survival rate of bilateral sequential lung transplantation was estimated at over 50% in patients with multifocal BAC, invasive adenocarcinoma, and NSCLC (Ahmad U et al., 2012; Paloyan EB et al., 2000; Zorn GL et al., 2003; de Perrot M et al., 2004). Another a case series reported a post-transplant recurrence-free survival of 23 to 56 months in three patients (Garver RI et al., 1999). Moreover, there is an unmet need for patients who have lung-limited metastasis after successful treatment for primary tumors such as sarcomas or colorectal cancer (CRC). As with liver transplantation for CRC patients who have liver-confined metastases (Dueland S et at., 2020; Hernandez-Alejandro R et al., 2022), the applicability of lung transplantation in lung-limited metastatic patients should be explored. There is also an unmet need for patients with respiratory failure with a history of cancer in the last 5 years. MethodsThis is a prospective registration trial to evaluate outcomes of patients who undergo double lung transplantation for the treatment of the select groups of medically refractory cancers (primary lung cancers or metastatic cancers in lungs). Overall survival (OS), disease-free survival (DFS), allograft rejection (AR) and allograft survival (AS) as well as molecular and genetic biomarkers will be monitored to investigate the correlation with prognosis.The study duration will be 10 years including surveillance. Recruitment is to occur during the first 5 years of the study. The goal is to enroll 125 participants through the Northwestern Medicine Clinical Programs.Essential Criteria:1.The tumor should be without any extrapulmonary metastasis as determined by standard of care diagnostic and staging workup.2.All standard of care or experimental oncological treatments known to improve survival should have failed or deemed infeasible 3.Patients should meet the general criteria for lung transplant evaluation and listing Study cohorts:•Cohort A: Primary lung cancers - Examples include, but not limited to, invasive mucinous/non-mucinous non-small cell lung cancers and multifocal carcinomas.•Cohort B: Metastatic cancers to the lung only - Examples include, but not limited to, germ cell tumors, head & neck tumors, colorectal tumors, renal cell tumors, testicular cancers.•Cohort C: Respiratory failure with a history of cancer in the last 5 years- Examples include, but not limited to interstitial lung disease (ILD), pulmonary fibrosis (idiopathic or secondary), advanced chronic obstructive pulmonary disease (COPD), bronchiectasis, emphysema, cystic fibrosis (CF), emphysema due to alpha-1 antitrypsin deficiency, and pulmonary arterial hypertension (PAH) Clinical trial registry number : NCT05671887.Enrollment began November 16, 2022. Trial is open and continues to enroll participants as of Jan 8, 2024. Citation Format: Young Kwang Chae, Liam Il-Young Chung, Rade Tomic, Ankit Bharat. [DREAM] Double lung transplant registry aimed for lung-limited malignancies - a prospective registry study for medically refractory cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT278.

Long-Term SGRQ Stability in a Cohort of Individuals with Alpha-1 Antitrypsin Deficiency-Associated Lung Disease.

Health-related quality of life (HRQoL) assessments such as St. George's Respiratory Questionnaire (SGRQ) are often used as outcome measures to evaluate patient-perceived changes in health status among individuals with lung disease. Several factors have been linked to deterioration in SGRQ, including symptoms (dyspnea, wheezing) and exercise intolerance. Whether these findings apply to individuals with alpha-1 antitrypsin deficiency (AATD) remains incompletely studied. This longitudinal study examines the trajectory of SGRQ scores in a cohort of United States individuals with AATD-associated lung disease and defines factors associated with longitudinal change. Individuals with AATD-associated lung disease enrolled in AlphaNet, a disease management program, who had ≥3 SGRQ measurements collected between 2009 and 2019, and baseline data for clinically important variables were included in these analyses. Data collected after lung transplants were excluded. Mixed-effects model analyses were used to evaluate the changes in SGRQ total and subscale scores over time and by modified Medical Research Council (mMRC) Scale, use of oxygen, age, sex, productive cough, and exacerbation frequency at baseline. Sensitivity analyses were conducted to examine the potential effect of survivor bias. Participants (n=2456, mean age 57.1±9.9 years, 47% female) had a mean SGRQ total score of 44.7±18.9 at baseline, 48% used oxygen regularly, and 55% had ≥2 exacerbations per year. The median length of follow-up was 6 (IQR 3-9) years. The SGRQ total score and subscales remained stable throughout the observation period. Age, mMRC categories, presence or absence of productive cough, frequency of exacerbations, and use of oxygen at baseline were significantly associated with the rate of change of SGRQ total (p<0.0001). We observed long-term stability in HRQoL and an association between the rate of change in SGRQ and baseline mMRC, exacerbation frequency, productive cough, and use of oxygen in this cohort of individuals with AATD-associated lung disease.

Variants in autophagy genes MTMR12 and FAM134A are putative modifiers of the hepatic phenotype in α1-antitrypsin deficiency.

In the classical form of α1-antitrypsin deficiency a misfolded variant α1-antitrypsin Z accumulates in the endoplasmic reticulum of liver cells and causes liver cell injury by gain-of-function proteotoxicity in a sub-group of affected homozygotes but relatively little is known about putative modifiers. Here we carried out genomic sequencing in a uniquely affected family with an index case of liver failure and 2 homozygous siblings with minimal or no liver disease. Their sequences were comparedto sequences in well-characterized cohorts of homozygotes with or without liver disease and then candidate sequence variants were tested for changes in kinetics of ATZ degradation in iPS-derived hepatocyte-like cells derived from the affected siblings themselves. Specific variants in autophagy genes MTMR12 and FAM134A could each accelerate the degradation of ATZ in cells from the index patient but both MTMR12 and FAM134A variants were needed to slow degradation of ATZ in cells from a protected sib, indicating that inheritance of both variants is needed to mediate the pathogenic effects of hepatic proteotoxicity at the cellular level. Analysis of homozygote cohorts showed that multiple patient-specific variants in proteostasis genes are likely to explain liver disease susceptibility at the population level. These results validate the concept that genetic variation in autophagy function can determine susceptibility to liver disease in ATD and provide evidence that polygenic mechanisms and multiple patient-specific variants are likely needed for proteotoxic pathology.

The importance of Alpha-1 Antitrypsin (AAT) and respiratory rehabilitation in patients with lung diseases

Abstract: Background: The incidence of lung diseases is very high worldwide, especially in the case of lung cancer, pulmonary tuberculosis, and obstructive ventilatory dysfunctions. Alpha-1 antitrypsin (AAT) is synthesized mainly by hepatocytes, and one of its roles is to inhibit protease activity in the body's biological fluids following the phenomenon of programmed cell death, which is also called apoptosis. Acute lung diseases, but especially chronic ones, can cause, in addition to pulmonary and extrapulmonary manifestations, social and psychological impact, which is why a complex, interdisciplinary respiratory rehabilitation program is necessary. Objectives: Our study aimed to determine the correlation between alpha-1 antitrypsin values and lung diseases (pulmonary tuberculosis, lung cancer, asthma, and COPD) and to evaluate the influence of the individualized respiratory rehabilitation program in these diseases. Methods: We carried out a retrospective study between February 2022 and March 2023 in the Pneumology Department of the "Victor Babeș" Clinical Hospital of Infectious Diseases and Pneumoftiziology, Craiova. It included 189 patients diagnosed with pulmonary tuberculosis, lung cancer, or obstructive ventilatory dysfunctions (chronic obstructive pulmonary disease – COPD or asthma). Alpha-1 antitrypsin was collected from all patients. Respiratory rehabilitation was carried out both during hospitalization and in an out-patient setting for a maximum period of 6 months after discharge, with some patients even using telemedicine. Results: Increased values of alpha-1 antitrypsin were detected in advanced stages of the disease, and a clear improvement of clinical and functional parameters was observed after inclusion in the rehabilitation program. Conclusions: Detection of alpha-1 antitrypsin deficiency (AATD) is rare. The majority of patients diagnosed with lung cancer in advanced stages showed increased values of alpha-1 antitrypsin, AAT being able to be used as a follow-up marker in response to oncological treatment. Respiratory rehabilitation benefits in pulmonary tuberculosis, lung cancer, COPD, and asthma, regardless of the form of the disease. An interdisciplinary approach is necessary for the optimal treatment and control of lung diseases.

Current Advances and Applications in CRISPR-Cas Technology, Plant Sciences and Nanotechnology

The CRISPR toolbox can perform precise programmable genetic sequence insertions to the development of new technologies. The Cas9 nuclease is one of the proteins that make up the so-called genetic scissors, a system of directed cutting of foreign DNA and, RNA that is the subject of extensive research among all known Cas proteins. The correction of alpha1 antitrypsin deficiency and cancer immunotherapy are two important therapeutic development scenarios where HDR-mediated CRISPR-Cas9 editing has demonstrated encouraging outcomes in the clinical testing. Protospacers are DNA segments that are targeted by the prokaryotic immune system and resemble the corresponding spacers at the CRISPR locus, with the exception of the PAM motif. The transpiration is the loss of water by a plant, mostly through the stomata on its leaves. Drought is a dangerous occurrence that significantly affects how well plants perform. It sets off physiological and biochemical processes that help the plant withstand drought by lessening its impacts. Medicinal plants and other soil-grown agricultural goods are often impacted by oil pollution. The existence of hazardous heavy metals in the soil, such as cadmium, mercury, lead, chromium, arsenic, nickel, copper, and zinc, is one of the many other explanations for why some bacteria and germs have become resistant to medications this century.

Review article: New developments in biomarkers and clinical drug development in alpha-1 antitrypsin deficiency-related liver disease.

Alpha-1 antitrypsin liver disease (AATLD) occurs in a subset of patients with alpha-1 antitrypsin deficiency. Risk factors for disease progression and specific pathophysiologic features are not well known and validated non-invasive assessments for disease severity are lacking. Currently, there are no approved treatments for AATLD. To outline existing understanding of AATLD and to identify knowledge gaps critical to improving clinical trial design and development of new treatments. This report was developed following a multi-stakeholder forum organised by the Alpha-1 Antitrypsin Deficiency Related Liver Disease Expert Panel in which experts presented an overview of the available literature on this topic. AATLD results from a 'gain of toxic function' and primarily manifests in those with the homozygous Pi*ZZ genotype. Accumulation of misfolded 'Z' AAT protein in liver cells triggers intracellular hepatocyte injury which may ultimately lead to hepatic fibrosis. Male gender, age over 50 years, persistently elevated liver tests, concomitant hepatitis B or C virus infection, and metabolic syndrome, including obesity and type 2 diabetes mellitus, are known risk factors for adult AATLD. While the gold standard for assessing AATLD disease activity is liver histology, less invasive measures with low intra- and inter-observer variability are needed. Measurement of liver stiffness shows promise; validated thresholds for staging AATLD are in development. Such advances will help patients by enabling risk stratification and personalised surveillance, along with streamlining the development process for novel therapies. This inaugural forum generated a list of recommendations to address unmet needs in the field of AATLD.

Characteristics associated with SF-36 in alpha-1 antitrypsin deficiency-associated COPD: a cross-sectional analysis

BackgroundGeneric measures of health-related quality of life (HRQoL), such as the 36-Item Short Form Survey (SF-36), are widely used in assessing chronic conditions. These tools have an advantage over disease-specific instruments, as they allow comparisons across different health conditions and with the general population. In alpha-1 antitrypsin deficiency (AATD)-associated chronic obstructive pulmonary disease (COPD), HRQoL research remains scarce. This cross-sectional study evaluates the factors associated with HRQoL in a cohort of patients with AATD-associated COPD.MethodsOur study included participants of AlphaNet (2008-2019), a health management organization for people with AATD in the US who are prescribed augmentation therapy. Norm-based SF-36 scores for the mental and physical component summary scores (MCS and PCS, mean of 50 ± 10 in the general US population) and 8 individual scales were evaluated. Individuals with lung disease and data available on ≥1 measurement on any SF-36 scale and clinically relevant characteristics such as modified Medical Research Council (mMRC) scale, exacerbation frequency, productive cough, and use of oxygen were included in these analyses. Generalized linear regression models were fit to examine the association of baseline characteristics with MCS and PCS scores. Age, sex, regular use of oxygen, exacerbation frequency, mMRC, and productive cough were included in these models.ResultsParticipants (n=4398, mean age 57.6 [SD=10.6] years, 45.4% female) had a mean MCS score of 51.2 ± 10.8 and PCS of 36.3 ± 9.8. The average mMRC score was 2.4 ± 1.3, and 56.4% had 2 or more exacerbations per year. Overall, the physical component of SF-36 was more severely impacted compared to the mental component. In multivariable regression analyses, PCS scores were significantly associated with exacerbation frequency, mMRC, regular use of oxygen, and productive cough; MCS was associated with age, sex, exacerbation frequency, mMRC, and productive cough.ConclusionsThese findings demonstrate that patient-perceived physical health is significantly impaired in this cohort of people with AATD-associated COPD compared to mental health. Longitudinal studies are needed to evaluate the change in physical and mental health status over time in this population.

Computational Tools to Assist in Analyzing Effects of the SERPINA1 Gene Variation on Alpha-1 Antitrypsin (AAT).

In the rapidly advancing field of bioinformatics, the development and application of computational tools to predict the effects of single nucleotide variants (SNVs) are shedding light on the molecular mechanisms underlying disorders. Also, they hold promise for guiding therapeutic interventions and personalized medicine strategies in the future. A comprehensive understanding of the impact of SNVs in the SERPINA1 gene on alpha-1 antitrypsin (AAT) protein structure and function requires integrating bioinformatic approaches. Here, we provide a guide for clinicians to navigate through the field of computational analyses which can be applied to describe a novel genetic variant. Predicting the clinical significance of SERPINA1 variation allows clinicians to tailor treatment options for individuals with alpha-1 antitrypsin deficiency (AATD) and related conditions, ultimately improving the patient's outcome and quality of life. This paper explores the various bioinformatic methodologies and cutting-edge approaches dedicated to the assessment of molecular variants of genes and their product proteins using SERPINA1 and AAT as an example.

Network-base approaches to identify therapeutic biomarkers in hepatocellular carcinoma and search for drug hunting utilizing molecular dynamics simulations

The presence of conditions like Alpha-1 antitrypsin deficiency, hemochromatosis, non-alcoholic fatty liver diseases and metabolic syndrome can elevate the susceptibility to hepatic cellular carcinoma (HCC). Utilizing network-based gene expression profiling via network analyst tools, presents a novel approach for drug target discovery. The significance level (p-score) obtained through Cytoscape in the intended center gene survival assessment confirms the identification of all target center genes, which play a fundamental role in disease formation and progression in HCC. A total of 1064 deferential expression genes were found. These include MCM2 with the highest degree, followed by 4917 MCM6 and MCM4 with a 3944-degree score. We investigated the regulatory kinases involved in establishing the protein-protein interactions network using X2K web tool. The docking approach yields a favorable binding affinity of −8.7 kcal/mol against the target MCM2 using Auto-Dock Vina. Interestingly after simulating the complex system via AMBER16 package, results showed that the root mean square deviation values remained within 4.74 Å for a protein and remains stable throughout the time intervals. Additionally, the ligand’s fit to the protein exhibited fluctuations at some intervals but remains stable. Finally, Gibbs free energy was found to be at its lowest at 1 kcal/mol which presents the real time interactive binding of the atomic residues among inhibitor and protein. The displacement of the ligand was measured showing stable movement and displacement along the active site. These findings increased our understanding for potential biomarkers in hepatocellular carcinoma and an experimental approach will further enhance our outcomes in future. Communicated by Ramaswamy H. Sarma

Otras enfermedades hepáticas de causa genética, metabólica y endocrinológica

Liver diseases of genetic origin comprise a series of diseases that manifest as abnormalities in liver structure and/or function due to genetic mutations. This update will discuss some of them, such as alpha-1 antitrypsin deficiency (A1AT), Wilson's disease, lysosomal acid lipase deficiency (LAL-D), and other congenital diseases related to bile acid and bilirubin metabolism.Alpha-1 antitrypsin deficiency is an autosomal codominant condition characterized by a decrease in secretion of alpha-1 antitrypsin protein, which acts as an inhibitor of neutrophil elastase. This results in liver and lung damage due to an accumulation of misfolded protein in hepatocytes and uncontrolled elastase activity. On the other hand, in Wilson's disease, an autosomal recessive disorder, mutations in the ATP7B gene impair copper metabolism. This results in an accumulation of toxic copper in the liver and other organs, causing hepatitis, cirrhosis, and neuropsychiatric manifestations. Lysosomal acid lipase deficiency is an autosomal recessive disorder caused by mutations in the LIPA gene. This results in the accumulation of cholesterol and triglyceride esters in lysosomes, leading to hepatomegaly, hyperlipidemia, and premature atherosclerosis. Finally, the set of diseases related to bilirubin and bile acid metabolism involve abnormalities in the production, transport, and excretion of bilirubin and bile acids. They are associated with cholestasis and hepatocellular damage, which can lead to liver failure and death.

Alpha-1 Antitrypsin Phenotyping: An Unmet Educational Need of Healthcare Providers.

Diagnosing alpha-1 antitrypsin deficiency (A1ATD) involves two-step laboratory testing, determination of serum alpha-1 antitrypsin (A1AT) level and phenotyping if A1AT < 100 mg/dL. Whether these guidelines are effectuated in clinical practice is uncertain. To begin to address this issue, we determined whether A1AT phenotyping is performed in patients with serum A1AT 57 - 99 mg/dL at our institution. We reviewed the medical records of patients seen at Jesse Brown Veterans Affairs Medical Center from January 2019 to October 2022 with serum A1AT between 57 and 99 mg/dL. In each case, pertinent demographic, clinical, and pulmonary function tests data were extracted. Data were presented as means and standard deviation (SD) where appropriate. The Student's t-test was used for statistical analysis. P < 0.05 was considered statistically significant. Thirty patients (90% males; 60 ± 18 years) with serum A1ATD < 100 mg/mL were identified. Fourteen were African Americans, four Hispanics, and 12 non-Hispanic Whites. The majority were current or ex-smokers. Fourteen (47%) patients had lung disease, 14 (47%) liver disease and one had concomitant lung and liver diseases. Mean ± SD forced expiratory volume in 1 s (FEV1) and lung diffusing capacity were 2.57 ± 1.41 L (67±19% predicated) and 18.7 ± 10 mL/min/mm Hg (64±28% predicted), respectively. Only 13 patients (43%) underwent phenotype testing (seven African Americans, five Whites, and one Hispanic). Six patients had MZ phenotype, four MS, and three SZ. One patient died from acute respiratory failure during the study period. Phenotyping of patients with serum A1AT 57 - 99 mg/dL at our institution is inadequate. Accordingly, regular continuous medical educational programs on A1AT phenotyping targeting healthcare providers are warranted.

Recurrent spontaneous pneumothorax in a patient with wilson disease who is on long-term D-penicillamine: Case report

Introduction: Recurrent spontaneous pneumothoraces (PSP) in association with liver disease is well known to occur with alpha 1 antitrypsin deficiency (AATD). Wilson disease (WD) association with recurrent PSP is not a known entity. Case presentation: A 42-year-old nonsmoker man with a history of recurrent PSP was admitted with a large right pneumothorax. Following intercostal chest drain (ICD) patient’s breathing improved and the lung expanded. Despite that, he continued to have a small residual pneumothorax (&lt;2cm). Twelve years ago, he was diagnosed with WD. The patient was on treatment with D-penicillamine. After 3 years of the diagnosis of WD, the patient developed left-sided recurrent PSPs where he ended up with a left-pleurectomy in 2015. For the current event, initially expectant management was done for residual pneumothorax. All the possible causes for PSP were excluded. On follow-up, he continued to be symptomatic. A thoracic surgical referral was arranged for Video-Assisted Thoracoscopic Surgery (VATS) and redo-pleurectomy. The safety of future treatment with D-penicillamine is not concluded as there is no convincing evidence to prove it as a culprit agent for PSPs. Multidisciplinary discussion was arranged and consideration of treatment with alternative copper chelating therapy was emphasized. Conclusion: Though rare, it is important to observe for occurrence of PSP in WD patients. This case report will be eye-opening for the association of lung disease and WD and related treatment.

Monocyte NLRP3 inflammasome and interleukin-1β activation modulated by alpha-1 antitrypsin therapy in deficient individuals

IntroductionAltered complement component 3 (C3) activation in patients with alpha-1 antitrypsin (AAT) deficiency (AATD) has been reported. To understand the potential impact on course of inflammation, the aim of this...

Alpha 1 antitrypsin deficiency - etiology, symptoms in various organs, diagnosis, treatment, prognosis

Introduction: Alpha-1 antitrypsin (AAT) is a glycoprotein produced by liver, belonging to the serine protease inhibitor family. Alpha-1 antitrypsin deficiency (AATD) is very common autosomal recessive genetic disease caused by point mutation in SERPINA1 gene. Mutations in the alpha-1 antitrypsin gene lead to production of misfolded AAT resulting in impaired release into the blood. This disorder leads to destruction of connecting tissue especially in lungs and to accumulation of retarded protein in the liver.  Purpose: Most studies addressing AAT deficiency focus on presenting symptoms related to the lungs and liver. We want to take a broader look at this issue, so we have closely examined scientific reports on the presentation of the disease in organs other than the lungs and liver. The goal is to gather holistic knowledge about the disease to enhance awareness and treatment.   Material and methods:    In our paper, we endeavored to address the issue of AAT deficiency comprehensively. We explored symptoms with an emphasis on organs beyond the liver and lungs. We also delved into the etiology, diagnosis, treatment, and prognosis of this disease.   Discussion:   The clinical symptoms of alpha 1 antitrypsin deficiency extending beyond the liver and lungs remain inadequately described. We know that AAT deficiency can lead to excessive destruction of connective tissue in any organ, not just the lungs and liver. Unfortunately, this condition continues to go undiagnosed, and the number of scientific publications on symptoms from other organs is too limited. This affects the insufficient attention given by doctors to tissue destruction in organs other than the lungs and liver.

Efficacy and safety of the Spiration Valve System™ for the treatment of severe emphysema in patients with Alpha-1 antitrypsin deficiency (EMPROVE)

ObjectivesAlpha-1 antitrypsin deficiency (AATD) is a hereditary condition associated with emphysema. This study analyzed the efficacy and safety of Spiration Valve System TM (SVS) among AATD patients with severe emphysema. MethodsThis multicenter prospective study included 20 patients demonstrating AATD as assessed by quantitative levels of AAT and genotype containing two ZZ alleles. Most diseased lobe based on high resolution computed tomography was selected for treatment with endobronchial SVS. The change from baseline in forced expiratory volume in 1 s (FEV1) at 6 months (Primary outcome) and at 12 months, quality-of-life (QoL) measured by St. George's Respiratory Questionnaire (SGRQ) as health status, dyspnea scale measured by mMRC, Chronic obstructive pulmonary disease (COPD) Assessment Test (CAT), 36-item Short Form Health Survey (SF-36) physical component summary (PCS) and safety were assessed. ResultsLung function (FEV1) significantly improved at 6 months (P = 0.02); but did not reach statistical significance at 12 months (P = 0.22). Significant improvement was observed in dyspnea (at all time points), QoL measures (3, 6, and 12 months), CAT score and PCS of SF-36 (1, 3 and 6 months). Response rates based on minimal clinically important difference reached 50–80% for all variables. Overall, 4.4 valves/patient were used to isolate the target lobe, with a mean procedure time of 20.3 min. Serious adverse events included COPD exacerbations (5%), pneumonia (10%), pneumothorax (15%) and death (5%), occurring within first three months. ConclusionSVS endobronchial valve treatment showed improvement in lung function, dyspnea, and QoL in AATD patients with severe emphysema.

Detection of Alpha-1 Antitrypsin Levels in Chronic Obstructive Pulmonary Disease in Respiratory Clinics in Spain: Results of the EPOCONSUL 2021 Audit.

Alpha-1 antitrypsin deficiency (AATD) is an underdiagnosed condition despite being one of the most common inherited disorders in adults that is associated with an increased risk of developing chronic obstructive pulmonary disease (COPD). The aim was to evaluate the frequency of performing AAT levels and associated factors in COPD patients in an audit conducted in 2021-2022, as well as to compare with a previous audit conducted in 2014-2015. EPOCONSUL 2021 is a cross-sectional audit that evaluated the outpatient care provided to COPD patients in respiratory clinics in Spain based on available data from medical registries. 4225 patients with a diagnosis of COPD from 45 centers were audited in 2021. A total of 1670 (39.5%) patients underwent AAT determination. Being treated at a specialized COPD outpatient clinic (OR 1.88, p = 0.007), age ≤ 55 years old (OR 1.84, p = 0.007) and a FEV1 < 50% (OR 1.86, p < 0.001) were associated with a higher likelihood of being tested for AAT, while Charlson index ≥ 3 (OR 0.63, p < 0.001) and genotyping of AATD availability (OR 0.42, p < 0.001) showed a statistically significant negative association. The analysis of cases included in respiratory units that participated in both audits showed an increase in the proportion of cases with AAT serum level testing available (adjusted OR 2.81, p < 0.001). The percentage of individuals with serum AAT levels < 60 mg/dL (a severe AATD) was 4%. Our analysis identifies significant improvements in adherence to the recommendation to test AAT levels in COPD patients, performed in 4 out of 10 patients, being more likely at younger ages and with higher COPD severity, and with a detection of severe AATD of 4% among those tested, suggesting that clinicians still perform AAT testing in COPD patients selectively. Therefore, efforts are still needed to optimize AATD screening and establish new early detection strategies to reduce morbidity and mortality in these patients.

Characteristics of alpha-1 antitrypsin deficiency related lung disease exacerbations using a daily symptom diary and urinary biomarkers.

Pulmonary exacerbations in alpha-1 antitrypsin deficiency (AATD) related lung disease are a significant contributor to disease burden, as with usual COPD. Separating the early stages of an exacerbation from the day-to-day variation in stable COPD is central to the concerns of both clinicians and patients and has been identified as a research priority by NIHR. Clinical tools that distinguish baseline symptoms from those of an exacerbation could allow early and appropriate treatment of AECOPD to reduce the impact and potentially may slow disease progression thereby improving survival and quality of life. Candidate tools include symptom diaries and biomarkers of infection and acute inflammation. Urinary biomarkers of AECOPD have yet to be explored in AATD related COPD. 55 patients with AATD related lung disease with a history of 2 or more AECOPD in the preceding year were prospectively followed for 18 months. Each patient recorded symptom scores daily via an electronic symptom diary (eDiary) based on Bronkotest. Urinary biomarkers for AAT, NE, CRP, TIMP1 and desmosine were measured weekly using a home urinary lateral flow device. During self-reported AECOPD patients were asked to perform urine analysis on the first 7 consecutive days. Type I Anthonisen exacerbations and episodes occurring in autumn/winter lasted longer than Type II/III exacerbations and spring/summer episodes respectively. Median urinary CRP concentration across all study participants increased during Type I AECOPD. eDiary adherence was 68% over a median of 17.8 months (IQR 15.7 to 18.5). Use of an eDiary and urinary biomarkers to detect and characterise AECOPD remotely in AATD related lung disease is feasible over a prolonged period and paves the way for precision detection of exacerbations.

Sirtuin3 promotes the degradation of hepatic Z alpha-1 antitrypsin through lipophagy.

Alpha-1 antitrypsin deficiency (AATD) is a genetic disease caused by misfolding and accumulation of mutant alpha-1 antitrypsin (ZAAT) in the endoplasmic reticulum of hepatocytes. Hepatic ZAAT aggregates acquire a toxic gain-of-function that impacts the endoplasmic reticulum which is theorized to cause liver disease in individuals with AATD who present asymptomatic until late-stage cirrhosis. Currently, there is no treatment for AATD-mediated liver disease except liver transplantation. In our study of mitochondrial RNA, we identified that Sirtuin3 (SIRT3) plays a role in the hepatic phenotype of AATD. Utilizing RNA and protein analysis in an in vitro AATD model, we investigated the role of SIRT3 in the pathophysiology of AATD-mediated liver disease while also characterizing our novel, transgenic AATD mouse model. We show lower expression of SIRT3 in ZAAT-expressing hepatocytes. In contrast, the overexpression of SIRT3 increases hepatic ZAAT degradation. ZAAT degradation mediated by SIRT3 appeared independent of proteasomal degradation and regular autophagy pathways. We observed that ZAAT-expressing hepatocytes have aberrant accumulation of lipid droplets, with ZAAT polymers localizing on the lipid droplet surface in a direct interaction with Perilipin2, which coats intracellular lipid droplets. SIRT3 overexpression also induced the degradation of lipid droplets in ZAAT-expressing hepatocytes. We observed that SIRT3 overexpression induces lipophagy by enhancing the interaction of Perilipin2 with HSC70. ZAAT polymers then degrade as a consequence of the mobilization of lipids through this process. In this context, SIRT3 activation may eliminate the hepatic toxic gain-of-function associated with the polymerization of ZAAT, providing a rationale for a potential novel therapeutic approach to the treatment of AATD-mediated liver disease.