1,158 results match your criteria Alpha1-Antitrypsin Deficiency

Fazirsiran for Liver Disease Associated with Alpha-Antitrypsin Deficiency.

N Engl J Med 2022 Jun 25. Epub 2022 Jun 25.

From the Department of Internal Medicine III, University Hospital, RWTH (Rheinisch-Westfälische Technische Hochschule) Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE-LIVER), Aachen, Germany (P.S., C.T.); the Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, ERN RARE-LIVER, Vienna (M.M.); the Department of Respiratory Medicine, Royal Infirmary of Edinburgh University Hospital, University of Edinburgh, Edinburgh (G.C.), and the Department of Hepatology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge (W.G.) - both in the United Kingdom; the Division of Gastroenterology, University of California San Diego School of Medicine, La Jolla (R.L.), and Arrowhead Pharmaceuticals, Pasadena (T.S., T.C., M.Y., B.D.G., J.C.H., J.S.M.) - both in California; and the Departments of Pediatrics and Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis (J.H.T.).

Background: Alpha-antitrypsin (AAT) deficiency results from carriage of a homozygous "Z" mutation (proteinase inhibitor [PI] ZZ). The Z allele produces a mutant AAT protein called Z-AAT, which accumulates in hepatocytes and can lead to progressive liver disease and fibrosis. This open-label, phase 2 trial investigated the safety and efficacy of fazirsiran, an RNA interference therapeutic, in patients with liver disease associated with AAT deficiency. Read More

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Protein-losing Enteropathy as a Complication and/or Differential Diagnosis of Common Variable Immunodeficiency.

J Clin Immunol 2022 Jun 23. Epub 2022 Jun 23.

Université de Lille, UFR Médecine, 59000, Lille, France.

As protein-losing enteropathy (PLE) can lead to hypogammaglobulinemia and lymphopenia, and since common variable immunodeficiency (CVID) is associated with digestive complications, we wondered if (1) PLE could occur during CVID and (2) specific features could help determine whether a patient with antibody deficiency has CVID, PLE, or both. Eligible patients were thus classified in 3 groups: CVID + PLE (n = 8), CVID-only (= 19), and PLE-only (n = 13). PLE was diagnosed using fecal clearance of α1-antitrypsin or 111In-labeled albumin. Read More

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[Proteolysis and deficiency of α1-proteinase inhibitor in SARS-CoV-2 infection].

Biomed Khim 2022 Jun;68(3):157-176

Siberian State Medical University, Tomsk, Russia.

The SARS-CoV-2 pandemia had stimulated the numerous publications emergence on the α1-proteinase inhibitor (α1-PI, α1-antitrypsin), primarily when it was found that high mortality in some regions corresponded to the regions with deficient α1-PI alleles. By analogy with the last century's data, when the root cause of the α1-antitrypsin, genetic deficiency leading to the elastase activation in pulmonary emphysema, was proven. It is evident that proteolysis hyperactivation in COVID-19 may be associated with α1-PI impaired functions. Read More

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Feasibility of a genotyping system for the diagnosis of alpha1 antitrypsin deficiency: a multinational cross-sectional analysis.

Respir Res 2022 Jun 10;23(1):152. Epub 2022 Jun 10.

CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain.

Introduction: Currently, strategies for improving alpha1 antitrypsin deficiency (AATD) diagnosis are needed. Here we report the performance of a multinational multiplex-based genotyping test on dried blood spots and buccal swabs sent by post or courier and with web registration for subjects with suspected AATD in Argentina, Brazil, Chile, Colombia, Spain, and Turkey.

Methods: This was an observational, cross-sectional analysis of samples from patients with suspected AATD from March 2018 to January 2022. Read More

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Developing lung cancer in COPD: Possible role of carrying Alpha-1 antitrypsin deficiency variants.

Respir Med Case Rep 2022 21;38:101667. Epub 2022 May 21.

Department of Chest Diseases, Health Sciences University, Yedikule Chest Diseases and Thoracic Surgery Training and Research Hospital, Istanbul, Turkey.

Introduction: Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation and airway inflammation, with a prevalence of 10.1%. Among the many causes of COPD, Smoking is the leading and another big cause is (AATD α1-antitrypsin deficiency)' an inherited disorder. Read More

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Liver-directed gene therapy attenuates progression of spontaneous and tobacco smoke-induced emphysema in α1-antitrypsin null mice.

Mol Ther Methods Clin Dev 2022 Jun 13;25:425-438. Epub 2022 Apr 13.

The Li Weibo Institute for Rare Diseases Research, Horae Gene Therapy Center, 368 Plantation Street, Worcester, MA 01605, USA.

α-antitrypsin deficiency is a rare genetic condition that can cause liver and/or lung disease. There is currently no cure for this disorder, although repeated infusions of plasma-purified protein may slow down emphysema progression. Gene therapy in which a single recombinant adeno-associated viral vector (rAAV) administration would lead to sustained protein expression could therefore similarly affect disease progression, and provide the added benefits of reducing treatment burden and thereby improving the patient's quality of life. Read More

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Alpha Antitrypsin Deficiency: Does Increased Neutrophil Adhesion Contribute to Lung Damage?

Am J Respir Cell Mol Biol 2022 May 6. Epub 2022 May 6.

Imperial College London, 4615, National Heart and Lung Institute, London, United Kingdom of Great Britain and Northern Ireland;

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A Role for Hepatic Insulin Signaling in α1-Antitrypsin Deficiency.

Gastroenterology 2022 Jul 29;163(1):49-51. Epub 2022 Apr 29.

Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address:

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The lipid ties of α1-antitrypsin: Structural and functional aspects.

Cell Immunol 2022 05 16;375:104528. Epub 2022 Apr 16.

Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.

α1-antitrypsin (AAT) is an acute-phase protein that functions as an inhibitor of serine proteases, such as neutrophil elastase. A significant body of evidence shows that AAT has a pivotal role in protecting tissues from neutrophil-induced damage, preserving endothelial function, and improving outcomes of cardiovascular and cerebrovascular diseases, though the mechanism of its activity is not fully elucidated. In terms of several significant anti-inflammatory and immunomodulatory properties, AAT's capacity to inhibit elastase has been determined to be non-essential. Read More

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Clinical manifestations of a new alpha-1 antitrypsin genetic variant: .

Respirol Case Rep 2022 May 14;10(5):e0936. Epub 2022 Apr 14.

Department of Medicine and Surgery, Respiratory Disease and Lung Function Unit University of Parma Parma Italy.

Alpha-1 antitrypsin deficiency is an autosomal, codominant disorder caused by mutations of the gene. Several mutations of have been described associated with the development of pulmonary emphysema and/or chronic liver disease and cirrhosis. Here, we report a very rare variant identified for the first time in an Italian family originally from the city of Parma in Northern Italy. Read More

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Associations of Enteric Protein Loss, Vaccine Response, Micronutrient Deficiency, and Maternal Depressive Symptoms with Deviance in Childhood Linear Growth: Results from a Multicountry Birth Cohort Study.

Am J Trop Med Hyg 2022 Apr 11. Epub 2022 Apr 11.

Nutrition and Clinical Services Division, International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Dhaka, Bangladesh.

We identified the determinants of positive (children who had a birth weight < 2.5 kg and/or maternal height < 145 cm but were nonstunted at 24 months of age) and negative (children who had a birth weight ≥ 2.5 kg and maternal height ≥ 145 cm but were stunted at 24 months of age) deviance in childhood linear growth. Read More

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Z-α-antitrypsin polymers impose molecular filtration in the endoplasmic reticulum after undergoing phase transition to a solid state.

Sci Adv 2022 Apr 8;8(14):eabm2094. Epub 2022 Apr 8.

Cambridge Institute for Medical Research (CIMR), Department of Medicine, University of Cambridge, The Keith Peters Building, Hills Road, Cambridge CB2 0XY, UK.

Misfolding of secretory proteins in the endoplasmic reticulum (ER) features in many human diseases. In α-antitrypsin deficiency, the pathogenic Z variant aberrantly assembles into polymers in the hepatocyte ER, leading to cirrhosis. We show that α-antitrypsin polymers undergo a liquid:solid phase transition, forming a protein matrix that retards mobility of ER proteins by size-dependent molecular filtration. Read More

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The Relationship between Plasma Alpha-1-Antitrypsin Polymers and Lung or Liver Function in ZZ Alpha-1-Antitrypsin-Deficient Patients.

Biomolecules 2022 02 28;12(3). Epub 2022 Feb 28.

Department of Pulmonology, Leiden University Medical Center, Member of European Reference Network Lung, Section Alpha-1-Antitrypsin Deficiency, 2333 ZA Leiden, The Netherlands.

Alpha-1-Antitrypsin (AAT) is a protein of the SERPINA1 gene. A single amino acid mutation (Lys342Glu) results in an expression of misfolded Z-AAT protein, which has a high propensity to intra- and extra-cellular polymerization. Here, we asked whether levels of circulating Z-AAT polymers are associated with the severity of lung disease, liver disease, or both. Read More

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February 2022

LMAN1-MCFD2 complex is a cargo receptor for the ER-Golgi transport of α1-antitrypsin.

Biochem J 2022 04;479(7):839-855

Genomic Medicine Institute, Lerner Research Institute of Cleveland Clinic, Cleveland, OH, U.SA.

α1-antitrypsin (AAT) is a serine protease inhibitor synthesized in hepatocytes and protects the lung from damage by neutrophil elastase. AAT gene mutations result in AAT deficiency (AATD), which leads to lung and liver diseases. The AAT Z variant forms polymer within the endoplasmic reticulum (ER) of hepatocytes and results in reduction in AAT secretion and severe disease. Read More

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Comparative biochemical efficacy analysis of an alpha-proteinase inhibitor (Glassia®) in patients with alpha-1 antitrypsin deficiency.

Pulm Pharmacol Ther 2022 06 18;73-74:102124. Epub 2022 Mar 18.

Takeda Development Center Americas, Inc., 650 East Kendall Street, Cambridge, MA, 02142, USA.

Alpha-proteinase inhibitor (A1PI) augmentation is the only specific treatment targeting the underlying deficiency in alpha-antitrypsin deficiency (AATD). The demonstration of efficacy has been based on maintaining the biochemical surrogate endpoints of plasma antigenic and functional A1PI levels above >11 μM. Here we report a biochemical comparability analysis based on data from a phase 2/3, randomized, double-blind, two-arm study with partial crossover of Glassia® (Baxalta US Inc. Read More

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Regulation of PGC1α Downstream of the Insulin Signaling Pathway Plays a Role in the Hepatic Proteotoxicity of Mutant α1-Antitrypsin Deficiency Variant Z.

Gastroenterology 2022 Jul 15;163(1):270-284. Epub 2022 Mar 15.

Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri; Department of Cell Biology, Washington University School of Medicine, St Louis, Missouri.

Background & Aims: Insulin signaling is known to regulate essential proteostasis mechanisms.

Methods: The analyses here examined effects of insulin signaling in the PiZ mouse model of α1-antitrypsin deficiency in which hepatocellular accumulation and proteotoxicity of the misfolded α1-antitrypsin Z variant (ATZ) causes liver fibrosis and cancer.

Results: We first studied the effects of breeding PiZ mice to liver-insulin-receptor knockout (LIRKO) mice (with hepatocyte-specific insulin-receptor gene disruption). Read More

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Severe α-antitrypsin deficiency associated with lower blood pressure and reduced risk of ischemic heart disease: a cohort study of 91,540 individuals and a meta-analysis.

Respir Res 2022 Mar 9;23(1):55. Epub 2022 Mar 9.

Department of Clinical Biochemistry, Zealand University Hospital, Køge, Denmark.

Background: Increased elastase activity in α-antitrypsin deficiency may affect elasticity of the arterial walls, and thereby blood pressure and susceptibility to cardiovascular disease. We hypothesized that severe α-antitrypsin deficiency is associated with reduced blood pressure and susceptibility to cardiovascular disease.

Methods: We genotyped 91,353 adults randomly selected from the Danish general population and 187 patients from the Danish α-Antitrypsin Deficiency Registry and recorded baseline blood pressure, baseline plasma lipids and cardiovascular events during follow-up. Read More

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Biological Treatments and Target Therapies for Pediatric Respiratory Medicine: Not Only Asthma.

Front Pediatr 2022 15;10:837667. Epub 2022 Feb 15.

Pediatric Pulmonology & Respiratory Intermediate Care Unit, Academic Department of Pediatrics, Bambino Gesù Children's Hospital IRCCS, Rome, Italy.

We present a description of pediatric pneumology biological medications and other target therapies. The article aims at introducing the importance of a molecular approach to improve treatments. The first item treated was T2-High asthma and its current biological treatment and prescribing indications to propose a flow-chart to guide the clinical choice. Read More

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February 2022

Dark-field chest x-ray imaging: first experience in patients with alpha1-antitrypsin deficiency.

Eur Radiol Exp 2022 03 1;6(1). Epub 2022 Mar 1.

Department of Diagnostic and Interventional Radiology, School of Medicine & Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.

Background: Spirometry and conventional chest x-ray have limitations in investigating early emphysema, while computed tomography, the reference imaging method in this context, is not part of routine patient care due to its higher radiation dose. In this work, we investigated a novel low-dose imaging modality, dark-field chest x-ray, for the evaluation of emphysema in patients with alpha1-antitrypsin deficiency.

Methods: By exploiting wave properties of x-rays for contrast formation, dark-field chest x-ray visualises the structural integrity of the alveoli, represented by a high signal over the lungs in the dark-field image. Read More

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Alpha1-antitrypsin deficiency and asthma.

Monaldi Arch Chest Dis 2022 Feb 22. Epub 2022 Feb 22.

Department of Respiratory Diseases, Bolzano Hospital.

α1-antitrypsin deficiency (AATD) is a genetically inherited autosomal-codominant disease with a variable clinical spectrum of lung-related diseases. Pulmonary involvement of α1-antitrypsin deficiency may also include emphysema with variable functional and radiological abnormalities, asthma, and bronchiectasis. Asthma and AATD are mutually exclusive disease entities, but the commonality of neutrophil inflammation across the diseases might suggest common underlying mechanisms of effect. Read More

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February 2022

An Italian expert consensus on the management of alpha1-antitrypsin deficiency: a comprehensive set of algorithms.

Panminerva Med 2022 Feb 11. Epub 2022 Feb 11.

Patients' association Associazione Nazionale Alfa1-At per la tutela dei pazienti con Deficit di Alfa1-antitripsina, Sarezzo, Brescia, Italy.

Background: Alpha1-antitrypin deficiency (AATD) is a genetic-based risk condition, mainly affecting the lungs and liver. Despite its wide distribution, it is largely underdiagnosed, thus being considered a rare disease, and is consequently managed in ad hoc reference centers. Unfortunately, an easy-to-use algorithm for managing such a complex disease is still lacking. Read More

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February 2022

Towards unveiling the nature of short SERPINA1 transcripts: Avoiding the main ORF control to translate alpha1-antitrypsin C-terminal peptides.

Int J Biol Macromol 2022 Apr 26;203:703-717. Epub 2022 Jan 26.

A.N. Belozersky Research Institute of Physical and Chemical Biology, Lomonosov Moscow State University, Leninskie Gory, Moscow 119992, Russia.

Alternative ORFs in-frame with the known genes are challenging to reveal. Yet they may contribute significantly to proteome diversity. Here we focused on the individual expression of the SERPINA1 gene exon 5 leading to direct translation of alpha1-antitrypsin (AAT) C-terminal peptides. Read More

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Alpha1-antitrypsin deficiency recognized by failure to gain weight in infancy.

Pediatr Int 2022 Jan;64(1):e14874

Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan.

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January 2022

Clinical characterization of a novel alpha1-antitrypsin null variant: PiQ0.

Respir Med Case Rep 2022 3;35:101570. Epub 2022 Jan 3.

Department of Pneumology and Critical Care Medicine, Thoraxklinik University of Heidelberg, Translational Lung Research Center Heidelberg (TLRC-H), German Center for Lung Research (DZL), Heidelberg, Germany.

The clinical characterization of a null variant of - PiQ0 - resulting in alpha1-antitrypsin (AAT) deficiency is described. This rare mutation (c.-5+5 G > A) has been previously identified but not clinically described. Read More

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January 2022

and modulation of NADPH oxidase activity and reactive oxygen species production in human neutrophils by α-antitrypsin.

ERJ Open Res 2021 Oct 6;7(4). Epub 2021 Dec 6.

Irish Centre for Genetic Lung Disease, Dept of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.

Oxidative stress from innate immune cells is a driving mechanism that underlies COPD pathogenesis. Individuals with α-1 antitrypsin (AAT) deficiency (AATD) have a dramatically increased risk of developing COPD. To understand this further, the aim of this study was to investigate whether AATD presents with altered neutrophil NADPH oxidase activation, due to the specific lack of plasma AAT. Read More

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October 2021

Sensitive and specific measurement of alpha-antitrypsin activity with an elastase complex formation immunosorbent assay (ECFISA).

J Pharm Biomed Anal 2022 Feb 23;209:114476. Epub 2021 Nov 23.

R&D Plasma Derived Therapies, Baxalta Innovations GmbH, a Takeda Company, Austria. Electronic address:

Functionally active alpha-antitrypsin (AAT) is measured predominantly with a chromogenic elastase inhibition assay, where the concentration of AAT activity inversely correlates with the levels of residual elastase. This standard assay has moderate sensitivity as it hardly allows the measurement of samples containing less than 10 µg of functionally active AAT per mL. To overcome this drawback, we developed a new assay format for the measurement of functionally active AAT, which we termed the elastase complex formation immunosorbent assay (ECFISA). Read More

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February 2022

The emerging role of proteases in α-antitrypsin deficiency and beyond.

ERJ Open Res 2021 Oct 22;7(4). Epub 2021 Nov 22.

University Hospital Southampton NHS Foundation Trust, Southampton, UK.

α-Antitrypsin deficiency (AATD) has been historically under-recognised and under-diagnosed; recently it has begun to receive greater interest in terms of attempts at deeper elucidation of pathology and treatment options. However, the concept of disease phenotypes within AATD (emphysema, chronic bronchitis, bronchiectasis or a combination of phenotypes) has not been proposed or studied. Of the three neutrophil serine proteases, neutrophil elastase was historically believed to be the sole contributor to disease pathology in AATD. Read More

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October 2021

Alternative poly-adenylation modulates α1-antitrypsin expression in chronic obstructive pulmonary disease.

PLoS Genet 2021 11 16;17(11):e1009912. Epub 2021 Nov 16.

Department of Biology, University of North Carolina, Chapel Hill, North Carolina, United States of America.

α1-anti-trypsin (A1AT), encoded by SERPINA1, is a neutrophil elastase inhibitor that controls the inflammatory response in the lung. Severe A1AT deficiency increases risk for Chronic Obstructive Pulmonary Disease (COPD), however, the role of A1AT in COPD in non-deficient individuals is not well known. We identify a 2. Read More

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November 2021

Methodologies for the Determination of Blood Alpha1 Antitrypsin Levels: A Systematic Review.

J Clin Med 2021 Oct 31;10(21). Epub 2021 Oct 31.

Unidad Médico-Quirúrgica de Enfermedades Respiratorias, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío, Universidad de Sevilla, 41013 Seville, Spain.

Background: The study of hematic concentrations of alpha1 antitrypsin (AAT) is currently one step in the diagnosis of AAT deficiency. To try to clarify the relevance of the laboratory techniques, we carried out a systematic review of the literature.

Methods: Studies evaluating the quantification of AAT in peripheral blood were searched in PubMed in July 2021. Read More

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October 2021

α -Antitrypsin Z allele and risk of venous thromboembolism in the general population.

J Thromb Haemost 2022 01 30;20(1):115-125. Epub 2021 Oct 30.

Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.

Background: The α -antitrypsin Z (rs28929474) allele may lead to alterations in hemostasis either through liver disease or effects on coagulation factors.

Objectives: To test the hypothesis that the α -antitrypsin Z genetic variant is associated with increased risk of venous thromboembolism.

Methods: A total of 107 075 individuals from the Copenhagen General Population Study were used to test the association of the α -antitrypsin Z genetic variant with risk of venous thromboembolism, including deep venous thrombosis and pulmonary embolism, prospectively. Read More

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January 2022