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Alpha 1 antitrypsin deficiency

Mark L Brantly, Jorge E Lascano, Abbas Shahmohammadi
Alpha-1 antitrypsin deficiency (AATD) is a largely monogenetic disorder associated with a high risk for the development of chronic obstructive pulmonary disease (COPD) and cirrhosis. Intravenous alpha-1 antitrypsin (AAT) therapy has been available for the treatment of individuals with AATD and COPD since the late 1980s. Initial Food and Drug Administration (FDA) approval was granted based on biochemical efficacy. Following its approval, the FDA, scientific community and third-party payers encouraged manufacturers of AAT therapy to determine its clinical efficacy...
November 28, 2018: Chronic Obstructive Pulmonary Diseases: Journal of the COPD Foundation
Radmila Choate, David M Mannino, Kristen E Holm, Robert A Sandhaus
Background : The aim of this study was to examine differences in demographic, health, and behavioral characteristics in individuals with ZZ and SZ genotypes of alpha-1 antitrypsin deficiency (AATD) within AlphaNet's Disease Management and Prevention Program (ADMAPP). Methods : Self-reported data from 3535 patients with AATD, including 3031 (85.7%) patients with ZZ, ZNull, and NullNull genotypes (referred to here as ZZ), and 504 (14.3%) with the SZ genotype were analyzed using t-tests, ANOVAs, and Chi-squared tests...
November 30, 2018: Chronic Obstructive Pulmonary Diseases: Journal of the COPD Foundation
Jan Sieluk, Joseph Levy, Robert A Sandhaus, Henry Silverman, Kristen E Holm, C Daniel Mullins
Background : This study is the first to utilize a large claims database to estimate medical costs of patients with alpha-1 antitrypsin deficiency (AATD) in the United States. Methods: Adult AATD patients were identified from the OptumLabs™ Data Warehouse. Insurer and patient out-of-pocket costs were categorized into the following cost buckets, stratified by augmentation therapy use: physician visits (PV), emergency department visits (ED), inpatient stays (IP), augmentation therapy (AUG), other prescription drug costs (RX), and other costs (OTH)...
November 8, 2018: Chronic Obstructive Pulmonary Diseases: Journal of the COPD Foundation
James K Stoller
No abstract text is available yet for this article.
January 14, 2019: Chronic Obstructive Pulmonary Diseases: Journal of the COPD Foundation
S J Rottier, J de Jonge, L C Dreuning, J van Pelt, A A W van Geloven, X D Y Beele, P M Huisman, W Y Deurholt, C A Rottier, M A Boermeester, W H Schreurs
PURPOSE: The underling pathophysiological mechanisms that cause the formation of colonic diverticula (diverticulosis) remain unclear. Connective tissue changes due to ageing that cause changes in collagen structure of the colonic wall is one theory. Alpha-1-antitrypsin (A1AT) is a protease inhibitor known to protect connective tissue in other organs. Associations between (carriers of) A1AT deficiency and the development of colonic diverticula will be the main focus of this study. METHODS: A multicentre prospective case-controlled study...
February 15, 2019: International Journal of Colorectal Disease
Marc Miravitlles, Joanna Chorostowska-Wynimko, Ilaria Ferrarotti, Noel G McElvaney, Karen O'Hara, Jan Stolk, Robert A Stockley, Alice Turner, Marion Wilkens, Timm Greulich
No abstract text is available yet for this article.
February 2019: European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology
Senani N H Rathnayake, Maarten Van den Berge, Alen Faiz
PURPOSE OF REVIEW: In asthma and chronic obstructive pulmonary disease (COPD), the movement towards genetic profiling with a push towards 'personalized medicine' has been hindered by complex environment--gene interactions and lack of tools to identify clear causal genetic traits. In this review, we will discuss the need for genetic profiling in asthma and COPD, what methods are currently used in the clinics and the recent finding using new sequencing methods. RECENT FINDINGS: Over the past 10-15 years, genome-wide association studies analysis of common variants has provide little in the way of new genetic profiling markers for asthma and COPD...
February 11, 2019: Current Opinion in Pulmonary Medicine
Rob Janssen, Ianthe Piscaer, Frits Me Franssen, Emiel Fm Wouters
Distinct pathologies can cause chronic obstructive pulmonary disease (COPD). Emphysema is a COPD-phenotype characterized by destruction of lung parenchyma. Alpha-1 antitrypsin deficiency (AATD) is a genetic cause of emphysema, whereas smoking is the most important risk factor of non-AATD emphysema. A general underappreciation of non-AATD emphysema has hampered progress in the field, and clinical guidelines have prohibited the use of emphysema as a diagnosis. Non-AATD emphysema, however, is far from irrelevant as it associates with dyspnea, reduced exercise capacity and relevant outcome measures...
February 14, 2019: Expert Review of Respiratory Medicine
Nan He, Bradley H Rosen, Jaimie S Gray, Idil A Evans, Marina Zieger, Ziying Yan, Florie Borel, Bo Liang, Xingshen Sun, Shashanna R Moll, Michael H Brodsky, Christian Mueller, John F Engelhardt
RATIONALE: The most prevalent genetic cause of chronic obstructive pulmonary disease is alpha-1 antitrypsin (A1AT) deficiency, a disorder that has yet to be widely modeled in animals because of species-specific differences between rodents and humans. OBJECTIVES: To address these challenges, we engineered two A1AT ferret models using zygote gene editing to test the hypothesis that unopposed protease activity within the lung leads to emphysema and bronchitis. METHODS: Guide RNAs targeting exon 2 (for knockout) and exon 5 (for Z-allele mutation, Pi*Z) of the ferret A1AT gene were injected into ferret zygotes with Cas9 mRNA...
December 2018: Annals of the American Thoracic Society
Suresh Garudadri, Prescott G Woodruff
Chronic obstructive pulmonary disease (COPD) is now well recognized to be a phenotypically heterogeneous disease, and this heterogeneity is underpinned by biological heterogeneity. An "endotype" is a group of patients who share the same observed characteristic(s) because of shared underlying biology, and the "endotype" concept has emerged as one way of bringing order to this phenotypic heterogeneity by focusing on its biological underpinnings. In principle, biomarkers can help identify endotypes and mark these specific groups of patients as suitable candidates for targeted biological therapies...
December 2018: Annals of the American Thoracic Society
Boris M Baranovski, Ronen Schuster, Omer Nisim, Ido Brami, Yotam Lior, Eli C Lewis
Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder which most commonly manifests as pulmonary emphysema. Accordingly, alpha-1 antitrypsin (AAT) augmentation therapy aims to reduce the progression of emphysema, as achieved by life-long weekly slow-drip infusions of plasma-derived affinity-purified human AAT. However, not all AATD patients will receive this therapy, due to either lack of medical coverage or low patient compliance. To circumvent these limitations, attempts are being made to develop lung-directed therapies, including inhaled AAT and locally-delivered AAT gene therapy...
September 19, 2018: Chronic Obstructive Pulmonary Diseases: Journal of the COPD Foundation
Joseph E Kaserman, Andrew A Wilson
PIZZ alpha-1 antitrypsin deficiency (AATD) is an autosomal recessive disease affecting approximately 100,000 individuals in the United States and one of the most common hereditary causes of liver disease.1 The most common form of the disease results from a single base pair mutation (Glu342Lys), known as the "Z" mutation, that encodes a mutant protein (Z alpha-1 antritypsin [AAT]) that is prone to misfolding and is retained in the endoplasmic reticulum (ER) rather than appropriately secreted. Some of the retained mutant protein attains an unusual aggregated or polymerized conformation...
September 15, 2018: Chronic Obstructive Pulmonary Diseases: Journal of the COPD Foundation
Katie M Stiles, Dolan Sondhi, Stephen M Kaminsky, Bishnu P De, Jonathan B Rosenberg, Ronald G Crystal
Alpha-1 antitrypsin deficiency (AATD) manifests primarily as early-onset emphysema caused by the destruction of the lung by neutrophil elastase due to low amounts of the serine protease inhibitor alpha-1 antitrypsin (AAT). The current therapy involves weekly intravenous infusions of AAT-derived from pooled human plasma that is efficacious, yet costly. Gene therapy applications designed to provide constant levels of the AAT protein are currently under development. The challenge is for gene therapy to provide sufficient amounts of AAT to normalize the inhibitor level and anti-neutrophil elastase capacity in the lung...
August 17, 2018: Chronic Obstructive Pulmonary Diseases: Journal of the COPD Foundation
David A Lomas
Alpha-1antitrypsin deficiency (AATD) results from the intracellular polymerization and retention of mutant alpha-1antitrypsin (AAT) within the endoplasmic reticulum of hepatocytes. This causes cirrhosis whilst the deficiency of circulating AAT predisposes to early onset emphysema. This is an exciting time for researchers in the field with the development of novel therapies based on understanding the pathobiology of disease. I review here augmentation therapy to prevent the progression of lung disease and a range of approaches to treat the liver disease associated with the accumulation of mutant AAT: modifying proteostasis networks that are activated by Z AAT polymers, stimulating autophagy, small interfering RNA and small molecules to block intracellular polymerization, and stem cell technology to correct the genetic defect that underlies AATD...
August 6, 2018: Chronic Obstructive Pulmonary Diseases: Journal of the COPD Foundation
Manon Allaire, Pierre-Emmanuel Rautou, Patrice Codogno, Sophie Lotersztajn
Autophagy is a self-eating catabolic pathway that contributes to liver homeostasis through its role on energy balance and in the quality control of the cytoplasm, by removing misfolded proteins, damaged organelles and lipid droplets. Autophagy not only regulates hepatocyte functions but also impact on non-parenchymal cells such as endothelial cells, macrophages and hepatic stellate cells. Deregulation of autophagy has been linked to many liver diseases and its modulation is now recognized as a potential new therapeutic strategy...
January 31, 2019: Journal of Hepatology
Liguo Wang, George W Marek, Ryan A Hlady, Ryan T Wagner, Xia Zhao, Virginia C Clark, Alex Xiucheng Fan, Chen Liu, Mark Brantly, Keith D Robertson
Alpha-1 Antitrypsin Deficiency (AATD) liver disease is characterized by marked heterogeneity in presentation and progression despite a common underlying gene mutation, strongly suggesting the involvement of other genetic and/or epigenetic modifiers. Variation in clinical phenotype has added to the challenge of detection, diagnosis, and testing of new therapies in AATD patients. We examined the contribution of DNA methylation (5mC) to AATD liver disease heterogeneity since 5mC responds to environmental and genetic cues, and its deregulation is a major driver of liver disease...
January 25, 2019: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Philip M Boone, Rachel M Scott, Stefan J Marciniak, Elizabeth P Henske, Benjamin A Raby
A genetic influence on spontaneous pneumothoraces - those occurring without a traumatic or iatrogenic cause - is supported by several lines of evidence: 1) Pneumothorax can cluster in families (i.e. familial spontaneous pneumothorax); 2) Mutations in the FLCN gene have been found in both familial and sporadic cases; and 3) Pneumothorax is a known complication of several genetic syndromes. Herein we review known genetic contributions to both sporadic and familial pneumothorax. We summarize the pneumothorax-associated genetic syndromes, including Birt-Hogg-Dubé syndrome, Marfan syndrome, vascular (type IV) Ehlers-Danlos syndrome, alpha-1-antitrypsin deficiency, tuberous sclerosis complex/lymphangioleiomyomatosis (LAM), Loeys-Dietz syndrome, cystic fibrosis, homocystinuria, and cutis laxa, among others...
January 25, 2019: American Journal of Respiratory and Critical Care Medicine
Hanan A Tanash, Eeva Piitulainen
BACKGROUND: The proportion of adults with liver disease due to severe alpha-1-antitrypsin deficiency (AATD), with PiZZ phenotype, is not clear. The markers of the AATD liver disease, how it progresses, and measures for its prevention have not been established. The aim of this study was to analyze the risk of liver disease in individuals with severe AAT deficiency (PiZZ). METHODS: Longitudinal clinical and laboratory data were obtained from the Swedish National registers, by cross-linkage between the Swedish national AATD register, the Swedish National Patient Register, the National Cancer Register and the National Causes of Death Register...
January 24, 2019: Journal of Gastroenterology
W J Xu, Y Q Chen, J F Xiao, Y M Chen, P X Xu, J Q Ding
No abstract text is available yet for this article.
December 20, 2018: Zhonghua Gan Zang Bing za Zhi, Zhonghua Ganzangbing Zazhi, Chinese Journal of Hepatology
Barjinder S Buttar, Mark Bernstein
Alpha-1 antitrypsin deficiency (AATD) is a common genetic disorder that is easily managed if diagnosed and treated at an early age. It is often missed, however, especially in patients with long histories of smoking and alcohol use. This is mainly due to a lack of awareness and proper screening of the disorder, especially in the primary care setting. Here, we will focus on a case report of a young male whose diagnosis and treatment of AATD was significantly delayed. His lung and liver complications had initially been attributed to his smoking and drinking history...
October 25, 2018: Curēus
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