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antitrypsin deficiency

Mattia Laffranchi, Romina Berardelli, Riccardo Ronzoni, David A Lomas, Annamaria Fra
The most common genotype associated with severe α1-antitrypsin deficiency (AATD) is the Z homozygote. The Z variant (Glu342Lys) of α1-antitrypsin (AAT) undergoes a conformational change and is retained within the endoplasmic reticulum (ER) of hepatocytes leading to the formation of ordered polymeric chains and inclusion bodies. Accumulation of mutated protein predisposes to cirrhosis whilst plasma AAT deficiency leads to emphysema. Increased risk of liver and lung disease has also been reported in heterozygous subjects who carry Z in association with the milder S allele (Glu264Val) or even with wild-type M...
March 10, 2018: Human Molecular Genetics
Jessica Lacy Yasuda, Paul A Rufo
A 20-month-old boy presented with a 2-week history of pallor and progressive abdominal distention. Nutritional history revealed long-standing excessive cow milk intake. He was subsequently found to be profoundly iron deficient and hypoproteinemic, with an elevated fecal α-1-antitrypsin level and occult blood positive stool, consistent with protein-losing enteropathy. He was treated with cow milk restriction and oral iron supplements, which resulted in resolution of his edema and laboratory anomalies. While small numbers of previous case reports have described the potential association between excessive cow milk intake and severe iron deficiency and protein-losing enteropathy, this constellation of clinical symptoms is infrequently recognized in clinical practice...
January 2018: Journal of Investigative Medicine High Impact Case Reports
Atakan Comba, Fatma Demirbaş, Gönül Çaltepe, Esra Eren, Ayhan G Kalayci
BACKGROUND: α-1 Antitrypsin (AAT) deficiency is the most frequently occurring genetic liver disorder. The association among classical α-1 antitrypsin deficiency (AATD), chronic liver disease, and cirrhosis is common in adult patients but rare in children. AIM: To assess the clinical characteristics of children with AATD and to compare symptoms between homozygous and heterozygous children. MATERIALS AND METHODS: The study included 20 children who were found to have mutant Pi alleles...
March 2, 2018: European Journal of Gastroenterology & Hepatology
Mikael Bjursell, Michelle J Porritt, Elke Ericson, Amir Taheri-Ghahfarokhi, Maryam Clausen, Lisa Magnusson, Therese Admyre, Roberto Nitsch, Lorenz Mayr, Leif Aasehaug, Frank Seeliger, Marcello Maresca, Mohammad Bohlooly-Y, John Wiseman
α1-antitrypsin (AAT) is a circulating serine protease inhibitor secreted from the liver and important in preventing proteolytic neutrophil elastase associated tissue damage, primarily in lungs. In humans, AAT is encoded by the SERPINA1 (hSERPINA1) gene in which a point mutation (commonly referred to as PiZ) causes aggregation of the miss-folded protein in hepatocytes resulting in subsequent liver damage. In an attempt to rescue the pathologic liver phenotype of a mouse model of human AAT deficiency (AATD), we used adenovirus to deliver Cas9 and a guide-RNA (gRNA) molecule targeting hSERPINA1...
February 19, 2018: EBioMedicine
Karen Jülicher, Annabell Wähner, Kerstin Haase, Karen W Barbour, Franklin G Berger, Lutz Wiehlmann, Colin Davenport, Karin Schuster-Gossler, Jörn Stitz, Tobias Cantz, Reto Eggenschwiler
The generation of authentic mouse-models for human α1-antitrypsin-deficiency is difficult due to the high complexity of the mouse Serpina1 gene locus. Depending on the exact mouse strain, three to five paralogs are expressed, with different proteinase inhibitory properties. With nowadays CRISPR-technology, genome editing of complex genomic loci is feasible and could be employed for generation of α1-antitrypsin-deficiency mouse-models. In preparation of a CRISPR/Cas9-based genome-engineering approach we identified cDNA clones with a functional CDS for the Serpina1-paralog DOM-7...
March 1, 2018: Biological Chemistry
John Ong, Maria Paola Serra, Joe Segal, Ana-Maria Cujba, Soon Seng Ng, Richard Butler, Val Millar, Stephanie Hatch, Salman Zimri, Hiroyuki Koike, Karen Chan, Andrew Bonham, Michelle Walk, Ty Voss, Nigel Heaton, Ragai Mitry, Anil Dhawan, Daniel Ebner, Davide Danovi, Hiromitsu Nakauchi, S Tamir Rashid
Use of hepatocytes derived from induced pluripotent stem cells (i-Heps) is limited by their functional differences in comparison with primary cells. Extracellular niche factors likely play a critical role in bridging this gap. Using image-based characterization (high content analysis; HCA) of freshly isolated hepatocytes from 17 human donors, we devised and validated an algorithm (Hepatocyte Likeness Index; HLI) for comparing the hepatic properties of cells against a physiological gold standard. The HLI was then applied in a targeted screen of extracellular niche factors to identify substrates driving i-Heps closer to the standard...
February 15, 2018: Stem Cell Reports
A Perciaccante, P Charlier, C Negri, A Coralli, O Appenzeller, R Bianucci
A1AT deficiency- a genetically inherited autosomal codominant disease with more than 120 identified alleles- was first identified by Laurell and Eriksson in 1963. The most common hereditary disorder in adults, A1AT causes an increased risk of developing pulmonary emphysema and liver disease. In A1AT patients, lung disease generally presents at a younger age than "usual" chronic obstructive pulmonary disease (COPD) and it may be misdiagnosed as asthma. Because A1AT deficiency patients can show the same clinical features as non-deficient COPD (including increased evidence of bronchiectasis, frequent exacerbations, impaired health status and a degree of reversibility of airflow obstruction), the World Health Organization recommend to test every patient with a diagnosis of COPD or adult-onset asthma for A1AT deficiency...
February 2018: COPD
Gerard M Turino
This article assesses developments in cardiorespiratory medicine since the Nobel Prize in Physiology or Medicine was awarded in 1956 for advancements in the study of cardiorespiratory disease. In chronic obstructive pulmonary disease, advances were accelerated by the discovery of a genetically determined cause for pulmonary emphysema in the genetic abnormality alpha-1 antitrypsin deficiency. This causes a deficiency of the inhibitor of neutrophil elastase, which results in increased degradation of lung elastin and the development of pulmonary emphysema...
February 2018: Annals of the American Thoracic Society
John B West
One of the most interesting unanticipated findings by André Cournand and Dickinson Richards in their groundbreaking studies of cardiac catheterization was the very low pressure in the normal pulmonary circulation. At the time, in the 1940s, the significance of this was not appreciated. For example, in their speeches at the Nobel Prize ceremony, neither of these laureates referred to the low pressure, although they did discuss other features of the pulmonary circulation. It was up to the cardiologist, William Dock, to point out that these low pressures implied a very uneven distribution of blood flow in the lung, and in particular that in the normal upright lung, the blood flow to the apex would be extremely small...
February 2018: Annals of the American Thoracic Society
Malgorzata Hadzik-Blaszczyk, Aneta Zdral, Tadeusz M Zielonka, Ada Rozy, Renata Krupa, Andrzej Falkowski, Kazimierz A Wardyn, Joanna Chorostowska-Wynimko, Katarzyna Zycinska
Alpha-1 antitrypsin (A1AT) deficiency is one of the most common genetic disorders in Caucasian population. There is a link between granulomatosis with polyangiitis (GPA) and most frequent variants of SERPINA1 gene encoding severe alpha-1 antitripsin deficiency. However, the potential effect of Pi*Z, Pi*S as well as other SERPINA1 variants on clinical course of vasculitis are not well understood. The aim of the study was to analyze the potential effect of A1AT protein phenotype representing the SERPINA1 gene variants on the clinical course of GPA...
February 20, 2018: Advances in Experimental Medicine and Biology
Florie Borel, Huaming Sun, Marina Zieger, Andrew Cox, Brynn Cardozo, Weiying Li, Gabriella Oliveira, Airiel Davis, Alisha Gruntman, Terence R Flotte, Michael H Brodsky, Andrew M Hoffman, Mai K Elmallah, Christian Mueller
Chronic obstructive pulmonary disease affects 10% of the worldwide population, and the leading genetic cause is α-1 antitrypsin (AAT) deficiency. Due to the complexity of the murine locus, which includes up to six Serpina1 paralogs, no genetic animal model of the disease has been successfully generated until now. Here we create a quintuple Serpina1a-e knockout using CRISPR/Cas9-mediated genome editing. The phenotype recapitulates the human disease phenotype, i.e., absence of hepatic and circulating AAT translates functionally to a reduced capacity to inhibit neutrophil elastase...
February 16, 2018: Proceedings of the National Academy of Sciences of the United States of America
S A Townsend, R G Edgar, P R Ellis, D Kantas, P N Newsome, A M Turner
BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is estimated to affect three million people worldwide. It causes liver disease in a proportion of carriers of the PiS and PiZ allele due to the formation and retention of polymers within the endoplasmic reticulum of hepatocytes. The reason for this selective penetrance is not known. Although clinical trials are underway, liver transplantation is the only effective treatment for liver disease due to AATD. AIMS: To report the prevalence and natural history of liver disease among individuals with AATD, and assess the outcomes of liver transplantation through systematic review...
February 15, 2018: Alimentary Pharmacology & Therapeutics
Ivan Curjuric, Medea Imboden, Robert Bettschart, Seraina Caviezel, Julia Dratva, Marco Pons, Thomas Rothe, Arno Schmidt-Trucksäss, Daiana Stolz, Gian Andri Thun, Arnold von Eckardstein, Florian Kronenberg, Ilaria Ferrarotti, Nicole M Probst-Hensch
BACKGROUND AND AIMS: Alpha-1 antitrypsin (A1AT) is the most abundant serine protease inhibitor in human blood and exerts important anti-inflammatory and immune-modulatory effects. In combination with smoking or other long-term noxious exposures such as occupational dust and fumes, genetic A1AT deficiency can cause chronic obstructive pulmonary disease, a condition with elevated cardiovascular risk. The effects of A1AT deficiency on cardiovascular risk have hardly been studied today. METHODS: Using data from 2614 adults from the population-based SAPALDIA cohort, we tested associations of serum A1AT and SERPINA1 mutations with carotid intima-media thickness (CIMT, measured by B-mode ultrasonography) or self-reported arterial hypertension or cardiovascular disease in multiple regression models using a Mendelian Randomization like analysis design...
January 31, 2018: Atherosclerosis
Robert C Oh, Thomas R Hustead, Syed M Ali, Matthew W Pantsari
Mild, asymptomatic elevations (less than five times the upper limit of normal) of alanine transaminase and aspartate transaminase levels are common in primary care. It is estimated that approximately 10% of the U.S. population has elevated transaminase levels. An approach based on the prevalence of diseases that cause asymptomatic transaminase elevations can help clinicians efficiently identify common and serious liver disease. The most common causes of elevated transaminase levels are nonalcoholic fatty liver disease and alcoholic liver disease...
December 1, 2017: American Family Physician
Kenneth R Chapman, Joanna Chorostowska-Wynimko, A Rembert Koczulla, Ilaria Ferrarotti, Noel G McElvaney
Alpha 1 antitrypsin deficiency is a hereditary condition characterized by low alpha 1 proteinase inhibitor (also known as alpha 1 antitrypsin [AAT]) serum levels. Reduced levels of AAT allow abnormal degradation of lung tissue, which may ultimately lead to the development of early-onset emphysema. Intravenous infusion of AAT is the only therapeutic option that can be used to maintain levels above the protective threshold. Based on its biochemical efficacy, AAT replacement therapy was approved by the US Food and Drug administration in 1987...
2018: International Journal of Chronic Obstructive Pulmonary Disease
Rashika Joshi, Andrea Heinz, Qiang Fan, Shuling Guo, Brett Monia, Christian E H Schmelzer, Anthony S Weiss, Matthew Batie, Harikrishnan Parameshwaran, Brian M Varisco
RATIONALE: α1-antitrypsin (AAT) deficiency-related emphysema is the fourth leading indication for lung transplantation. Chymotrypsin-like elastase 1 (Cela1) is a digestive protease that is expressed during lung development in association with regions of elastin remodeling, exhibits stretch-dependent expression during lung regeneration, and binds lung elastin in a stretch-dependent manner. AAT covalently neutralizes Cela1 in vitro. OBJECTIVES: We sought to determine the role of Cela1 in postnatal lung physiology, whether it interacted with AAT in vivo, and any effects it may have in the context of AAT deficiency...
February 8, 2018: American Journal of Respiratory Cell and Molecular Biology
Brian P Peppers, Jamie Zacharias, Chelsea R Michaud, John A Frith, Priya Varma, Mark Henning, Linda M Quinn, Haig Tcheurekdjian, Timothy Craig, Robert W Hostoffer
BACKGROUND: In patients with humoral immunodeficiency, the progression of bronchiectasis has been known to occur despite adequate gammaglobulin therapy and in the absence of recurrent infections. This observation suggests that factors other than gammaglobulin replacement might play a part in the prevention of lung damage in this population. α1-Antitrypsin deficiency can be associated with bronchiectasis, a chronic inflammatory lung disease. The protective levels of α1-antitrypsin and phenotype in preventing bronchiectasis have not been thoroughly studied in the immunodeficient population...
February 2018: Annals of Allergy, Asthma & Immunology
A Perciaccante, C Negri, A Coralli, P Charlier, O Appenzeller, R Bianucci
Niccolò Ugo Foscolo (1778-1827), known as Ugo, is one of the masters of the Italian poetry. A writer and a revolutionary, he embraced the ideals of the French Revolution and took part in the stormy political discussions, which the fall of the Republic of Venice had provoked. Despite his poor health, Foscolo lived an adventurous life serving as a volunteer in the Guardia Nazionale and in the Napoleonic army. Following Napoleon's fall (1814), he went into voluntary exile in early 1815. He reached London in Sept...
February 2018: Medical Hypotheses
J Benzaquen, J Pradelli, B Padovani, C H Marquette, S Leroy
INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a common condition that may initially look simple but may conceal other diseases capable of accelerating its natural history or even simulating it. We describe four cases presenting as COPD with emphysema that were reclassified on the basis of certain clinical characteristics and the radiological pattern. CASE REPORTS: A 52 year old never smoking woman presenting with emphysema was eventually diagnosed as having lymphangioleiomyomatosis on the basis of an abdominal CT scan showing kidney angiomyolipomas...
January 2018: Revue des Maladies Respiratoires
Leonor Meira, Rita Boaventura, Susana Seixas, Maria Sucena
Alpha-1 antitrypsin deficiency (AATD) is an autosomal co-dominant disease characterised by low serum levels of this molecule. Its epidemiology remains unknown in many countries, mainly due to its underdiagnosed state and lack of patients' registries. We aim to evaluate and characterise a sample of Portuguese individuals tested for AATD, between 2006 and 2015, based on a retrospective analysis from the database of a laboratory offering AATD genetic diagnosis service. 1684 individuals were considered, covering almost every region in Portugal...
February 2, 2018: COPD
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