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Marginean CM, Pirscoveanu D, Popescu M, Docea AO, Radu A, Popescu AIS, Vasile CM, Mitrut R, Marginean IC, Iacob GA, Firu DM, Mitrut P. Diagnostic Approach and Pathophysiological Mechanisms of Anemia in Chronic Liver Disease—An Overview. GASTROENTEROLOGY INSIGHTS 2023; 14:327-341. [DOI: 10.3390/gastroent14030024] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
Hematological abnormalities are frequently linked to chronic liver disease of any etiology. About 75% of patients with advanced chronic liver disease experience anemia. The causes of anemia are complex and multifactorial, particularly in cirrhotic patients. Acute and long-term blood loss from the upper gastrointestinal tract, malnutrition, an enlarged spleen brought on by portal hypertension, hemolysis, and coagulation issues are the main causes of anemia. Alcohol, a common cause of chronic liver disease, determines anemia through direct toxicity on the bone marrow, with the suppression of hematopoiesis, through vitamin B6, B12, and folate deficiency due to low intake and malabsorption. In patients with chronic hepatitis C virus infection, antiviral drugs such as pegylated interferon and ribavirin can also cause significant anemia. The use of interferon has been linked to bone marrow toxicity, and hemolytic anemia brought on by ribavirin is a well-known dose-dependent side effect. Within six months of the infection with hepatitis B, hepatitis C, and Epstein–Barr viruses, aplastic anemia associated with hepatitis is seen. This anemia is characterized by pancytopenia brought on by hypocellular bone marrow. Esophageal varices, portal hypertensive gastropathy, and gastric antral vascular ectasia can all cause acute and chronic blood loss. These conditions can progress to iron deficiency anemia, microcytic anemia, and hypochromic anemia. Another common hematologic abnormality in liver cirrhosis is macrocytosis, with multifactorial causes. Vitamin B12 and folate deficiency are frequent in liver cirrhosis, especially of alcoholic etiology, due to increased intestinal permeability, dysbiosis, and malnutrition. Many chronic liver diseases, like viral and autoimmune hepatitis, have a chronic inflammatory substrate. Proinflammatory cytokines, including tumor necrosis factor and interleukin 1, 6, and 10, are the main factors that diminish iron availability in progenitor erythrocytes and subsequent erythropoiesis, leading to the development of chronic inflammatory, normochromic, normocytic anemia.
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Affiliation(s)
- Cristina Maria Marginean
- Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Denisa Pirscoveanu
- Department of Neurology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Mihaela Popescu
- Department of Endocrinology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Anca Oana Docea
- Department of Toxicology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Antonia Radu
- Department of Pharmaceutical Botany, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | | | - Corina Maria Vasile
- Department of Pediatric and Adult Congenital Cardiology, Bordeaux University Hospital, 33600 Pessac, France
| | - Radu Mitrut
- Department of Cardiology, University and Emergency Hospital, 050098 Bucharest, Romania
| | | | - George Alexandru Iacob
- Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Dan Mihai Firu
- Department of Medical Semiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Paul Mitrut
- Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
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Perron S, McCormack DG, Parraga G, Ouriadov A. Undersampled Diffusion-Weighted 129Xe MRI Morphometry of Airspace Enlargement: Feasibility in Chronic Obstructive Pulmonary Disease. Diagnostics (Basel) 2023; 13:diagnostics13081477. [PMID: 37189579 DOI: 10.3390/diagnostics13081477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 04/10/2023] [Accepted: 04/18/2023] [Indexed: 05/17/2023] Open
Abstract
Multi-b diffusion-weighted hyperpolarized gas MRI measures pulmonary airspace enlargement using apparent diffusion coefficients (ADC) and mean linear intercepts (Lm). Rapid single-breath acquisitions may facilitate clinical translation, and, hence, we aimed to develop single-breath three-dimensional multi-b diffusion-weighted 129Xe MRI using k-space undersampling. We evaluated multi-b (0, 12, 20, 30 s/cm2) diffusion-weighted 129Xe ADC/morphometry estimates using a fully sampled and retrospectively undersampled k-space with two acceleration-factors (AF = 2 and 3) in never-smokers and ex-smokers with chronic obstructive pulmonary disease (COPD) or alpha-one anti-trypsin deficiency (AATD). For the three sampling cases, mean ADC/Lm values were not significantly different (all p > 0.5); ADC/Lm values were significantly different for the COPD subgroup (0.08 cm2s-1/580 µm, AF = 3; all p < 0.001) as compared to never-smokers (0.05 cm2s-1/300 µm, AF = 3). For never-smokers, mean differences of 7%/7% and 10%/7% were observed between fully sampled and retrospectively undersampled (AF = 2/AF = 3) ADC and Lm values, respectively. For the COPD subgroup, mean differences of 3%/4% and 11%/10% were observed between fully sampled and retrospectively undersampled (AF = 2/AF = 3) ADC and Lm, respectively. There was no relationship between acceleration factor with ADC or Lm (p = 0.9); voxel-wise ADC/Lm measured using AF = 2 and AF = 3 were significantly and strongly related to fully-sampled values (all p < 0.0001). Multi-b diffusion-weighted 129Xe MRI is feasible using two different acceleration methods to measure pulmonary airspace enlargement using Lm and ADC in COPD participants and never-smokers.
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Affiliation(s)
- Samuel Perron
- Department of Physics and Astronomy, The University of Western Ontario, London, ON N6A 3K7, Canada
| | - David G McCormack
- Division of Respirology, Department of Medicine, The University of Western Ontario, London, ON N6A 3K7, Canada
| | - Grace Parraga
- Robarts Research Institute, London, ON N6A 5B7, Canada
- Department of Medical Biophysics, The University of Western Ontario, London, ON N6A 3K7, Canada
- Graduate Program in Biomedical Engineering, The University of Western Ontario, London, ON N6A 3K7, Canada
| | - Alexei Ouriadov
- Robarts Research Institute, London, ON N6A 5B7, Canada
- Department of Medical Biophysics, The University of Western Ontario, London, ON N6A 3K7, Canada
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Kalas MA, Chavez L, Leon M, Taweesedt PT, Surani S. Abnormal liver enzymes: A review for clinicians. World J Hepatol 2021; 13:1688-1698. [PMID: 34904038 PMCID: PMC8637680 DOI: 10.4254/wjh.v13.i11.1688] [Citation(s) in RCA: 84] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 07/24/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023] Open
Abstract
Liver biochemical tests are some of the most commonly ordered routine tests in the inpatient and outpatient setting, especially with the automatization of testing in this technological era. These tests include aminotransferases, alkaline phosphatase, gamma-glutamyl transferase, bilirubin, albumin, prothrombin time and international normalized ratio (INR). Abnormal liver biochemical tests can be categorized based on the pattern and the magnitude of aminotransferases elevation. Generally, abnormalities in aminotransferases can be classified into a hepatocellular pattern or cholestatic pattern and can be further sub-classified based on the magnitude of aminotransferase elevation to mild [< 5 × upper limit of normal (ULN)], moderate (> 5-< 15 × ULN) and severe (> 15 × ULN). Hepatocellular pattern causes include but are not limited to; non-alcoholic fatty liver disease/non-alcoholic steatohepatitis, alcohol use, chronic viral hepatitis, liver cirrhosis (variable), autoimmune hepatitis, hemochromatosis, Wilson's disease, alpha-1 antitrypsin deficiency, celiac disease, medication-induced and ischemic hepatitis. Cholestatic pattern causes include but is not limited to; biliary pathology (obstruction, autoimmune), other conditions with hyperbilirubinemia (conjugated and unconjugated). It is crucial to interpret these commonly ordered tests accurately as appropriate further workup, treatment and referral can greatly benefit the patient due to prompt treatment which can improve the natural history of several of the diseases mentioned and possibly reduce the risk of progression to the liver cirrhosis.
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Affiliation(s)
- M Ammar Kalas
- Department of Internal Medicine, Texas Tech University Health Science Center, El Paso, TX 79905, United States
| | - Luis Chavez
- Department of Internal Medicine, Texas Tech University Health Science Center, El Paso, TX 79905, United States
| | - Monica Leon
- Department of General Surgery, University of Mexico, Ciudad de Mexico 01120, Mexico
| | - Pahnwat Tonya Taweesedt
- Department of Medicine, Corpus Christi Medical Center, Corpus Christi, TX 78412, United States
| | - Salim Surani
- Department of Medicine, Texas A&M University, College Station, TX 77843, United States
- Department of Anesthesiology, Mayo Clinic, Rochester, MN 55905, United States.
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Oxidative Stress and Endoplasmic Reticulum Stress in Rare Respiratory Diseases. J Clin Med 2021; 10:jcm10061268. [PMID: 33803835 PMCID: PMC8003245 DOI: 10.3390/jcm10061268] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 03/12/2021] [Accepted: 03/15/2021] [Indexed: 02/07/2023] Open
Abstract
Several studies have shown that some rare respiratory diseases, such as alpha-1 antitrypsin deficiency (AATD), idiopathic pulmonary fibrosis (IPF), cystic fibrosis (CF), and primary ciliary dyskinesia (PCD) present oxidative stress (OS) and endoplasmic reticulum (ER) stress. Their involvement in these pathologies and the use of antioxidants as therapeutic agents to minimize the effects of OS are discussed in this review.
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Potilinski MC, Tate PS, Lorenc VE, Gallo JE. New insights into oxidative stress and immune mechanisms involved in age-related macular degeneration tackled by novel therapies. Neuropharmacology 2021; 188:108513. [PMID: 33662390 DOI: 10.1016/j.neuropharm.2021.108513] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 02/14/2021] [Accepted: 02/22/2021] [Indexed: 12/20/2022]
Abstract
The prevalence of age-related macular degeneration (AMD) has increased in the last years. Although anti-VEGF agents have improved the prognosis of exudative AMD, dry AMD has still devastating effects on elderly people vision. Oxidative stress and inflammation are mechanisms involved in AMD pathogenesis and its progression. Molecular pathways involving epidermal growth factor receptor (EGFR), bone morphogenetic protein (BMP4) and the nuclear erythroid related factor 2 (Nrf2) are behind oxidative stress in AMD due to their participation in antioxidant cellular pathways. As a consequence of the disbalance produced in the antioxidant mechanisms, there is an activation of innate and adaptative immune response with cell recruitment, changes in complement factors expression, and modification of cellular milieu. Different therapies are being studied to treat dry AMD based on the possible effects on antioxidant molecular pathways or their action on the immune response. There is a wide range of treatments presented in this review, from natural antioxidant compounds to cell and gene therapy, based on their mechanisms. Finally, we hypothesize that alpha-1-antitrypsin (AAT), an anti-inflammatory and immunomodulatory molecule that can also modulate antioxidant cellular defenses, could be a good candidate for testing in AMD. This article is part of the special ssue on 'The Quest for Disease-Modifying Therapies for Neurodegenerative Disorders'.
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Affiliation(s)
- María Constanza Potilinski
- Nanomedicine & Vision Lab, Instituto de Investigaciones en Medicina Translacional, Universidad Austral, CONICET, Pilar, Buenos Aires, Argentina
| | - Pablo S Tate
- Laboratorio de Enfermedades Neurodegenerativas, Instituto de Investigaciones en Medicina Translacional, Universidad Austral, CONICET, Pilar, Buenos Aires, Argentina
| | - Valeria E Lorenc
- Nanomedicine & Vision Lab, Instituto de Investigaciones en Medicina Translacional, Universidad Austral, CONICET, Pilar, Buenos Aires, Argentina
| | - Juan E Gallo
- Nanomedicine & Vision Lab, Instituto de Investigaciones en Medicina Translacional, Universidad Austral, CONICET, Pilar, Buenos Aires, Argentina; Departamento de Oftalmología, Hospital Universitario Austral, Pilar, Buenos Aires, Argentina.
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Sazonova MA, Sinyov VV, Ryzhkova AI, Sazonova MD, Kirichenko TV, Khotina VA, Khasanova ZB, Doroschuk NA, Karagodin VP, Orekhov AN, Sobenin IA. Some Molecular and Cellular Stress Mechanisms Associated with Neurodegenerative Diseases and Atherosclerosis. Int J Mol Sci 2021; 22:E699. [PMID: 33445687 PMCID: PMC7828120 DOI: 10.3390/ijms22020699] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 12/29/2020] [Accepted: 01/04/2021] [Indexed: 12/14/2022] Open
Abstract
Chronic stress is a combination of nonspecific adaptive reactions of the body to the influence of various adverse stress factors which disrupt its homeostasis, and it is also a corresponding state of the organism's nervous system (or the body in general). We hypothesized that chronic stress may be one of the causes occurence of several molecular and cellular types of stress. We analyzed literary sources and considered most of these types of stress in our review article. We examined genes and mutations of nuclear and mitochondrial genomes and also molecular variants which lead to various types of stress. The end result of chronic stress can be metabolic disturbance in humans and animals, leading to accumulation of reactive oxygen species (ROS), oxidative stress, energy deficiency in cells (due to a decrease in ATP synthesis) and mitochondrial dysfunction. These changes can last for the lifetime and lead to severe pathologies, including neurodegenerative diseases and atherosclerosis. The analysis of literature allowed us to conclude that under the influence of chronic stress, metabolism in the human body can be disrupted, mutations of the mitochondrial and nuclear genome and dysfunction of cells and their compartments can occur. As a result of these processes, oxidative, genotoxic, and cellular stress can occur. Therefore, chronic stress can be one of the causes forthe occurrence and development of neurodegenerative diseases and atherosclerosis. In particular, chronic stress can play a large role in the occurrence and development of oxidative, genotoxic, and cellular types of stress.
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Affiliation(s)
- Margarita A. Sazonova
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, 125315 Moscow, Russia; (V.V.S.); (A.I.R.); (M.D.S.); (T.V.K.); (V.A.K.); (V.P.K.); (A.N.O.); (I.A.S.)
- Laboratory of Medical Genetics, National Medical Research Center of Cardiology, 121552 Moscow, Russia; (Z.B.K.); (N.A.D.)
| | - Vasily V. Sinyov
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, 125315 Moscow, Russia; (V.V.S.); (A.I.R.); (M.D.S.); (T.V.K.); (V.A.K.); (V.P.K.); (A.N.O.); (I.A.S.)
- Laboratory of Medical Genetics, National Medical Research Center of Cardiology, 121552 Moscow, Russia; (Z.B.K.); (N.A.D.)
| | - Anastasia I. Ryzhkova
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, 125315 Moscow, Russia; (V.V.S.); (A.I.R.); (M.D.S.); (T.V.K.); (V.A.K.); (V.P.K.); (A.N.O.); (I.A.S.)
| | - Marina D. Sazonova
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, 125315 Moscow, Russia; (V.V.S.); (A.I.R.); (M.D.S.); (T.V.K.); (V.A.K.); (V.P.K.); (A.N.O.); (I.A.S.)
| | - Tatiana V. Kirichenko
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, 125315 Moscow, Russia; (V.V.S.); (A.I.R.); (M.D.S.); (T.V.K.); (V.A.K.); (V.P.K.); (A.N.O.); (I.A.S.)
- Laboratory of Medical Genetics, National Medical Research Center of Cardiology, 121552 Moscow, Russia; (Z.B.K.); (N.A.D.)
- Laboratory of Cellular and Molecular Pathology of Cardiovascular System, Research Institute of Human Morphology, 117418 Moscow, Russia
| | - Victoria A. Khotina
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, 125315 Moscow, Russia; (V.V.S.); (A.I.R.); (M.D.S.); (T.V.K.); (V.A.K.); (V.P.K.); (A.N.O.); (I.A.S.)
- Laboratory of Cellular and Molecular Pathology of Cardiovascular System, Research Institute of Human Morphology, 117418 Moscow, Russia
| | - Zukhra B. Khasanova
- Laboratory of Medical Genetics, National Medical Research Center of Cardiology, 121552 Moscow, Russia; (Z.B.K.); (N.A.D.)
| | - Natalya A. Doroschuk
- Laboratory of Medical Genetics, National Medical Research Center of Cardiology, 121552 Moscow, Russia; (Z.B.K.); (N.A.D.)
| | - Vasily P. Karagodin
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, 125315 Moscow, Russia; (V.V.S.); (A.I.R.); (M.D.S.); (T.V.K.); (V.A.K.); (V.P.K.); (A.N.O.); (I.A.S.)
- Department of Commodity Science and Expertise, Plekhanov Russian University of Economics, 125993 Moscow, Russia
| | - Alexander N. Orekhov
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, 125315 Moscow, Russia; (V.V.S.); (A.I.R.); (M.D.S.); (T.V.K.); (V.A.K.); (V.P.K.); (A.N.O.); (I.A.S.)
- Laboratory of Cellular and Molecular Pathology of Cardiovascular System, Research Institute of Human Morphology, 117418 Moscow, Russia
- Institute for Atherosclerosis Research, Skolkovo Innovative Centre, 143024 Moscow, Russia
| | - Igor A. Sobenin
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, 125315 Moscow, Russia; (V.V.S.); (A.I.R.); (M.D.S.); (T.V.K.); (V.A.K.); (V.P.K.); (A.N.O.); (I.A.S.)
- Laboratory of Medical Genetics, National Medical Research Center of Cardiology, 121552 Moscow, Russia; (Z.B.K.); (N.A.D.)
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Kelly C, Nayagam JS, Vogli S, Samyn M, Joshi D. Paediatric cholestatic liver disorders for the adult gastroenterologist: a practical guide. Frontline Gastroenterol 2020; 12:404-413. [PMID: 35401959 PMCID: PMC8989003 DOI: 10.1136/flgastro-2020-101554] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 06/16/2020] [Accepted: 06/20/2020] [Indexed: 02/04/2023] Open
Abstract
With improvements in the outcomes for cholestatic liver diseases that present in childhood, increasing numbers of patients will require ongoing care as adults. The recent advances in management options coupled with the fact that each adult physician will have a limited number of patients with these conditions means there is a need for those in adult services to develop expertise in these conditions that were historically the domain of paediatrics. This review provides an overview of the most common paediatric cholestatic liver diseases and outlines the clinical manifestations and potential complications, and identifies key management issues unique to each condition for effective ongoing care of these patients.
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Affiliation(s)
- Claire Kelly
- Institute of Liver Studies, King's College Hospital, London, UK
| | | | - Stamatina Vogli
- Institute of Liver Studies, King's College Hospital, London, UK
| | - Marianne Samyn
- Institute of Liver Studies, King's College Hospital, London, UK
| | - Deepak Joshi
- Institute of Liver Studies, King's College Hospital, London, UK
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Lommatzsch ST. Infection prevention and chronic disease management in cystic fibrosis and noncystic fibrosis bronchiectasis. Ther Adv Respir Dis 2020; 14:1753466620905272. [PMID: 32160809 PMCID: PMC7068740 DOI: 10.1177/1753466620905272] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Bronchiectasis is a chronic lung disease (CLD) characterized by irreversible bronchial dilatation noted on computed tomography associated with chronic cough, ongoing viscid sputum production, and recurrent pulmonary infections. Patients with bronchiectasis can be classified into two groups: those with cystic fibrosis and those without cystic fibrosis. Individuals with either cystic fibrosis related bronchiectasis (CFRB) or noncystic fibrosis related bronchiectasis (NCFRB) experience continuous airway inflammation and suffer airway architectural changes that foster the acquisition of a unique polymicrobial community. The presence of microorganisms increases airway inflammation, triggers pulmonary exacerbations (PEx), reduces quality of life (QOL), and, in some cases, is an independent risk factor for increased mortality. As there is no cure for either condition, prevention and control of infection is paramount. Such an undertaking incorporates patient/family and healthcare team education, immunoprophylaxis, microorganism source control, antimicrobial chemoprophylaxis, organism eradication, daily pulmonary disease management, and, in some cases, thoracic surgery. This review is a summary of recommendations aimed to thwart patient acquisition of pathologic organisms, and those therapies known to mitigate the effects of chronic airway infection. A thorough discussion of airway clearance techniques and treatment of or screening for nontuberculous mycobacteria (NTM) is beyond the scope of this discussion.
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Dong CD, Chen CW, Chen YC, Chen HH, Lee JS, Lin CH. Polystyrene microplastic particles: In vitro pulmonary toxicity assessment. JOURNAL OF HAZARDOUS MATERIALS 2020; 385:121575. [PMID: 31727530 DOI: 10.1016/j.jhazmat.2019.121575] [Citation(s) in RCA: 319] [Impact Index Per Article: 63.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 09/16/2019] [Accepted: 10/30/2019] [Indexed: 05/21/2023]
Abstract
Microplastics (MPs) have become a global environmental concern. Recent studies have shown that MPs, of which the predominant type is often polystyrene (PS; known as PS-MPs), can extend to and affect remote, sparsely inhabited areas via atmospheric transport. Although exposure to inhaled MPs may induce lung dysfunction, further experimental verification of the pulmonary toxic potential of MPs and the mechanism underlying the toxicity is needed. Here we used normal human lung epithelial BEAS-2B cells to clarify the association between pulmonary toxicity and PS-MPs. Results revealed that PS-MPs can cause cytotoxic and inflammatory effects in BEAS-2B cells by inducing reactive oxygen species formation. PS-MPs can decrease transepithelial electrical resistance by depleting zonula occludens proteins. Indeed, decreased α1-antitrypsin levels in BEAS-2B cells suggest that exposure to PS-MPs increases the risk for chronic obstructive pulmonary disease, and high concentrations of PS-MPs can induce these adverse responses. While low PS-MP levels can only disrupt the protective pulmonary barrier, they may also increase the risk for lung disease. Collectively, our findings indicate that PS-MP inhalation may influence human respiratory health.
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Affiliation(s)
- Cheng-Di Dong
- Department of Marine Environmental Engineering, National Kaohsiung University of Science and Technology, Kaohsiung, 81157, Taiwan
| | - Chiu-Wen Chen
- Department of Marine Environmental Engineering, National Kaohsiung University of Science and Technology, Kaohsiung, 81157, Taiwan
| | - Yi-Chun Chen
- Department of Biotechnology, National Formosa University, Yunlin, 63208, Taiwan
| | - Hung-Hsiang Chen
- Department of Biotechnology, National Formosa University, Yunlin, 63208, Taiwan
| | - Jin-Sun Lee
- Department of Marine Environmental Engineering, National Kaohsiung University of Science and Technology, Kaohsiung, 81157, Taiwan.
| | - Chia-Hua Lin
- Department of Biotechnology, National Formosa University, Yunlin, 63208, Taiwan.
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Cakir M, Sag E, Islek A, Baran M, Tumgor G, Aydogdu S. Liver Involvement in Children with Alpha-1 Antitrypsin Deficiency: A Multicenter Study. Pediatr Gastroenterol Hepatol Nutr 2020; 23:146-153. [PMID: 32206627 PMCID: PMC7073375 DOI: 10.5223/pghn.2020.23.2.146] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 01/10/2020] [Indexed: 11/14/2022] Open
Abstract
PURPOSE Alpha-1 antitrypsin deficiency (A1ATD) in one of the most common genetic causes of liver disease in children. We aimed to analyze the clinical characteristics and outcomes of patients with A1ATD. METHODS This study included patients with A1ATD from five pediatric hepatology units. Demographics, clinical findings, genetics, and outcome of the patients were recorded (n=25). RESULTS Eight patients (32.0%) had homozygous PiZZ genotype while 17 (68.0%) had heterozygous genotype. Patients with PiZZ genotype had lower alpha-1 antitrypsin levels than patients with PiMZ genotype (37.6±7.7 mg/dL vs. 66.5±22.7 mg/dL, p=0.0001). Patients with PiZZ genotype were diagnosed earlier than patients with PiMZ genotype, but this was not significant (13±6.8 months vs. 23.7±30.1 months, p=0.192). Follow-up revealed the death of one patient (12.5%) with a homozygous mutation, and revealed that one patient had child A cirrhosis, five patients (62.5%) had chronic hepatitis, and one patient (12.5%) was asymptomatic. Nine of the 17 patients with a heterozygous mutation had chronic hepatitis (52.9%), two (11.7%) had child A cirrhosis, and six (35.2%) were asymptomatic. Overall, 18 (72%) of the 25 children had liver pathology in the long-term. CONCLUSION Although prevalence is rare, patients with liver disorders should be checked for alpha-1 antitrypsin levels. Moreover, long-term follow-up is essential because most patients have a liver pathology.
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Affiliation(s)
- Murat Cakir
- Department of Pediatric Gastroenterology Hepatology and Nutrition, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey
| | - Elif Sag
- Department of Pediatric Gastroenterology Hepatology and Nutrition, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey
| | - Ali Islek
- Department of Pediatric Gastroenterology Hepatology and Nutrition, Faculty of Medicine, Atatürk University, Erzurum, Turkey
| | - Masallah Baran
- Department of Pediatric Gastroenterology Hepatology and Nutrition, Faculty of Medicine, Katip Çelebi University, Izmir, Turkey
| | - Gokhan Tumgor
- Department of Pediatric Gastroenterology Hepatology and Nutrition, Faculty of Medicine, Cukurova University, Adana, Turkey
| | - Sema Aydogdu
- Department of Pediatric Gastroenterology Hepatology and Nutrition, Faculty of Medicine, Ege University, Izmir, Turkey
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Akbari S, Arslan N, Senturk S, Erdal E. Next-Generation Liver Medicine Using Organoid Models. Front Cell Dev Biol 2019; 7:345. [PMID: 31921856 PMCID: PMC6933000 DOI: 10.3389/fcell.2019.00345] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 12/03/2019] [Indexed: 12/24/2022] Open
Abstract
"Liver medicine" refers to all diagnostic and treatment strategies of diseases and conditions that cause liver failure directly or indirectly. Despite significant advances in the field of liver medicine in recent years, improved tools are needed to efficiently define the pathophysiology of liver diseases and provide effective therapeutic options to patients. Recently, organoid technology has been established as the state-of-the-art cell culture tool for studying human biology in health and disease. In general, organoids are simplified three-dimensional (3D) mini-organ structures that can be grown in a 3D matrix where the structural and functional aspects of real organs are efficiently recapitulated. The generation of organoids is facilitated by exogenous factors that regulate multiple signaling pathways and promote the self-renewal, proliferation, and differentiation of the cells to promote spontaneous self-organization and tissue-specific organogenesis. Newly established protocols suggest that liver-specific organoids can be derived from either pluripotent stem cells or liver-specific stem/progenitor cells. Today, robust and long-term cultures of organoids with the closest physiology to in vivo liver, in terms of cellular composition and function, open a new era in studying and understanding the disease pathology as well as high-throughput drug screening. Of note, these next-generation cell culture systems have immense potential to be further improved by genome editing and bioengineering technologies to foster the development of patient-specific therapeutic options for clinical applications. Here, we will discuss recent advances and challenges in the generation of human liver organoids and highlight emerging concepts for their potential applications in liver medicine.
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Affiliation(s)
| | - Nur Arslan
- İzmir Biomedicine and Genome Center, İzmir, Turkey
- Department of Pediatric Gastroenterology and Metabolism, Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey
| | - Serif Senturk
- İzmir Biomedicine and Genome Center, İzmir, Turkey
- Department of Genome Sciences and Molecular Biotechnology, İzmir International Biomedicine and Genome Institute, Dokuz Eylul University, İzmir, Turkey
| | - Esra Erdal
- İzmir Biomedicine and Genome Center, İzmir, Turkey
- Department of Medical Biology and Genetics, Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey
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12
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Ouriadov A, Guo F, McCormack DG, Parraga G. Accelerated 129 Xe MRI morphometry of terminal airspace enlargement: Feasibility in volunteers and those with alpha-1 antitrypsin deficiency. Magn Reson Med 2019; 84:416-426. [PMID: 31765497 DOI: 10.1002/mrm.28091] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Revised: 10/29/2019] [Accepted: 10/30/2019] [Indexed: 12/21/2022]
Abstract
PURPOSE Multi-b diffusion-weighted hyperpolarized inhaled-gas MRI provides imaging biomarkers of terminal airspace enlargement including ADC and mean linear intercept (Lm ), but clinical translation has been limited because image acquisition requires relatively long or multiple breath-holds that are not well-tolerated by patients. Therefore, we aimed to accelerate single breath-hold 3D multi-b diffusion-weighted 129 Xe MRI, using k-space undersampling in imaging direction using a different undersampling pattern for different b-values combined with the stretched exponential model to generate maps of ventilation, apparent transverse relaxation time constant ( T 2 ∗ ), ADC, and Lm values in a single, short breath-hold; accelerated and non-accelerated measurements were directly compared. METHODS We evaluated multi-b (0, 12, 20, 30, and 45.5 s/cm2 ) diffusion-weighted 129 Xe T 2 ∗ /ADC/morphometry estimates using acceleration factor (AF = 1 and 7) and multi-breath sampling in 3 volunteers (HV), and 6 participants with alpha-1 antitrypsin deficiency (AATD). RESULTS For the HV subgroup, mean differences of 5%, 2%, and 8% were observed between fully sampled and undersampled k-space for ADC, Lm , and T 2 ∗ values, respectively. For the AATD subgroup, mean differences were 9%, 6%, and 12% between fully sampled and undersampled k-space for ADC, Lm and T 2 ∗ values, respectively. Although mean differences of 1% and 4.5% were observed between accelerated and multi-breath sampled ADC and Lm values, respectively, mean ADC/Lm estimates were not significantly different from corresponding mean ADCM /Lm M or mean ADCA /Lm A estimates (all P > 0.60 , A = undersampled and M = multi-breath sampled). CONCLUSIONS Accelerated multi-b diffusion-weighted 129 Xe MRI is feasible at AF = 7 for generating pulmonary ADC and Lm in AATD and normal lung.
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Affiliation(s)
- Alexei Ouriadov
- Department of Physics and Astronomy, The University of Western Ontario, London, Canada.,Lawson Health Research Institute, London, Canada
| | - Fumin Guo
- Sunnybrook Research Institute, University of Toronto, Toronto, Canada
| | - David G McCormack
- Division of Respirology, Department of Medicine, The University of Western Ontario, London, Canada
| | - Grace Parraga
- Division of Respirology, Department of Medicine, The University of Western Ontario, London, Canada.,Robarts Research Institute, The University of Western Ontario, London, Canada.,Department of Medical Biophysics, The University of Western Ontario, London, Canada
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13
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Khodayari N, Oshins R, Alli AA, Tuna KM, Holliday LS, Krotova K, Brantly M. Modulation of calreticulin expression reveals a novel exosome-mediated mechanism of Z variant α 1-antitrypsin disposal. J Biol Chem 2019; 294:6240-6252. [PMID: 30833329 DOI: 10.1074/jbc.ra118.006142] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Revised: 02/26/2019] [Indexed: 01/08/2023] Open
Abstract
α1-Antitrypsin deficiency (AATD) is an inherited disease characterized by emphysema and liver disease. AATD is most often caused by a single amino acid substitution at position 342 in the mature protein, resulting in the Z mutation of the AAT gene (ZAAT). This substitution is associated with misfolding and accumulation of ZAAT in the endoplasmic reticulum (ER) of hepatocytes, causing a toxic gain of function. ERdj3 is an ER luminal DnaJ homologue, which, along with calreticulin, directly interacts with misfolded ZAAT. We hypothesize that depletion of each of these chaperones will change the fate of ZAAT polymers. Our study demonstrates that calreticulin modulation reveals a novel ZAAT degradation mechanism mediated by exosomes. Using human PiZZ hepatocytes and K42, a mouse calreticulin-deficient fibroblast cell line, our results show ERdj3 and calreticulin directly interact with ZAAT in PiZZ hepatocytes. Silencing calreticulin induces calcium independent ZAAT-ERdj3 secretion through the exosome pathway. This co-secretion decreases ZAAT aggregates within the ER of hepatocytes. We demonstrate that calreticulin has an inhibitory effect on exosome-mediated ZAAT-ERdj3 secretion. This is a novel ZAAT degradation process that involves a DnaJ homologue chaperone bound to ZAAT. In this context, calreticulin modulation may eliminate the toxic gain of function associated with aggregation of ZAAT in lung and liver, thus providing a potential new therapeutic approach to the treatment of AATD-related liver disease.
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Affiliation(s)
- Nazli Khodayari
- From the Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine
| | - Regina Oshins
- From the Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine
| | - Abdel A Alli
- the Department of Physiology and Functional Genomics, College of Medicine, and
| | - Kubra M Tuna
- the Department of Physiology and Functional Genomics, College of Medicine, and
| | - L Shannon Holliday
- the Department of Orthodontics, College of Dentistry, University of Florida, Gainesville, Florida 32610 and
| | - Karina Krotova
- the Hormel Institute, University of Minnesota, Austin, Minnesota 55912
| | - Mark Brantly
- From the Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine,
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Abstract
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. AAT phenotyping was conducted on patients with a low serum AAT level. The exclusion criteria included infectious, anatomic, and metabolic conditions. Symptoms on presentation, physical examination findings, laboratory values, liver biopsy results, and follow-up periods were recorded for each patient. RESULTS The patients included six (30%) girls and 14 (70%) boys, with a mean age of 6.3±5.1 (1-16) years. The PiZZ phenotype was present in eight (40%) and PiMZ in 12 (60%) patients. The most frequent symptom was elevated liver function test results. Three patients were referred with neonatal cholestasis and one with compensated cirrhosis. Eight patients underwent liver biopsy; all patients except one had periodic acid-Schiff-positive diastase-resistant globules in the hepatocytes. The mean follow-up period was 34±33 (12-101) months. At the end of follow-up, all patients with PiZZ were found to have chronic hepatitis, and one with cirrhosis. On the contrary, two patients with PiMZ were found to have chronic hepatitis. CONCLUSION Children with classical AATD commonly have chronic liver disease. In heterozygous (PiMZ) children with AATD, enzyme levels can normalize with occasional fluctuations, sometimes causing delayed diagnosis.
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15
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Abstract
The inherited diseases causing conjugated hyperbilirubinemia are diverse, with variability in clinical severity, histologic appearance, and time of onset. The liver biopsy appearances can also vary depending on whether the initial presentation is in the neonatal period or later. Although many of the disorders have specific histologic features in fully developed and classic cases, biopsies taken early in the disease course may be nonspecific, showing either cholestatic hepatitis or an obstructive pattern of injury requiring close correlation with the laboratory and clinical findings to reach the correct diagnosis. Additionally, increased understanding of the range of hepatic changes occurring in mild deficiencies of bile canalicular transporter proteins suggest that these disorders, particularly ABCB4 deficiency, may be more common than previously recognized; improved awareness should prompt further investigation.
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Affiliation(s)
- Andrew D Clouston
- Faculty of Medicine, University of Queensland, Herston Road, Brisbane, Queensland 4006, Australia.
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16
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Aghajan M, Guo S, Monia BP. Knockdown of Z Mutant Alpha-1 Antitrypsin In Vivo Using Modified DNA Antisense Oligonucleotides. Methods Mol Biol 2018; 1639:127-138. [PMID: 28752452 DOI: 10.1007/978-1-4939-7163-3_12] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Alpha-1 antitrypsin (AAT) is a serum protease inhibitor, mainly expressed in and secreted from hepatocytes, important for regulating neutrophil elastase activity among other proteases. Various mutations in AAT cause alpha-1 antitrypsin deficiency (AATD), a rare hereditary disorder that results in liver disease due to accumulation of AAT aggregates and lung disease from excessive neutrophil elastase activity. PiZ transgenic mice contain the human AAT genomic region harboring the most common AATD mutation, the Glu342Lys (Z) point mutation. These mice effectively recapitulate the liver disease exhibited in AATD patients, including AAT protein aggregates, hepatocyte death, and eventual liver fibrosis. Previously, we demonstrated that modified antisense oligonucleotides (ASOs) can dramatically reduce Z-AAT RNA and protein levels in PiZ mice enabling inhibition, prevention, and reversal of the associated liver disease. Here, we describe in detail usage of AAT-ASOs to knock down Z-AAT in PiZ mice with a focus on preparation and in vivo delivery of ASOs, as well as detailed workflows pertaining to the analysis of Z-AAT mRNA, plasma protein, and soluble/insoluble liver protein levels following ASO administration.
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Affiliation(s)
- Mariam Aghajan
- Department of Antisense Drug Discovery, IONIS Pharmaceuticals, 2855 Gazelle Court, Carlsbad, 92010, CA, USA
| | - Shuling Guo
- Department of Antisense Drug Discovery, IONIS Pharmaceuticals, 2855 Gazelle Court, Carlsbad, 92010, CA, USA
| | - Brett P Monia
- Department of Antisense Drug Discovery, IONIS Pharmaceuticals, 2855 Gazelle Court, Carlsbad, 92010, CA, USA.
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17
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Synthetic Cannabinoid Abuse and a Rare Alpha-1-Antitrypsin Mutant Causing Acute Fulminant Hepatitis: A Case Report and Review of the Literature. Case Reports Hepatol 2018; 2017:9627452. [PMID: 29333304 PMCID: PMC5733121 DOI: 10.1155/2017/9627452] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Revised: 05/25/2017] [Accepted: 06/18/2017] [Indexed: 11/17/2022] Open
Abstract
Synthetic cannabinoids (SCs) abuse is on the rise because they are easily obtained over the counter; they are potent psychoactive compounds and routine drug testing does not detect them. As their abuse is on the rise, so are their detrimental side effects; however, the occurrence of acute hepatitis due to SCs abuse has been reported only once before. In this case, testing revealed that the patient was also heterozygous for alpha-1-antitrypsin (A-1-AT) with the phenotype of PI⁎EM. This mutant phenotype has never been reported as a cause of A-1-AT disease and the abuse of SCs in a patient with this phenotype has also never been reported. This case illustrates the possible need to expand routine drug testing for SCs and consider A-1-AT phenotyping in certain clinical scenarios.
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18
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Carvalho MOS, Souza ALCS, Carvalho MB, Pacheco APAS, Rocha LC, do Nascimento VML, Figueiredo CVB, Guarda CC, Santiago RP, Adekile A, Goncalves MDS. Evaluation of Alpha-1 Antitrypsin Levels and SERPINA1 Gene Polymorphisms in Sickle Cell Disease. Front Immunol 2017; 8:1491. [PMID: 29163550 PMCID: PMC5681845 DOI: 10.3389/fimmu.2017.01491] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Accepted: 10/23/2017] [Indexed: 12/11/2022] Open
Abstract
Alpha-1 antitrypsin (AAT) is an inhibitor of neutrophil elastase and a member of the serine proteinase inhibitor (serpin) superfamily, and little is known about its activity in sickle cell disease (SCD). We hypothesize that AAT may undergo changes in SCD because of the high oxidative stress and inflammation associated with the disease. We have found high AAT levels in SCD patients compared to controls, while mutant genotypes of SERPINA1 gene had decreased AAT levels, in both groups. AAT showed negative correlation with red blood cells, hemoglobin (Hb), hematocrit, high-density lipoprotein cholesterol, urea, creatinine, and albumin and was positively correlated with mean corpuscular Hb concentration, white blood cells, neutrophils, Hb S, bilirubin, lactate dehydrogenase, ferritin, and C-reactive protein. Patients with higher levels of AAT had more infection episodes (OR = 1.71, CI: 1.05–2.65, p = 0.02), gallstones (OR = 1.75, CI: 1.03–2.97, p = 0.02), and had more blood transfusions (OR = 2.35, CI: 1.51–3.65, p = 0.0001). Our data on AAT association with laboratory indices of hemolysis and inflammation suggest that it may be positively associated with SCD severity; the negative correlations with renal parameters suggest a cytoprotective mechanism in SCD patients. In summary, AAT may need to be included in studies related to SCD and in the discussion of further therapeutic strategies.
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Affiliation(s)
- Magda Oliveira Seixas Carvalho
- Instituto Gonçalo Moniz-Fiocruz-Bahia (IGM-FIOCRUZ-Ba), Salvador, Brazil.,Complexo Hospitalar Universitário Professor Edgard Santos, Salvador, Brazil
| | | | | | | | | | | | - Camylla Vilas Boas Figueiredo
- Instituto Gonçalo Moniz-Fiocruz-Bahia (IGM-FIOCRUZ-Ba), Salvador, Brazil.,Universidade Federal da Bahia (UFBA), Salvador, Brazil
| | - Caroline Conceição Guarda
- Instituto Gonçalo Moniz-Fiocruz-Bahia (IGM-FIOCRUZ-Ba), Salvador, Brazil.,Universidade Federal da Bahia (UFBA), Salvador, Brazil
| | - Rayra Pereira Santiago
- Instituto Gonçalo Moniz-Fiocruz-Bahia (IGM-FIOCRUZ-Ba), Salvador, Brazil.,Universidade Federal da Bahia (UFBA), Salvador, Brazil
| | - Adekunle Adekile
- Department of Pediatrics, Kuwait University, Kuwait City, Kuwait
| | - Marilda de Souza Goncalves
- Instituto Gonçalo Moniz-Fiocruz-Bahia (IGM-FIOCRUZ-Ba), Salvador, Brazil.,Universidade Federal da Bahia (UFBA), Salvador, Brazil
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19
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Akbas N, Gonzalez G, Buffone GJ, Grenache DG, Devaraj S. A Library of Rare α1-Antitrypsin (AAT) Variant Phenotypes to Aid in the Diagnosis of AAT Deficiency. Am J Clin Pathol 2016; 146:289-93. [PMID: 27543976 DOI: 10.1093/ajcp/aqw112] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVES α1-Antitrypsin (AAT) deficiency is a hereditary disorder due to defective production of the serine protease inhibitor, AAT, which can cause lung and liver diseases. Severity of disease depends particularly on the phenotypic representation of AAT variants in the patient. METHODS In this study, we present determination of seven common and nine rare variant phenotypes of AAT using pediatric samples collected in Texas Children's Hospital to address the knowledge gap in the identification of rare variants. We tested 16 different AAT variants that had been stored in a -80 °C freezer over the years to add to the reference library of AAT variants. The gold-standard isoelectric focusing electrophoresis method was used for analysis and interpretation of AAT variants. Each variant was inspected visually by comparing multiple bands, unique to phenotypic identity, with a previously identified pattern. RESULTS Seven common M, S, and Z variants were identified as M1M1, M2M2, M1M2, MS, SS, SZ, and ZZ. Nine rare variants were identified as FM, FS, FZ, PM, XM, YM, IM, TS, and EP. These were interpreted independently and in a blinded manner by an experienced technologist and two clinical chemists from two different institutions. CONCLUSIONS Our results add to the reference library to identify the rare variant phenotypes of AAT protein. This report will guide clinical laboratories for proper assessment of rare variants and in turn contribute to accurate diagnosis and management of AAT deficiency.
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Affiliation(s)
- Neval Akbas
- From the Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX Texas Children's Hospital, Houston
| | | | - Gregory J Buffone
- From the Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX Texas Children's Hospital, Houston
| | - David G Grenache
- Department of Pathology, University of Utah School of Medicine, Salt Lake City
| | - Sridevi Devaraj
- From the Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX Texas Children's Hospital, Houston
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20
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Hoth KF, Wamboldt FS, Ford DW, Sandhaus RA, Strange C, Bekelman DB, Holm KE. The social environment and illness uncertainty in chronic obstructive pulmonary disease. Int J Behav Med 2015; 22:223-32. [PMID: 25008041 PMCID: PMC4289471 DOI: 10.1007/s12529-014-9423-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
PURPOSE Illness uncertainty is associated with worse outcomes in patients with chronic health conditions. Research on social factors associated with uncertainty has focused on the beneficial role of social support. The goal of this study was to develop a more nuanced understanding of the social factors that are associated with uncertainty. METHODS Four hundred sixty-two individuals with alpha-1 antitrypsin deficiency (AATD)-associated chronic obstructive pulmonary disease (COPD) completed a mailed questionnaire. Measures of the social environment included general family functioning, perceived criticism from family members, whether the participant had family members with AATD or COPD, and participation in support groups. Uncertainty was measured using the Mishel Uncertainty in Illness Scale including subscales for ambiguity (uncertainty about physical cues and symptoms) and complexity (uncertainty about treatment and the medical system). Hierarchical regression was used to identify social correlates of ambiguity and complexity while adjusting for demographic and medical characteristics and psychological distress. RESULTS Perceived criticism was associated with more complexity (b = 0.21, SE = 0.09, p = 0.015) and ambiguity (b = 0.40, SE = 0.12, p = 0.001). Having a family member with AATD or COPD was associated with more ambiguity (b = 3.28, SE = 1.00, p = 0.001). Participation in support groups was associated with less ambiguity. Individuals who attended three or more support groups in the prior year reported less ambiguity than individuals who had not attended any (b = -3.31, SE = 1.29, p = 0.010). CONCLUSIONS The social environment is complex and encompasses more than social support. Multiple aspects of the social environment are associated with uncertainty, including perceived criticism, having a family member with a similar illness, and participation in support groups.
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Affiliation(s)
- Karin F Hoth
- Department of Psychiatry, University of Iowa Carver College of Medicine, 200 Hawkins Drive, W278GH, Iowa City, IA, 52242, USA,
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21
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Abstract
The distribution of the anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV) is not uniform across geographical regions and ethnic and racial groups, suggesting that genetic and environmental factors affect the pathogenesis of these diseases. In addition, genetic factors affect not only the clinical syndrome phenotypes and their prognosis, but also ANCA specificity; these data suggest that AAV may need reclassification. Several genes have been evaluated, including ANCA targets and those of the immune system, for example co-stimulatory molecules, signaling regulators, cytokines, Fc and other receptors, and other proteins. This article provides a review of genetic factors affecting the pathogenesis and prognosis of AAV. Further studies to determine the effect of genetic factors on the clinical syndrome phenotypes and ANCA specificity need to be performed across different ethnic groups.
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22
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Scorza M, Elce A, Zarrilli F, Liguori R, Amato F, Castaldo G. Genetic diseases that predispose to early liver cirrhosis. Int J Hepatol 2014; 2014:713754. [PMID: 25132997 PMCID: PMC4123515 DOI: 10.1155/2014/713754] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Accepted: 06/30/2014] [Indexed: 12/11/2022] Open
Abstract
Inherited liver diseases are a group of metabolic and genetic defects that typically cause early chronic liver involvement. Most are due to a defect of an enzyme/transport protein that alters a metabolic pathway and exerts a pathogenic role mainly in the liver. The prevalence is variable, but most are rare pathologies. We review the pathophysiology of such diseases and the diagnostic contribution of laboratory tests, focusing on the role of molecular genetics. In fact, thanks to recent advances in genetics, molecular analysis permits early and specific diagnosis for most disorders and helps to reduce the invasive approach of liver biopsy.
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Affiliation(s)
- Manuela Scorza
- CEINGE—Biotecnologie Avanzate Scarl, Via Gaetano Salvatore 486, 80145 Napoli, Italy
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Via Sergio Pansini 5, 80131 Napoli, Italy
| | - Ausilia Elce
- CEINGE—Biotecnologie Avanzate Scarl, Via Gaetano Salvatore 486, 80145 Napoli, Italy
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Via Sergio Pansini 5, 80131 Napoli, Italy
- Università Telematica Pegaso, Piazza Trieste e Trento 48, 80132 Napoli, Italy
| | - Federica Zarrilli
- CEINGE—Biotecnologie Avanzate Scarl, Via Gaetano Salvatore 486, 80145 Napoli, Italy
- Dipartimento di Bioscienze e Territorio, Università del Molise, Contrada Fonte Lappone, Pesche, 86090 Isernia, Italy
| | - Renato Liguori
- CEINGE—Biotecnologie Avanzate Scarl, Via Gaetano Salvatore 486, 80145 Napoli, Italy
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Via Sergio Pansini 5, 80131 Napoli, Italy
| | - Felice Amato
- CEINGE—Biotecnologie Avanzate Scarl, Via Gaetano Salvatore 486, 80145 Napoli, Italy
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Via Sergio Pansini 5, 80131 Napoli, Italy
| | - Giuseppe Castaldo
- CEINGE—Biotecnologie Avanzate Scarl, Via Gaetano Salvatore 486, 80145 Napoli, Italy
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Via Sergio Pansini 5, 80131 Napoli, Italy
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Affiliation(s)
- Cathy R Kessenich
- Cathy R. Kessenich is a professor of nursing and MSN program director at University of Tampa, Tampa, Fla. Kathryn Bacher is a graduate assistant at the University of Tampa, Tampa, Fla
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Suh-Lailam BB, Procter M, Krautscheid P, Haas J, Kumar S, Mao R, Grenache DG. Challenging identification of a novel PiISF and the rare PiMmaltonZ α1-antitrypsin deficiency variants in two patients. Am J Clin Pathol 2014; 141:742-6. [PMID: 24713750 DOI: 10.1309/ajcpr7eiqs8pimlv] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
OBJECTIVES α1-Antitrypsin (AAT) deficiency is associated with an increased risk for lung and liver disease. Identification of AAT deficiency as the underlying cause of these diseases is important in correct patient management. METHODS AAT deficiency is commonly diagnosed by demonstrating low concentrations of AAT followed by genotype and/or phenotype testing. However, this algorithm may miss novel AAT phenotypes. RESULTS We report two cases of AAT deficiency in two patients: a case of the novel phenotype PiISF, misclassified as PiII by phenotyping, and a case of the rare phenotype PiMmaltonZ misclassified as PiM2Z. CONCLUSIONS These cases highlight the importance of understanding the limitations of a commonly used diagnostic algorithm, use of further gene sequencing in applicable cases, and the potential for underdiagnosis of AAT deficiency in patients with chronic obstructive pulmonary disease.
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Affiliation(s)
| | - Melinda Procter
- ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT
| | - Patti Krautscheid
- ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT
| | - Jason Haas
- Aurora St. Luke’s Medical Center, Milwaukee, WI
| | - Shiva Kumar
- Aurora St. Luke’s Medical Center, Milwaukee, WI
| | - Rong Mao
- Department of Pathology, University of Utah School of Medicine, Salt Lake City
- ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT
| | - David G. Grenache
- Department of Pathology, University of Utah School of Medicine, Salt Lake City
- ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT
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25
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Qin L, Luo G, Zhang J, Xu N. A novel method of detecting alpha-1 antitrypsin deficiency of Z mutant (GAG(342)AAG) in a single PCR reaction using base-quenched probe. Clin Chim Acta 2014; 427:29-33. [PMID: 24099880 DOI: 10.1016/j.cca.2013.09.042] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2013] [Accepted: 09/27/2013] [Indexed: 11/20/2022]
Abstract
BACKGROUND Alpha-1 antitrypsin (A1AT) is a protease inhibitor that protects the tissues from degradation by neutrophil elastase under certain pathological process. Alpha-1 antitrypsin deficiency (A1ATD) could associate with both lung and liver pathogenicities. Of all the deficiency alleles, Z mutant is the most common variant and causes severe complications. Here, we described a novel and quick method to detect Z mutant using the base-quenched probe technique in only one single PCR reaction. METHODS Primers and probe were designed based on the base-quenched probe technique. Two vectors, representing the two genotypes, were constructed as amplification templates for validating the method. The Z mutant (GAG(342)AAG) was analyzed according to the melting curve. Finally, the accuracy was confirmed by direct sequencing. RESULTS Z mutant could be accurately distinguished from the wild type. The wild type resulted in high melting temperature (TM) (48.64±1.33°C), while when the Z mutation was present, the TM was shifted to an obvious low TM (41.38±0.9017°C). The sensitivity reached a low of 10(3) copies of template DNA with a clear melting valley and a complete concordance occurred between this method and the direct DNA sequencing. CONCLUSION The present described method is simple, quick and economic as well as suitable for large-scale genotyping studies and clinical testing of Z mutant in patients with emphysema and cirrhosis.
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Affiliation(s)
- Li Qin
- Comprehensive Laboratory, Changzhou Key Lab of Individualized Diagnosis and Treatment Associated with High Technology Research, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China
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Guo S, Booten SL, Aghajan M, Hung G, Zhao C, Blomenkamp K, Gattis D, Watt A, Freier SM, Teckman JH, McCaleb ML, Monia BP. Antisense oligonucleotide treatment ameliorates alpha-1 antitrypsin-related liver disease in mice. J Clin Invest 2013; 124:251-61. [PMID: 24355919 DOI: 10.1172/jci67968] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2012] [Accepted: 10/15/2013] [Indexed: 02/04/2023] Open
Abstract
Alpha-1 antitrypsin deficiency (AATD) is a rare genetic disease that results from mutations in the alpha-1 antitrypsin (AAT) gene. The mutant AAT protein aggregates and accumulates in the liver leading to AATD liver disease, which is only treatable by liver transplant. The PiZ transgenic mouse strain expresses a human AAT (hAAT) transgene that contains the AATD-associated Glu342Lys mutation. PiZ mice exhibit many AATD symptoms, including AAT protein aggregates, increased hepatocyte death, and liver fibrosis. In the present study, we systemically treated PiZ mice with an antisense oligonucleotide targeted against hAAT (AAT-ASO) and found reductions in circulating levels of AAT and both soluble and aggregated AAT protein in the liver. Furthermore, AAT-ASO administration in these animals stopped liver disease progression after short-term treatment, reversed liver disease after long-term treatment, and prevented liver disease in young animals. Additionally, antisense oligonucleotide treatment markedly decreased liver fibrosis in this mouse model. Administration of AAT-ASO in nonhuman primates led to an approximately 80% reduction in levels of circulating normal AAT, demonstrating potential for this approach in higher species. Antisense oligonucleotides thus represent a promising therapy for AATD liver disease.
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An update on laboratory diagnosis of liver inherited diseases. BIOMED RESEARCH INTERNATIONAL 2013; 2013:697940. [PMID: 24222913 PMCID: PMC3816025 DOI: 10.1155/2013/697940] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/02/2013] [Accepted: 08/26/2013] [Indexed: 12/14/2022]
Abstract
Liver inherited diseases are a group of genetically determined clinical entities that appear with an early chronic liver involvement. They include Wilson's disease (hepatolenticular degeneration), hereditary hemochromatosis, and alpha-1-antitrypsin deficiency. In addition, cystic fibrosis, although it is not specifically a liver disease, may cause a severe liver involvement in a significant percentage of cases. For all these pathologies, the disease gene is known, and molecular analysis may contribute to the unequivocal diagnosis. This approach could avoid the patient invasive procedures and limit complications associated with a delay in diagnosis. We review liver inherited diseases on the basis of the genetic defect, focusing on the contribution of molecular analysis in the multistep diagnostic workup.
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Eggenschwiler R, Loya K, Wu G, Sharma AD, Sgodda M, Zychlinski D, Herr C, Steinemann D, Teckman J, Bals R, Ott M, Schambach A, Schöler HR, Cantz T. Sustained knockdown of a disease-causing gene in patient-specific induced pluripotent stem cells using lentiviral vector-based gene therapy. Stem Cells Transl Med 2013; 2:641-54. [PMID: 23926210 DOI: 10.5966/sctm.2013-0017] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Patient-specific induced pluripotent stem cells (iPSCs) hold great promise for studies on disease-related developmental processes and may serve as an autologous cell source for future treatment of many hereditary diseases. New genetic engineering tools such as zinc finger nucleases and transcription activator-like effector nuclease allow targeted correction of monogenetic disorders but are very cumbersome to establish. Aiming at studies on the knockdown of a disease-causing gene, lentiviral vector-mediated expression of short hairpin RNAs (shRNAs) is a valuable option, but it is limited by silencing of the knockdown construct upon epigenetic remodeling during differentiation. Here, we propose an approach for the expression of a therapeutic shRNA in disease-specific iPSCs using third-generation lentiviral vectors. Targeting severe α-1-antitrypsin (A1AT) deficiency, we overexpressed a human microRNA 30 (miR30)-styled shRNA directed against the PiZ variant of A1AT, which is known to cause chronic liver damage in affected patients. This knockdown cassette is traceable from clonal iPSC lines to differentiated hepatic progeny via an enhanced green fluorescence protein reporter expressed from the same RNA-polymerase II promoter. Importantly, the cytomegalovirus i/e enhancer chicken β actin (CAG) promoter-driven expression of this construct is sustained without transgene silencing during hepatic differentiation in vitro and in vivo. At low lentiviral copy numbers per genome we confirmed a functional relevant reduction (-66%) of intracellular PiZ protein in hepatic cells after differentiation of patient-specific iPSCs. In conclusion, we have demonstrated that lentiviral vector-mediated expression of shRNAs can be efficiently used to knock down and functionally evaluate disease-related genes in patient-specific iPSCs.
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Affiliation(s)
- Reto Eggenschwiler
- Research Group Translational Hepatology and Stem Cell Biology, Hannover Medical School, Hannover, Germany
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Rodeck B, Zimmer KP. Stoffwechselerkrankungen. PÄDIATRISCHE GASTROENTEROLOGIE, HEPATOLOGIE UND ERNÄHRUNG 2013. [PMCID: PMC7498805 DOI: 10.1007/978-3-642-24710-1_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Entsprechend ihrer Wanderung bei isoelektrischer Fokussierung werden die allelen Varianten des α1-AT als Proteinaseinhibitorphänotypen (Pi) klassifiziert. Die dominierende Isoform ist der normale Phänotyp M, daneben gibt es die Mangelvarianten S und Z sowie eine 0-Variante.
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Affiliation(s)
- Burkhard Rodeck
- Zentrum für Kinder- und Jugendmedizin, Christliches Kinderhospital Osnabrück, Johannisfreiheit 1, 49074 Osnabrück, Deutschland
| | - Klaus-Peter Zimmer
- grid.411067.50000000085849230Abteilung Allgemeine Pädiatrie und Neonatalogie, Universitätsklinikum Gießen und Marburg GmbH, Zentrum für Kinderheilkunde und Jugendmedizin, Feulgenstr. 12, 35392 Gießen, Deutschland
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Hoth KF, Ford DW, Sandhaus RA, Strange C, Wamboldt FS, Holm KE. Alcohol use predicts ER visits in individuals with alpha-1 antitrypsin deficiency (AATD) associated COPD. COPD 2012; 9:417-25. [PMID: 22651849 DOI: 10.3109/15412555.2012.684414] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Excessive alcohol use in COPD has been associated with increased mortality; however, little is known about alcohol use in AATD-associated COPD. A total of 538 individuals with AATD-associated COPD completed questionnaires at baseline and 330 also completed 2 years of follow-up questionnaires. Demographic and health information was collected, including information about alcohol use, ER visits for COPD, and hospitalizations for COPD. Problem alcohol use was characterized using the CAGE screening questionnaire and recent alcohol consumption. Demographic and clinical characteristics associated with problem drinking were identified using logistic regression. Problem drinking at baseline was examined as a predictor of ER visits and hospital admissions for COPD in the subsequent two years using logistic regression adjusting for demographic variables and baseline health status. 14% of the sample reported a history of problem drinking per the CAGE and 8% reported problem drinking in the past week. Problem drinking was associated with higher education and greater lifetime tobacco exposure. Recent alcohol consumption was a significant predictor of having an ER visit for COPD in the subsequent two years. Compared to individuals who reported problem drinking in the past week, individuals with no consumption (OR = 0.32, 95% CI = 0.10 to 0.97, p = .043) and individuals with low-to-moderate consumption (OR = 0.25, 95% CI = 0.08 to 0.77, p = .016) had significantly lower odds of an ER visit. Neither measure of problem drinking predicted hospital admission. Screening for recent excessive alcohol use in this population may identify individuals at risk for use of costly emergency health services.
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Affiliation(s)
- Karin F Hoth
- National Jewish Health, Department of Medicine, Denver, CO, United States.
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Czaja AJ. Cryptogenic chronic hepatitis and its changing guise in adults. Dig Dis Sci 2011; 56:3421-38. [PMID: 21647651 DOI: 10.1007/s10620-011-1769-9] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2011] [Accepted: 05/20/2011] [Indexed: 12/11/2022]
Abstract
Cryptogenic chronic hepatitis is a disease that is unexplained by conventional clinical, laboratory and histological findings, and it can progress to cirrhosis, develop hepatocellular carcinoma, and require liver transplantation. The goals of this review are to describe the changing phenotype of cryptogenic chronic hepatitis in adults, develop a diagnostic algorithm appropriate to current practice, and suggest treatment options. The frequency of cryptogenic hepatitis is estimated at 5.4%. Cryptogenic cirrhosis is diagnosed in 5-30% of patients with cirrhosis, and it is present in 3-14% of adults awaiting liver transplantation. Nonalcoholic fatty liver disease has been implicated in 21-63% of patients, and autoimmune hepatitis is a likely diagnosis in 10-54% of individuals. Viral infections, hereditary liver diseases, celiac disease, and unsuspected alcohol or drug-induced liver injury are recognized infrequently in the current cryptogenic population. Manifestations of the metabolic syndrome heighten the suspicion of nonalcoholic fatty liver disease, and the absence of hepatic steatosis does not discount this possibility. The diagnostic scoring system of the International Autoimmune Hepatitis Group can support the diagnosis of autoimmune hepatitis in some patients. Certain genetic mutations may have disease-specificity, and they suggest that some patients may have an independent and uncharacterized disease. Corticosteroid therapy is effective in patients with autoimmune features, and life-style changes and specific therapies for manifestations of the metabolic syndrome are appropriate for all obese patients. The 1- and 5-year survivals after liver transplantation have ranged from 72-85% to 58-73%, respectively.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street S.W., Rochester, MN 55905, USA.
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Silliman CC, Dzieciatkowska M, Moore EE, Kelher MR, Banerjee A, Liang X, Land KJ, Hansen KC. Proteomic analyses of human plasma: Venus versus Mars. Transfusion 2011; 52:417-24. [PMID: 21880043 DOI: 10.1111/j.1537-2995.2011.03316.x] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
BACKGROUND Plasma is vital for the resuscitation of injured patients and to restore necessary procoagulants, especially Factors (F)II, FV, FVII, FX, and FXIII; however, female plasma has been implicated in the majority of transfusion-related acute lung injury (TRALI) cases and male-only plasma transfusion regimens have significantly decreased the incidence of TRALI. Little is known about the human plasma proteome, and no comparisons have been made between male and female plasma; therefore, we hypothesize that there are significant differences between plasma from male and female donors. STUDY DESIGN AND METHODS Five units of fresh-frozen plasma each were collected from nulliparous female donors and male donors, and the proteome was analyzed by depleting the 14 most common proteins by immunoaffinity columns followed by protein separation by one dimension gel electrophoresis, tryptic digestion of the proteins, analysis of the peptides by liquid chromatography-tandem mass spectrometry, and identification employing human protein sequence databases. RESULTS Female plasma versus male plasma contained pregnancy zone protein (419- to 580-fold), FV (twofold), α(1)-antitrypsin (twofold), β(2) -microglobulin (twofold), and Complement Factors H and C4B (1.5- to 2-fold) at significantly higher concentrations than males and males contained significant increases in Fc-binding protein (twofold), protein Z-dependent protease inhibitor (twofold), phosphatidylinositol glycan-specific phospholipase (fourfold), protein S-100 (threefold), and transgelin-2 (14-fold) versus females (p < 0.005). The increases in FV, α(1)-antitrypsin, and β(2)-microglobulin were confirmed by an activity assay or immunoblots. CONCLUSION We conclude that there are proteomic differences between male and female plasma, which could be exploited to improve clinical outcomes in transfused patients.
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Baron J, Sheiner E, Abecassis A, Ashkenazi E, Shahaf G, Salem SY, Madar T, Twina G, Wiznitzer A, Holcberg G, Lewis EC. α1-Antitrypsin insufficiency is a possible contributor to preterm premature rupture of membranes. J Matern Fetal Neonatal Med 2011; 25:934-7. [DOI: 10.3109/14767058.2011.600369] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
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Abboud RT, Nelson TN, Jung B, Mattman A. Alpha1-antitrypsin deficiency: a clinical-genetic overview. Appl Clin Genet 2011; 4:55-65. [PMID: 23776367 PMCID: PMC3681178 DOI: 10.2147/tacg.s10604] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
Severe α1-antitrypsin deficiency (AATD) is an inherited disorder, leading to development of emphysema in smokers at a relatively young age with disability in their forties or fifties. The emphysema results from excessive elastin degradation by neutrophil elastase as a result of the severe deficiency of its major inhibitor α1-antitrypsin (AAT). The AAT expression is determined by the SERPINA1 gene which expresses codominant alleles. The three most common alleles are the normal M, the S with plasma levels of 60% of normal, and the severely deficient Z with levels of about 15% of normal. Homozygosity for the Z mutant allele is associated with retention of abnormal AAT in the liver, which may lead to neonatal hepatitis, liver disease in children, and liver disease in adults. Regular intravenous infusions of purified human AAT (AAT augmentation therapy) have been used to partially correct the biochemical defect and protect the lung against further injury. Two randomized controlled trials showed a trend of slower progression of emphysema by chest computerized tomography. Integrated analysis of these two studies indicated significantly slower progression of emphysema. AAT is quantified by immunologic measurement of AAT in serum, the phenotype characterized by isoelectric focusing, the common genotypes by targeted DNA analysis, and by sequencing the coding region of the gene when the AAT abnormality remains undefined. AATD is often unrecognized, and diagnosis delayed. Testing for AATD is recommended in patients with chronic irreversible airflow obstruction, especially in those with early onset of disease or positive family history. Testing is also recommended for immediate family members of those with AATD, asthmatics with persistent airflow obstruction, and infants and older subjects with unexplained liver disease. There are over 100 different AAT gene variants; most are rare and only some are associated with clinical disease.
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Affiliation(s)
- Raja T Abboud
- Department of Medicine, Respiratory Division, University of British Columbia, Vancouver, BC, Canada
| | - Tanya N Nelson
- Department of Pathology and Laboratory Medicine, Children’s and Women’s Health Centre of British Columbia, University of British Columbia, Vancouver, BC, Canada
| | - Benjamin Jung
- Department of Pathology and Laboratory Medicine, Children’s and Women’s Health Centre of British Columbia, University of British Columbia, Vancouver, BC, Canada
| | - Andre Mattman
- Department of Pathology and Laboratory Medicine, St. Paul’s Hospital, University of British Columbia, Vancouver, BC, Canada
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