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Paper 2
Published in Amanda Rabone, Benedict Thomson, Nicky Dineen, Vincent Helyar, Aidan Shaw, The Final FRCR, 2020
Amanda Rabone, Benedict Thomson, Nicky Dineen, Vincent Helyar, Aidan Shaw
This case describes alpha 1 antitrypsin deficiency. This is diagnosed with measurement of alpha 1 antitrypsin serum levels. Radiological features in the lungs include predominantly lower lobe emphysema and bronchiectasis in relatively young patients. The condition can also cause liver cirrhosis. Emphysema and cirrhosis are common causes of death. Therefore, abdominal ultrasound is the correct answer as the patient will likely have signs of liver disease and if chronic, may have features of portal hypertension with splenomegaly, varices and ascites. Other conditions associated with alpha 1 antitrypsin deficiency include asthma, pancreatitis and panniculitis.
Gene Therapy for Acute Diseases of the Lungs
Published in Kenneth L. Brigham, Gene Therapy for Diseases of the Lung, 2020
As will be detailed below, alpha-1 antitrypsin gene therapy may also have use in acute lung diseases. In addition, increased expression of the enzyme, prostaglandin synthase, in the lungs can result in increased production of PGE2, an anti-inflammatoiy prostanoid, and can protect the lungs from acute injury in some experimental situations (18). In each of these cases, efficacy of gene therapy will depend mainly on maximizing expression of the transgene in the lungs, regardless of the cell population(s) targeted.
Gastroenterology
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
B: Hepatitis surface antigen-negative hepatitis. Viral infection: hepatitis C (HCV).CMV.EBV.Autoimmune chronic hepatitis: primary biliary cirrhosis.Metabolic/genetic abnormalities: Wilson disease.Alpha-1 antitrypsin deficiency.CF.Drugs such as isoniazid.
Alpha-1 antitrypsin deficiency: current therapy and emerging targets
Published in Expert Review of Respiratory Medicine, 2023
Oisín F. McElvaney, Daniel D. Fraughen, Oliver J. McElvaney, Tomás P. Carroll, Noel G. McElvaney
Alpha-1 antitrypsin (AAT) is a glycosylated protein produced mainly in the liver [1]. It first came to prominence in the 1960s when Laurell and Eriksson, in Malmo, Sweden discovered that a lack of this protein was associated with an increased risk for emphysema [2]. Further work showed that the major role of AAT in the lung was to inhibit neutrophil elastase (NE), an omnivorous protease produced by neutrophils, which is capable of digesting many structural components of the lung in addition to proteins involved in immunity and inflammation [3]. This led to the development of the protease-antiprotease theory of emphysema in which the antiprotease protection in the lung, mainly provided by AAT, is markedly reduced, either functionally, in theory by cigarette smoke, or quantitatively by AAT deficiency (AATD), leading to the unopposed action of NE and subsequent lung destruction [4–6]. Further work elucidated the liver disease associated with AATD [7] and determined that the major cause of low levels of AAT in the blood and lungs of people with AATD was due to polymerization and retention of misfolded AAT protein in the liver [8,9].
Recent advancements in understanding the genetic involvement of alpha-1 antitrypsin deficiency associated lung disease: a look at future precision medicine approaches
Published in Expert Review of Respiratory Medicine, 2022
Auyon J. Ghosh, Brian D. Hobbs
One of the greatest challenges in clinical management and research of alpha-1 antitrypsin deficiency (AATD)-associated lung disease is the dramatic heterogeneity in clinical presentation and course of affected individuals. Identification of genome-wide genetic modifiers of lung disease and development of a polygenic risk score can help further stratify AATD-affected individuals at the highest risk of developing lung disease. With improved disease prediction, clinical trials implemented in subsets of higher risk individuals have a higher likelihood of success. However, while a polygenic risk score has been developed in usual COPD, we acknowledge that the clinical utility of these approaches is yet unrealized. Translating the advance in knowledge from research to application in clinical care remains a barrier in both usual COPD and AATD.
Reduced 25(OH) Vitamin D Association with Lower Alpha-1-Antitrypsin Blood Levels in Type 2 Diabetic Patients
Published in Journal of the American College of Nutrition, 2021
Virginia M. Lindley, Kamal Bhusal, Laura Huning, Steven N. Levine, Sushil K. Jain
Circulating 25(OH)VD is considered a comprehensive and stable metabolite and can be used to diagnose 25(OH)VD deficiencies and monitor VD consumption [1, 2]. Deficient 25(OH)VD levels are associated with impaired lung function and chronic lung diseases [10–12, 14]. Diabetic patients have increased vascular inflammation and a higher incidence of COPD [14]. Alpha-1-antitrypsin (AAT) is a protease inhibitor produced mainly by hepatocytes [7–9]. Its deficiency, AATD, is characterized by a point mutation that leads to misfolding of the alpha-1-antitrypsin protein [7]. The liver is the main site of AAT synthesis, so when the misfolded proteins accumulate in the endoplasmic reticulum of the hepatocytes, proteotoxic consequences can occur, including fibrosis, cirrhosis, and carcinogenesis [7–9]. Vitamin D deficiency has been shown to result in significantly lower AAT expression in the lungs and emphysema in mice exposed to cigarette smoke [15]. However, there is no previous study that determined ATT levels in type 2 diabetes or examined whether there is an association between ATT deficiency and 25(OH)VD deficiency in T2D patients.