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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
If the therapeutic transgene product is a secreted protein or is an enzyme that catalyzes production of a therapeutic substance that exits the cell and acts on other cells, then the delivery system should maximize production of the transgene product, but the population of cells expressing the transgene is less critical. In fact, the first human trials of gene therapy were done by removing cells from the patient, engineering them in vitro to express the normal adenosine deaminase gene (a secreted protein) and then returning the cells to the patient (16). In the lung, the analogous genetic disease is alpha-1 antitrypsin deficiency. In that case, if sufficient extracellular concentrations of the deficient protein could be achieved, it might be relatively unimportant where the protein was produced (17).
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.
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.
Obstructive lung diseases and risk of rheumatoid arthritis
Published in Expert Review of Clinical Immunology, 2020
H. Maura Friedlander, Julia A. Ford, Alessandra Zaccardelli, Alexsandra V. Terrio, Michael H. Cho, Jeffrey A. Sparks
COPD is defined by the presence of chronic, irreversible airflow limitation in the presence of risk factors and absent other etiologies of [88]. COPD includes chronic bronchitis and emphysema. Heavy smoking is a well-established risk factor for COPD, but up to 25% may have relatively low smoking history or never smoked [89]. Other inhalants such as pollution and occupational exposures may also contribute to COPD risk. Patients with COPD may also experience heterogeneous disease severity, some with relatively mild shortness of breath or cough and some that progress to respiratory failure and death [90]. A small minority of patients may have alpha-1 antitrypsin deficiency [91]. Patients may also have asthma-COPD overlap syndrome, which presents as clinical symptoms of both asthma and COPD [92]. The pathogenesis of COPD involves neutrophil and macrophage infiltration with smoking as a strong environmental factor [93]. It has been shown that there are higher levels of citrullination in COPD patient lung samples compared to patients with no airway disease [94]. Patients with COPD are also more likely to produce autoantibodies to a broad spectrum of self-antigens, which may increase susceptibility to RA [95]. Prior research has also found RA to be significantly associated with subsequent risk of developing COPD [96]. A phenome-wide association study found an association between HLA-C and autoimmune diseases and bronchiectasis, suggesting a genetic link between autoimmune disorders and obstructive lung disease [29].
Pharmacogenomics of chronic obstructive pulmonary disease
Published in Expert Review of Respiratory Medicine, 2019
The diagnosis and treatment of alpha-1 antitrypsin deficiency is the only fully developed application of COPD ‘pharmacogenomics’, although the disease was discovered based on protein phenotyping before the gene was identified. A substantial research effort is still needed to provide additional evidence for further COPD pharmacogenomics. Discovery-based studies, including GWAS, gene expression profiling, and whole genome sequencing, will be required to identify predictors of drug response. These studies will need appropriate subject consent and sample collections in COPD clinical trials. Ideally this research will leverage existing data from large COPD observational studies, such as COPDGene [109] and SPIROMICS [110], and from population-based studies, such as the U.K. Biobank [111], for discovery and validation. Large-scale COPD pharmacogenomics studies will require collaborations between academic and industry partners.