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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).
Inherited Differences in Alpha1-Antitrypsin
Published in Stephen D. Litwin, Genetic Determinants of Pulmonary Disease, 2020
Laurell and Eriksson [65] and Eriksson [66] first reported the association of alpha1-antitrypsin deficiency and pulmonary emphysema. In a large group of patients subsequently reported [32] Eriksson pointed out what seemed to be the characteristic features of the disease. The first symptoms began before 40 years of age in 60% and before 50 years of age in 90% of affecteds. Of 33 patients (17 men and 16 women) with alpha [-antitrypsin deficiency (defined as 10-15% of the normal mean concentration of a PiM phenotype), definite evidence of chronic obstructive pulmonary disease (COPD) was found in 23 (15 men, eight women). Recurrent episodes of respiratory infections were infrequent in this group; about 50% had "primary" emphysema.
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].
Experimental and investigational drugs for the treatment of alpha-1 antitrypsin deficiency
Published in Expert Opinion on Investigational Drugs, 2019
Alpha-1 antitrypsin deficiency (AATD) was first described when absence of the α1 band on protein electrophoresis of serum taken from a patient at a local respiratory hospital was associated with early onset emphysema [1]. AATD is also associated with chronic obstructive pulmonary disease (COPD), bronchiectasis [2], liver fibrosis and cirrhosis [3], vasculitis [4] and panniculitis [5]. Although AATD represents a predisposing factor for all of these phenotypes, not all subjects develop disease. Some variation in clinical presentation may be due to environmental factors, such as cigarette smoking or pollution [6], but there may also be genetic modifiers [7]. The diagnosis is usually made after investigation of pulmonary or liver disease. Currently, neonatal screening, which would allow diagnosis at birth, rather than when symptoms of disease develop is not adopted in routine practice. The classical presentation is with breathlessness and cough, similar to all COPD, though often at a younger age or with less smoke exposure [8].