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12 Cards in this Set
- Front
- Back
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A1AT Description |
Gene is located on Chromo 14 and known as the Pi gene Acute phase protein AKA Alpha-1protease inhibitor Glycoprotein secreted mainly by hepatocytes Circulates in plasma 52kDa Plasma protein that acts as a serine protease inhibitor |
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Role of A1AT |
To protect tissues from serine protease attacks Inhibits the proteolytic enzyme neutrophil elastase which is released at sites of inflammation Forms a 1:1 complex with elastase Natural substrate for elastase is elastin |
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Binding to Elastase |
Elastase recognises Met358 After binding and being cleaved elastase remains covalently attached This complex with alpha 2-macroglobulin is removed from circulation by the liver and spleen |
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Deficiency |
Discovered in 1960's Alteration in A1AT preventing release from hepatocytes and to build in ER Patient have low levels in plasma (less that 15%) -Normal range 1.1 to 2.1g/L Recessive disorder Gene is highly polymorphic over 90 variations in European populations Normal type is M (PiMM) Abnormal types are Z and S |
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Mutant Variation |
In Z Glu is converted to a Lys This opens the beta sheet structure The reactive group of other Z structures can also insert Leads to polymerisation Sometimes the protein can accept its own beta sheet rendering it thermostable and inctive |
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Epidemiology |
1 in 5000 have A1AT deficiency 1 in 500 in Denmark 5% of patients with COPD have A1AT Def 15% of Z genotype have neonatal jaundice Smoking accelerates the degradation of elastin in lungs PiSS: 50% will die by 70 PiZZ: Smokers by 40, non-smokers by 60 |
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Emphysema |
Weaken and collapsed air sacs with excess mucus Lack of elastin leads to damage of the lung tissue |
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Liver Disease |
The build of A1AT in ER of hepatocytes results in toxic function mechanisms this can lead to: Cirrhosis Liver damage Liver carcinomas Patients are more prone to hepatitis infections |
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Environmental Factors |
Smoking Air pollution Use of oxygen Oxidative stress |
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Dignosis |
Chest x-ray Pulmonary function Liver function tests Blood levels of A1AT Genotyping Isoelectric focusing |
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Treatment |
Stop smoking Avoid pollution Bronchodialators A1AT Replacement therapy (not approved in UK) Extreme measures: Lung training, transplant of liver or lung |
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A1AT Replacement therapy |
Prolastin is an example Approved in US and most european countries Costs £100,000 year and life long treatment Debates over long-term effectiveness against other treatments. |
