A1 antityrpsin deficiency Flashcards
Where is the antitrypsin gene located?
On chromosome 14
What is antitrypsin secreted from?
hepatocytes
What is antitrypsins role?
Plasma proteins that act as a serine protease inhibitor
Protect the tissue from protease attack
Inhibits a proteolytic enzyme neutrophil elastase (released at sites of inflammation)
Forms a 1:1 complex with elastase (known as a malloproteinase 8 (MMP-8)
What is the reactive centre specific for?
Elastase
The elastase recognises Met358
after binding and being cleaved, elastase remains covelently attached
The complex associates with a a2 macroglobulin and is removed from circulation by the liver and spleen
What is a1-antitrypsin associated to?
Panniculitis
What is Panniculitis?
Panniculitis is a group of diseases whose hallmark is inflammation of subcutaneous adipose tissue (the fatty layer under the skin - panniculus adiposus)
What is classed as a deficiency of a1 antitrypsin?
low level of plasma (15% off normal)
normal level 1.1-2.1 g/L
Having a low level of plasma leads to…
Emphysema
Hepatocellular damage
What is the deficiency due to?
An autosomal recessive disorder
The gene is highly polymorphic with more than 90 alleles in european population
What is the major genotype varient?
Pi (chromosome 14) MM (PiMM)
What are the abnormal types of varient?
Z and S
on Z, glutamic acid (pos,342) is converted to lysine (E342K)
Opens B sheet structure
Meaning a reactive loop of another Z structure can also insert
What is the epidemeology of A1 antitypsin deficiency?
1/3000 have ATT deficiency
1-3% of those have COPD aswell
ATT deficiency can be associated to…
Neonatal jaundice: 15% of Z genotype present, with 50% resolving and 30% progressing to cirrohisis and death by the age of 20
In smokers is the disease more severe or less?
More severe
What enviromental factors make ATT deficiency worse
Smoking
Smog
Use of Oxygen
