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What is Alpha 1 Antitrypsin Deficiency

 Alpha-1 antitrypsin deficiency (Alpha-1 or AATD) is an inherited genetic disorder that causes low levels of the Alpha 1 Antitrypsin protein (AAT) because a part of the AAT gets "stuck" in the liver cells. 
 

AAT is a protein principally produced by the liver, and plays various roles in the body:

  • AAT has an immunoregulatory and anti-inflammatory role, and a deficiency may cause autoimmune issues.

  • AAT provides an antiprotease protective screen throughout the body, but most importantly in the lung, where it can neutralize the activity of the serine protease neutrophil elastase. It’s effectively the off switch” for the enzyme called neutrophil elastase. Neutrophil elastase is important for fighting infections in the lungs, but it can also destroy your healthy lung tissue. After neutrophil elastase has had time to fight an infection, AAT shuts it off (inhibits) so it won’t damage your lungs. 

  • AAT is important in the process of remodeling and repair of the connective tissue like tendon, tendon sheath and ligaments. Elastase production increases with inflammation, and an individual with an AAT deficiency will have an increased probability of degradation of the connective tissue matrix, which may lead to decreased joint stability.

  • The AAT portion which gets stuck in the liver cells, causes a continues liver stress, a reduction in liver capacity, and it may lead to liver fibrosis and cirrhosis, especially at a mature age of >40 years, when the liver loses functional capacity through aging. (~35% loss at age 65)
     

​The result may lead to Lung issues, Autoimmune issuesJoint issues and Liver Issues in an individual with a deficiency.
 

The resulting liver issues (like a reduction in bile acid production) may also cause second and/or third order issues, like absorption issues in the small intestine, which in turn may cause vitamin and minerals deficiency issues causing e.g. neurological issues. These second and third order issues are hard to diagnose and trace back to an AAT deficiency. ​
 

Alpha-1-antitrypsin (AAT), is highly polymorphic, with more than 200 known variants and/ mutations.
The variants are designated by alphabet letters: the normal variant is called "M", whilst the most deficient variant is called "Z", which is abnormally conformed and is retained within the Hepatocyte cells of the liver instead of being regularly exported, and causes long term liver damage.
 

Two codominant alleles encode each 50% of the protein. Therefore, normal individuals with the "MM" genotype synthesize and regularly export two pools of "M" protein. (2x50%)

Although there are a larger number of variants the most known variants are;
MM – This is the normal variant which expresses 100% of the AAT protein
ZZ – The ZZ variant is the worst case variant and expresses only ~15% of AAT protein
MS – The MS variant expresses ~ 80% of the AAT protein
MZ – The MZ variant expresses ~ 50% of the AAT protein (~ 35Mil persons are affected world wide)

In case of the "MZ" genotype, about ~85% of the Z protein is retained within the hepatocyte cells together with ~6% of the "M" protein resulting in ~15% of the "Z" protein and ~94% of the "M" protein being exported in circulation. Besides the lower amount of AAT ~7% of the 55% is the not usable Z protein, resulting in ~48% usable AAT protein. It is also noted that the "Z" protein is suspected to be compromised in its anti-inflammatory properties. (In vitro)

The serum level of AAT is regulated by the Leukocytes (Neutrophils), which means that when you have an inflammation, the Neutrophils will increase, and as result the AAT will increase. You can see this nicely in the picture below for the different variants. (The CRP is a measure for the Inflammation)

You will find the related paper here

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