This document summarizes alpha-1 antitrypsin deficiency, an autosomal recessive disease caused by mutations in the SERPINA1 gene encoding alpha-1 antitrypsin. The most common mutation, called the Z allele, causes the protein to accumulate in liver cells, reducing levels in the blood and lungs. This allows an enzyme called elastase to break down lung tissue, causing emphysema. Smoking greatly exacerbates this risk. The mutation also causes liver disease, as the accumulated protein damages liver cells. While augmentation therapy can help, lung or liver transplantation may be needed for severe cases. Levels of alpha-1 antitrypsin also increase in a severe eye condition called vernal keratoconjunct

2. Mutation of an enzyme inhibitor
Autosomal recessive disease.
It is excessive in hepatocytes, consequently it
is decreased in blood and lungs.
Causes emphysema, COPD (chronic
obstructive pulmonary disease), and liver
cirrhosis.
Alpha 1 antitrypsin is a protein that inhibits
enzyme activity of elastase, which breaks
down neutrophil elastin(elasticity) in the
lungs.
Present in white populations, 1 in 5000 people
are affected and 2% are carriers.

4. Genetics:
Alpha 1 antitrypsin belongs to protease
inhibitors or serpins.
Serpina 1 is a gene that translates the
alpha 1 antitrypsin on chromosome
14q32.
Normal allele is “M”.
A missense mutation in exon 5
produces the mutant allele “Z”
(glu342lys)

5. In heterozygotes, blood levels of alpha 1
antitrypsin are reduced between 40% and
60%, which is sufficient to protect the lungs
in people who don’t smoke.
In homozygotes, alpha 1 antitrypsin levels
are less than 15% of normal and patients are
likely to develop emphysema at a young age,
50% of these will develop liver cirrhosis,
because it is accumulated in the liver and not
secreted well.
17% of homozygotes present with neonatal
jaundice and 20% of this group develop liver
cirrhosis.

6. Liver disease is caused by a novel property
mutation.
Mutation in “Z” allele causes alpha one
antitrypsin polymers to aggregate in
hepatocytes in a form of long bead like
shaped necklaces, which cannot be
released into the plasma anymore,
consequently it accumulates in the liver
and cause liver cirrhosis.
Note: it is a conformational disease,
because its shape or size will change and
become disposed in one place.

8. Two mechanisms contribute to the imbalance
between elastase and alpha 1 antitrypsin:
1. Only 15% of normal plasma
concentration of alpha 1 antitrypsin is
present.
2. Its activity is decreased, alpha 1
antitrypsin has only about 20% of the
ability of the normal alpha 1 antitrypsin
to inhibit elastase.

9. It is an ecogenic disorder:
It is greatly affected by
smoking, survival of 60% in
non smokers and 10%
survival in smokers.
This is caused by oxidation
of the active site
methionine 358 by
cigarrete smoke and
inflammatory cells, thus
reducing its affinity for
elastase 2000 fold.

10. Treatment:
Augmentation therapy (intravenous
infusions-replacement strategies).
Liver or lung transplantation
No smoking

11. VKC ( vernal keratoconjunctivitis) is a severe allergic disorder
that causes inflammation of the conjunctiva .
It was discovered that there is a rise in blood concentration of
alpha 1 antitrypsin when someone has VKC.
Conclusion: inc. and dec. of alpha 1 antitrypsin concentration in
the blood, can be used as a prognosis for VKC.

12. Bibliography:
-Ahsan A1, Salman KA2, Alam S1, et al, Alpha-
1 antitrypsin, a diagnostic and prognostic
marker of vernal keratoconjunctivitis,
8(5):CC08-10. doi:
10.7860/JCDR/2014/6342.4362, 2014 May, J
Clin Diagn Res. PubMed.
-By Robert L. Nussbaum, Roderick R. McInnes,
and Huntington F. Willard, alpha 1 antitrypsin
deficiency: mutations of an enzyme inhibitor,
358-359, AUG 2007, Thompson and Thompson
GENETICS IN MEDICINE.