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alpha-1 antitrypsin deficiency is a
genetic disorder where a protein called
alpha 1-antitrypsin is defective or
absent the name alpha 1-antitrypsin is a
holdover from when the protein was
discovered a name given before its
function was actually known as it turns
out alpha 1-antitrypsin is a protease
inhibitor that inactivates elastase
which is a type of protease an enzyme
that breaks down other proteins since
alpha 1-antitrypsin inactivates elastase
elastase can't break down elastin so
alpha 1-antitrypsin deficiency leads to
the opposite case elastin breakdown
which particularly affects the lungs in
addition defective alpha 1-antitrypsin
can cause damage to the liver
now in the lungs let's zoom in on a tiny
alveolus which is where gas exchange
happens if there's some sort of
infection or other cause of inflammation
inflammatory cells like neutrophils
arrive on the scene neutrophils make an
enzyme called neutrophil elastase a
protease capable of breaking down
elastin which is an extracellular matrix
protein that gives elasticity and
strength to the lung tissues so while
these little guys can help fight off
infection by breaking down proteins of
the bacteria they can also go on to
break down that precious elastin
fortunately the liver makes alpha
1-antitrypsin which gets released into
the blood and sent to the lungs where it
inhibits neutrophil elastase in
activating it before it can break down
the protein elastin without alpha
1-antitrypsin the opposite happens
neutrophil elastase goes unchecked and
it damages the walls of the alveoli and
without that elastin the alveoli lose
their elasticity and structural
integrity zooming out a bit and looking
at the acid s which is a bunch of
alveoli it just turns into one big
cavity this destruction and enlargement
of the air spaces is called emphysema it
turns out that emphysema can develop in
a couple different ways and alpha
1-antitrypsin deficiency causes pan
acinar emphysema meaning the whole acid
s is affected and it also tends to
affect the lungs lower lobes the most
another effect of unchecked inflammation
in Elfa one antitrypsin deficiency is
chronic bronchitis in bronchiectasis two
conditions resulting from chronic airway
inflammation so alpha 1-antitrypsin
deficiency can lead to emphysema
bronchiectasis and chronic bronchitis
all types of chronic obstructive
pulmonary disease or COPD another more
common cause of COPD is smoking and if
someone with alpha 1-antitrypsin
deficiency also smokes they tend to get
an earlier onset of COPD than they would
have otherwise an example of a gene
environment interaction the gene that
encodes alpha one antitrypsin protein is
called sir panel one which stands for
serine protease inhibitor clade a member
one which is found on the long arm of
chromosome 14 while some mutations in
sir Pinot one completely about
the genes message meaning no protein
gets made others like the most common
mutation called Piz results in a miss
folded alpha one antitrypsin protein
being made miss folded alpha one
antitrypsin can aggregate and get stuck
in the endoplasmic reticulum of the
liver hepatocyte swear it's made causing
some of those cells to die
now each wild-type or normal copy of
alpha one antitrypsin protein termed P I
M contributes 50% of normal alpha
1-antitrypsin or a 180 activity meaning
two normal copies gets you 100% which
just means that there's a normal amount
of alpha 1-antitrypsin in the blood if
instead they had one normal copy in one
mutant copy or z abbreviated PMZ the
mutated gene only contributes about 10%
of normal amounts so these individuals
only have about 60% the normal levels
which is usually enough to protect the
lungs in non-smokers if both copies of
the gene were mutant Z copies then
typically there's only 15 to 20 percent
of normal levels which results in alpha
1-antitrypsin deficiency while there is
some increased risk of lung and liver
injury in P imz individuals severe
deficiency with these two mutant genes
gives these individuals a much higher
risk of lung and liver disease
having said that though some people with
Piz Z deficiency can live their entire
lives with no longer liver disease if
their environmental exposures are
minimal symptoms of alpha 1-antitrypsin
deficiency typically involve the lungs
and liver the changes in the lungs that
cause chronic obstructive pulmonary
disease can result in shortness of
breath as well as wheezing mucus
production in a chronic cough the death
of liver cells can ultimately lead to
cirrhosis a process in which normal
liver tissues replaced with scar tissue
cirrhosis can ultimately lead to a
number of complications including an
inability to make coagulation factors
difficulty with detoxification leading
to a buildup of waste products that can
cause hepatic encephalopathy portal
hypertension that can lead to esophageal
varices and an increase in the risk of a
type of liver cancer called
hepatocellular carcinoma although
cirrhosis usually affects adults even
newborns can have complications like
jaundice which is a buildup of bilirubin
in the blood because of poor excretion
by the liver a very small minority of
infants who are born with 2z genes can
develop liver failure during their first
years of life and require a liver
transplant if though somebody has a
mutant syrup you know one that results
in no alpha 1-antitrypsin as opposed to
the misfolded ones that gets stuck then
they typically don't have liver disease
diagnosis of alpha 1-antitrypsin
deficiency often starts with a chest
x-ray or chest CT scan to look for
hyper-inflated lungs or evidence of
damaged lung tissue in addition
pulmonary function testing can be used
to measure how quickly air exits the
lungs which can be slower than normal
the level of alpha 1-antitrypsin in the
blood can also be measured cirrhosis
caused by alpha 1-antitrypsin can be
diagnosed with liver ultrasound or a
liver biopsy
when evaluating a biopsy microscopic
sections of liver tissue are stained
with a combination of two reagents
called periodic acid Schiff or pas this
test stains glycoproteins like alpha-1
antitrypsin a pink color the tissue is
also exposed to dye a space what is an
enzyme that normally destroys a lot of
glycoproteins but since alpha
1-antitrypsin is stuck and hidden away
in the endoplasmic reticulum the eye
states can't get to it and so it's
diastasis resistant so we say that they
be periodic acid shift+ or pas positive
as well as diastasis resistant in terms
of treatment augmentation therapy is
where you give intravenous infusions of
normal alpha 1-antitrypsin protein
purified from the blood of healthy
plasma donors this doesn't cure the lung
disease but it does slow or halt its
progression so other therapies for
chronic obstructive pulmonary disease
like inhalers and supplemental oxygen
are often needed as well supplementing
the deficient protein in the blood
doesn't fix the liver problems since
they're caused by defective alpha
1-antitrypsin building up in the
hepatocytes so standard treatments for
cirrhosis are usually needed like
lactulose to prevent hepatic
encephalopathy all right as a quick
recap in alpha 1-antitrypsin deficiency
the alveoli in the lungs are damaged by
neutrophil elastase since there's
insufficient alpha 1-antitrypsin to
counter it causing chronic obstructive
pulmonary disease and in the liver
misfolded alpha 1-antitrypsin builds up
killing hepatocyte sin leading to
cirrhosis
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