00:01
Welcome, in this talk,
we're going to be
covering an entity
called Alpha-1
Antitrypsin Deficiency,
or AAT.
00:08
This is going to be a disorder
that largely affects the liver
but can also have
manifestations in the lung.
00:15
Alpha-1 antitrypsin deficiency
is an autosomal disorder,
resulting in reduced production
and function of the protease
inhibitor Alpha One antitrypsin AAT.
00:27
Let's look at the epidemiology.
00:29
So this is not super common,
but it's something that
you should recognize
about 1 in 2000 live
births is the incidence.
00:38
It can be diagnosed as early
in life as two months of age,
and is the most
common genetic cause
of pediatric hepatic pathology.
00:47
It can lead to
chronic liver disease.
00:49
Patients with Alpha-1 antitrypsin
deficiency can develop cirrhosis.
00:53
But also importantly,
it is a cause of emphysema,
and typically emphysema occurring
either at an earlier age
than one would expect
or in a nonsmoker.
01:06
So what's the
pathophysiology of this?
The severity overall of the
disease depends on the genotype
of the protease
inhibitor SERPINA1.
01:20
And if you make more
of the SERPINA1,
you are in better shape.
01:24
If you make less of it,
or it's functionally impaired in terms
of its protease inhibitory activity,
you're in worse shape.
01:32
So this is an autosomal
gene, the SERPINA1,
and it is an autosomal
recessive disease.
01:39
So if you just have
one mutated copy,
in the vast majority
of cases, you're fine.
01:43
But if you have one
mutated copy from mom,
and even a different,
mutated copy,
mutated in a different
region from dad,
then you are at increased risk.
01:58
Pi stands for
protease inhibitor.
02:01
So this is an
ancient nomenclature.
02:04
It's based on what we can do in
terms of protein electrophoresis.
02:09
So this is before we
understood what was going on,
but we will look at
various proteins.
02:14
So Pi is protease inhibitor,
and MM is the wild type.
02:18
So that's the normal
100% level of expression
of a normal functional
SERPINA1 protein.
02:26
The typically mutated
alleles are called S and Z.
02:30
There are other mutations,
there are actually a whole
bunch of different mutations,
but we're going to
just look at S and Z.
02:35
If you are P i M and S that
means you're a heterozygote.
02:38
You will have about 80% of
the level of expression.
02:42
And in most cases,
you will have a modest
increase for lung disease
but not really significant.
02:47
But if you're PiSS,
so to mutated alleles,
or PiMZ or PiZZ,
Z is actually the lowest
level of expression
and is going to be the
most severe disease.
03:01
So you can kind of work
through in your own mind
if I'm PiMS or PiSS,
and I'm gonna say
what that spells,
PiMZ, PiSZ, etc,
those are all going to
be about 50% activity.
03:16
And then if you are PiZZ,
so the least level in the least
functionality of the protein,
you have the most severe disease
involving both the
lung and the liver.
03:29
So the mutated gene is making a
protein the Alpha-1 antitrypsin,
the gene may also have impact on
how much has been synthesized,
but the normal protein has to go
through a conformational folding
that goes on and rough
endoplasmic reticulum,
and then it is
excreted from the cell.
03:52
If there are mutations,
there's misfolding
that tends to retain the
abnormal misfolded protein
within the
endoplasmic reticulum.
04:01
So this is just a demonstration
of that happening.
04:04
The misfolded
Alpha-1 antitrypsin
is retained in the grid and
in the endoplasmic reticulum
and if you have a relatively
low level of this,
if you're a heterozygote,
your ER in your liver is more or
less able to accommodate that.
04:20
However, if you have
significantly elevated levels
of misfolded protein
or certain forms of
misfolded protein
that trigger more of the
misfolded protein response,
the ER stress response,
then you can get apoptosis
of the hepatocyte.
04:38
The liver cell just gives up
because it says we are
unfortunately overwhelmed
with misfolded protein.
04:45
And if you're interested
in this process,
I refer you back to the basic
cellular pathology talks
that are elsewhere within
the Lecturio portfolio.
04:56
Now, that's what's
going on in the liver,
and that's why you can have
cirrhosis and liver damage.
05:02
But what about not making enough
of this normal protein to
get out into the circulation?
Well, normal Alpha-1
antitrypsin is an anti protease.
05:12
It's going to protect alveoli
and other tissue structures
from the noxious effects
of released exoproteases,
from neutrophils.
05:22
So neutrophil elastase and
some of the other proteases
are inhibited by
Alpha-1 antitrypsin.
05:28
If you don't have
enough of that,
every time you release
neutrophil activity,
you will get more damage than
you would otherwise normally get.
05:36
And when this happens in lung,
this is going to give
rise now to emphysema
with big dilated airspaces
due to the effects of elastase
degrading the normal interstitium.
05:49
How does this
clinically present?
So it presents in
two different organs
at kind of two different times.
05:54
In the liver,
with patients who are going
to have severe disease,
it's usually neonatal
within the first few months.
06:01
There is impaired
coagulation factor synthesis,
so there's bleeding,
there'll be bleeding
from the umbilical
stump, from the GI tract,
from the intracranial space.
06:08
So injury, trauma
associated with childbirth
may lead to bleeding
around the brain,
or any unexplained bruising.
06:15
So it's kind of a signal that
something may be going on
with regards to a liver.
06:21
There will also be
inflammation of the liver
due to the ongoing injury
and a hepatocyte death.
06:30
And then we're also going
to get cholestatic jaundice.
06:32
So the baby will be
bleeding, and will be yellow.
06:35
Again, additional liver findings
in the pediatric population.
06:39
It is a progression
to cirrhosis.
06:41
And if you want to
know about cirrhosis,
that is another talk within
this GI pathophysiology series.
06:48
There will hepatomegaly,
splenomegaly, ascites,
esophageal varices,
scleral icterus.
06:54
And if you're interested
in any of those,
go to that other
talk on cirrhosis.
06:59
In the lungs,
now this is not in
the neonatal period,
but in later life,
there will be beginning in the second
third and fourth decade of life,
signs of emphysema,
coughing, dyspnea,
chronic sputum production,
wheezing associated with a loss
of interstitial parenchyma.
07:16
How are we going to
make the diagnosis?
This is going to be largely based
on: one, clinical suspicion,
but two, we're
going to do testing
looking for the levels of Alpha-1
antitrypsin in the bloodstream.
07:29
We will then do a
genetic analysis
and try to assess whether
we have an S mutation
or a Z mutation,
and whether we have a
heterozygote or homozygote.
07:39
We want to clearly assess
for the degree of
pulmonary disease
in addition to
the liver disease,
and liver disease, we're gonna
look at a variety of liver markers.
07:49
But we're also going
to do a biopsy.
07:50
And this is just showing you a
very characteristic appearance
on the liver biopsy.
07:55
It is a periodic acid-Schiff
stain or a PHS shiff stain
that is highlighting
glycoprotein.
08:01
And what we're seeing
in the hepatocytes
are these big pink globules.
08:06
Those are misfolded,
Alpha-1 antitrypsin glycoprotein
within the endoplasmic reticulum,
and cells that have
these big accumulations
will eventually
undergo apoptosis,
due to the ER stress
response and they will die.
08:23
How are we going to manage this?
So it's going to be
supportive treatment.
08:26
For lung disease,
we're going to want
to give vitamin E
and that's thought to reduce
the amount of inflammation
and free radical damage that
is going on in the lungs.
08:36
That is not really supported
by studies but it doesn't hurt.
08:40
We will want to have
the patient stop smoking
because smoking will
recruit the neutrophils
which will release -
which will exacerbate
the emphysema
and we don't want that.
08:52
We will try to prevent
them getting infections.
08:55
So every vaccination possible
against a respiratory illness,
influenza pneumococcus, COVID,
other things will be
something that we recommend
and strongly try to enforce.
09:07
And we also want to minimize
if at all possible any injury
to the liver from other sources,
such as hepatitis.
09:18
For pulmonary form only.
09:19
So, in many of the patients who
have Alpha-1 antitrypsin deficiency,
the accumulation of the
protein in the liver
is not sufficient to trigger
the ER stress response.
09:33
And so the liver
is largely okay,
but they can still have
severe lung disease.
09:37
So for those pulmonary forms,
only we can give exogenous
Alpha-1 antitrypsin.
09:43
For very severe forms, patients
may be eligible for liver
and or lung transplantation.
09:50
So with that,
an uncommon entity that
you should recognize
and it has a really interesting
kind of pathophysiology:
Alpha-1 antitrypsin deficiency.