00:01
Welcome.
00:02
With this talk we're
going to be covering
a rather interesting topic of
hereditary hemochromatosis.
00:09
Hereditary
hemochromatosis, or HH
is an autosomal
recessive disorder.
00:13
And it's caused
by gene mutations
primarily in the iron sensing
apparatus in the liver.
00:20
That will lead in turn to a
low production of hepcidin,
which is the major hormone that
regulates systemic levels of iron.
00:27
And if we don't make
enough hepcidin,
because we're not
sensing it appropriately,
that results in increased
iron absorption.
00:35
Let's cover some of
the epidemiology.
00:37
It is a reasonably
common entity,
HH.
00:42
It's about one and
200 to 500 people,
it's much more common people
of Celtic or Nordic origin,
the most common mutation
is a cysteine to a
tyrosine substitution
at amino acid 282
is called C282Y.
00:57
And it's in the HFE protein,
otherwise known as the human
homeostasis iron regulatory protein
that's going to be part of the
sensing apparatus in the liver.
01:07
That's the most common
mutation in patients with HH.
01:11
In about 85% of patients
will be homozygous for
the C282Y mutation.
01:18
You probably don't need to
memorize the exact mutation.
01:22
But you do need to understand
that this is in the sensing
apparatus in the liver
and the liver is
going to be the major
overall regulator
of iron levels.
01:30
It's also the liver is going
to be one of the major organs
most negatively impacted
by too much iron.
01:40
Overall, HH is going
to be much less common
in people of African descent,
it occurs more frequently
or seen and expressed
more frequently in
men than in women.
01:50
That's probably in
part because women
who go through regular
menstrual cycles
are regularly losing blood,
and therefore don't have
an iron accumulation.
02:02
The age of onset in men
is after the age of 40.
02:05
So it takes a while for
you to accumulate iron
to the point that you
become symptomatic.
02:10
In women, it's going to be
after the childbearing years
after they're no
longer menstruating
where they can now
accumulate the iron.
02:17
There is a form of HH that's
juvenile hemochromatosis,
or the onset is at
a much earlier age.
02:25
The pathophysiology.
02:27
So the common missense mutation
is just a change from
one amino acid to another
as the cysteine
282 to a tyrosine.
02:35
There are other mutations
in the same sensing protein,
the HFE protein,
such as a histidine,
to aspartic acid and amino
acid position number 63,
both of these change the ability
of that protein to participate
in the iron sensing apparatus.
02:54
There are also
other non HFE genes.
02:57
So there are several
proteins that are involved
in the sensing apparatus.
03:01
Most of the other mutations
in these other proteins
are relatively rare,
but they are found in
juvenile hemochromatosis,
and particularly a mutation
or protein called hemojuvelin.
03:14
To really understand
what's going on here,
we have to understand
normal iron homeostasis.
03:20
We have a schematic
of the GI tract,
and it's connected by the
portal circulation to the liver.
03:27
Iron is absorbed in the duodenum
about 1-2 mg per day.
03:32
We only lose about
1-2 mg per day.
03:35
So it is a very tightly
regulated loss and absorption.
03:43
The absorption is
occurring in the duodenum,
that's the only place that
we get iron absorption,
and the iron is being
absorbed by the enterocytes
by the duodenal
epithelial cells.
03:55
What is happening is that a
protein called ferroportin
on the basal surface
of the enteroctyes
allows the iron to
move from the GI tract
from the duodenum where
it's been absorbed
and into the bloodstream
and that iron then binds
up with transferrin
in is then circulated
around the body.
04:16
So we need to have
that ferroportin
to act as a mechanism to get
the iron from the enterocytes
into the bloodstream.
04:25
From the bloodstream
bound to transferrin
and the iron will go to bone marrow
into a variety of other tissues.
04:32
So the total iron content is
four grams roughly in the body.
04:37
We're only changing
about 1-2 mg each day,
absorbing and loss.
04:43
Most of the iron ends up
going to the bone marrow
and his skeletal muscle.
04:48
So in the bone marrow,
the iron is going to
erythroid precursors
eventually going to
become red blood cells.
04:56
In skeletal muscle,
it's going to myoglobin.
04:59
And basically 70% of
the total body iron
is in these two areas,
red cells and skeletal muscle.
05:07
But there's a substantial
amount of iron
in other places within the body.
05:11
And in particular, the
liver can be a major store.
05:15
It's also going to be
a mechanism a buffer,
by which too much
iron will be taken up
and tried to protect the rest
of the organs in the body.
05:24
Another place where iron is
stored is within macrophages.
05:28
And in both of these
storage places,
the iron is stored
in association with
an intracellular
protein called ferritin.
05:35
So we're still talking
about normal activities,
in terms of the iron absorption.
05:40
Here we have our iron
within the duodenum,
and it is going to be
transported via ferroportin.
05:47
Now the liver can
say, you know what,
everybody, we have enough iron,
we don't need any more iron.
05:55
And when we are replete,
the liver releases a
protein called hepcidin.
06:01
Hepcidin circulates
in the bloodstream
and when it interacts
with ferroportin,
it causes the down
regulation ferroportin
on the basal surface
of enteroctyes.
06:12
Hmm.
06:13
Now, iron cannot be transported
across into the bloodstream.
06:19
So they hepcidin is now allowing us
to keep that iron in the GI tract.
06:23
And when it goes
in the GI tract,
you just defecate it out
and you're not absorbing it.
06:29
And that's how we
regulate normal iron.
06:33
However, if we don't
have normal sensing,
and we don't make hepcidin
at the appropriate levels,
we won't cause the down
regulation of the ferroportin
and now the iron happily just keeps
going across into the bloodstream
at very high levels.
06:50
And we just keep absorbing
and absorbing and absorbing.
06:53
So if we don't sense iron
appropriately in the liver,
or we don't make
hepcidin appropriately
in response to
that iron sensing,
then we absorb in the
duodenum too much iron.
07:05
When that happens, we have
hereditary hemochromatosis.
07:10
So instead of just one
to two mg of iron a day,
we double that,
and that excess
iron accumulation
accumulates in the liver
and again the liver is going
to be a very important storage
overall for the iron.
07:23
And in many ways we'll protect the
rest of the body by taking it up.
07:27
But too much iron
is going to end up
being pathologic.
07:32
There can be other causes besides
a primary defect in sensing
or in hepcidin production.
07:39
So secondary iron
overload can occur
when we just take
in too much iron.
07:44
Main way this happens is
with increased transfusions.
07:48
We may also have
ineffective erythropoiesis
where we don't turn over
the iron appropriately,
and it will accumulate.
07:55
If we lose hepatocyte mass,
then we also reduce our
capacity to make hepcidin
and so in chronic liver
disease and cirrhosis,
patients will tend
to have less hepcidin
and tend to absorb
more iron as a result.
08:10
The iron regulation is mediated
by a variety of proteins.
08:13
The iron sensing involves the
HFE gene that we've talked about.
08:17
It involves the
transferrin receptor
to and involves hemojuvelin
and those are the
sensing apparatus
and then the product
when the liver says,
we have enough iron is hepcidin.
08:32
Another way to kind
of think about this
with increased iron,
the hepcidin goes up,
that reduces the amount
of iron that we absorb.
08:40
It's interesting with
increased inflammation,
hepcidin also goes up.
08:45
And the thought
is teleologically.
08:47
This is to limit the iron
availability to micro organisms.
08:50
So it turns out, hepcidin
is an acute phase reactant.
08:54
And whenever there is
systemic inflammation,
we tend to reduce
iron systemically.
09:01
You may hear of the
anemia of chronic disease.
09:05
That's because
chronic inflammation
leads to increased
hepcidin and production
and reduced iron absorption.
09:12
If you have increased
erythropoietin,
that's a signal that we need,
and this the signals
coming from the kidneys.
09:19
That's a signal that we
need to make more red cells.
09:22
In that setting, we want
to reduce the hepcidin
that so we get more
iron absorption
and more iron going into
the hematopoietic precursors
so that we can make
more red cells.
09:32
So hopefully this all
kind of makes sense.
09:36
In hereditary hemochromatosis,
the gene mutations involve
abnormal sensing of iron
levels in the liver.
09:44
And when they don't
sense it appropriately,
they don't realize that gee,
we're iron replete,
we have enough.
09:51
And so there's not
enough hepcidin produced
and as a result, the
duodenum absorbs more iron.
09:58
With increase iron absorption,
we get a progressive increase in
intracellular iron bound to the ferritin
and that's going to
be within macrophages,
and it's going to be within
the liver for the most part.
10:08
But then increased iron results
in excessive oxidative stress
because basically, it can
induce oxygen free radicals,
leading to cell injury,
and leading inflammation
and eventually organ damage.
10:22
Now, the main organs that
are going to be affected
is where iron tends
to accumulate,
the liver is going to be a
major site of accumulation,
but many other
organs in the body
with excess iron floating around
will also eventually
accumulate iron.
10:36
So it can go to the brain,
it can go to the heart,
it can go to the pancreas
and go to the skin.
10:41
And we're going to see those
manifestations in a moment.