00:01
Students always confuse the amount
of iron in microcytic anemia.
00:06
What does that even mean?
You shall see in sideroblastic.
00:10
There is absolutely no issue with
iron deficiency, yet it’s microcytic.
00:15
Let’s begin with MCV being less than 80
and we also began here with a
pretty prolonged and elaborate
conversation and discussion
of things that you need from biochemistry
so that the pathology makes sense.
00:30
Not to worry, I’m going to walk
you through every step of this.
00:33
So that by the time you go from start
to finish, you have a complete picture
of what sideroblastic anemia means
and along the way, you are then –
I am then going to point out to you a
couple of other interesting points
of what’s known as you porphyria pathway
and porphyria diseases from biochem.
00:55
Okay.
00:56
First and foremost,
please know where we are.
00:59
We’re in the bone marrow
and the fact that you even
have a nucleus in an RBC is --
Well, what kind of
RBC would this be?
Tell me about your RBC
that’s in circulation.
01:10
It is naked.
01:11
What does that mean?
It has no nucleus and
it has no mitochondria.
01:16
The only method by which iron
can then derive its energy from
would be anaerobic glycolysis and
it would then protect itself
by utilizing what’s known as your G6PD
pathway and your hexose monophosphate.
01:30
Are we clear about what a
normal RBC should look like?
And I showed you a picture earlier
in iron deficiency with the normal,
where it looks
pretty transparent.
01:38
The only thing that it truly
contains is hemoglobin.
01:41
Okay.
01:42
Enough discussion
about normal RBC.
01:44
So this is a nucleated RBC
and if you were to find this in your circulation,
that definitely would mean pathology.
01:51
But here, let’s go with normal though.
01:53
You have a nucleated RBC and
this would be located where?
Good, in your bone marrow.
01:58
Remember that RBC goes through the
production and the progression into maturity
which means that you have your erythroblast
and normoblasts, reticulocyte,
and then you have your –
everything has been plucked out,
meaning that the nucleus
has been plucked out
and the mitochondria
is not there anymore.
02:16
And so what this is is –
The gray shaded area that you see is
going to be inside the mitochondria.
02:24
And then, we have the cytosol, which
you see outside here at the bottom.
02:28
You see that, okay?
Identify where you are.
02:31
At first, we’re in our bone marrow
and we’re trying to produce what?
We’re trying to produce
hemoglobin, okay?
So in the nucleus,
and so that we can properly, properly,
equip the RBC with the hemoglobin
that it requires for oxygen
transport basically.
02:46
That’s what an RBC does.
02:48
It’s the truck, right?
The transporter of
oxygen to your tissue.
02:52
Let's begin at the top.
02:53
Now, so here’s my transferrin
and it’s a delivering.
02:55
I’ve told you this a few times now.
02:57
The transferrin is going to then deliver
the iron to the bone marrow, doesn’t it?
In the meantime
though, in your RBC,
you can have bone marrow macrophages
and we’ll go ahead and call that
ferritin or iron containing substances.
03:11
Keep that in mind please.
03:13
Because that’s important.
03:14
Bone marrow macrophages, which
is then responsible for
holding on to some of that iron.
03:19
That becomes important.
03:20
Okay, next, as you bring in the iron,
we’ll begin the process biochemically
by having succinyl-CoA
and glycin.
03:28
If you want to remember those,
that will be fantastic.
03:31
Now, what you truly want to remember
here are going to be these.
03:34
You definitely want to know
from pathology, vitamin B6
and you want to know ALA synthase,
which is rate-limiting enzyme.
03:42
When you do biochemistry, please make
sure that you begin every single pathway
that you need to know, the glycolytic
pathway, gluconeogenic pathway,
the HMP shunt pathway,
whatever it may be.
03:51
And you know that rate-limiting
step or rate-limiting enzyme
because that becomes
important for what?
It’s called feedback mechanism.
03:59
So whenever you get questions
about feedback mechanism,
if your producing enough of your product
and you produce too much of that product,
what kind of effect do you have
on your rate-limiting enzyme?
Good.
04:08
Negative feedback.
04:09
You decrease.
04:10
Why do you want more when you
already have so much product?
Clear?
But if you don’t have enough product,
then what do you want to do?
Then, obviously, you want to
stimulate the rate-limiting enzyme.
04:19
Are we clear?
So it’s important that you know
that type of relationship for sure.
04:25
Okay, so then you have the
rate-limiting enzyme, ALA synthase,
and we have vitamin B6.
04:30
What I’m going to do first is
lay down the normal foundation
and then we’re going to quickly
put in the pathologies
and you see as to
how this works.
04:37
With the synthase, you end up
forming aminolevulinic acid.
04:40
Say that three times fast.
04:42
I can’t.
04:42
I’ll do it once.
04:43
Aminolevulinic acid.
04:45
Next, you come out into the cytosol.
04:49
And you have an
important enzyme here.
04:50
This is not the rate limiting enzyme.
04:53
I do wish to point out to you, this will
make your life a little bit easier,
Pb in your periodic table is lead.
05:01
Why in the world did I say lead like that?
Because lead, D, that it ends in
is the enzyme ALA dehydrotase.
05:11
Students often get dehydrotase
confused with synthase.
05:15
No longer.
05:16
So whenever you have lead, it is
going to inhibit ALA dehydrase.
05:20
Do not choose ALA
synthase, is that clear?
So we’ll talk about synthase
more when the time is right.
05:26
You’re going to end up
forming porphobilinogen.
05:30
Okay.
05:31
So why did I pronounce this --
Why did break it up that way?
-Ogen means to you what?
Weak, weak, weak, weak, weak.
05:38
What do you mean?
Trypsinogen, pepsinogen, wherever
else, or fibrinogen, right?
So you need to cleave off that –ogen so
that you can form your proper porphyrins.
05:50
So there’s many steps here.
05:51
Hence, you find the dash lines.
05:53
And you tell me which is the most
common type of porphyria disease.
06:01
Good.
06:01
Porphyria cutanea tarda, isn’t it?
So your porphyrias, the one that
you definitely want to know.
06:07
Well, there’s two that you
definitely want to know,
but the most common will be
porphyria cutanea tarda.
06:13
In your porphyria cutanea tarda,
what component of that did you want
to remember from biochemistry?
The cutanea, why?
How is the patient
going to present?
"Doc, I have a rash."
Tell me about this rash
"Well, when I go out and sunbathe,
oh my goodness, this blister
develops and it hurts."
It hurts.
06:35
So painful blister upon
exposure to UV, ultraviolet,
is the history that that patient is going
to give you for porphyria cutanea tarda,
and with this, you are
then going to then look
for maybe the enzyme
deficiency called UROD.
06:49
And what you are then going
to find in the urine.
06:52
The second type will be known as
acute intermittent porphyria.
06:56
Another one that you want to know,
well, luckily with acute
intermittent porphyria,
you’ll be paying attention to
letter P, what does that mean?
Pink urine.
07:04
A little reddish.
07:05
You’ll have abdominal pain.
07:07
Ouch!
Maybe a little crazy.
07:10
What’s that?
Psychosis.
07:11
Remember psychosis begins
with the letter P.
07:13
All right, so many of these
issues that you have with AIP,
acute intermittent porphyria,
will begin with the letter P.
07:20
So those are discussions that you’ve had in
biochemistry, at least know two of these.
07:24
Porphyria cutanea tarda and number
two, acute intermittent porphyria.
07:29
Know the enzymes that are
deficient in those conditions
and you’ll be in fantastic shape.
07:35
Let’s continue forward.
07:36
What are you trying to form here?
Oh, I do believe we’re
trying to form hemoglobin.
07:40
Where am I?
Bone marrow.
07:42
What kind of cell is this?
A nucleated RBC.
07:46
Let’s go back into the mitochondria
and whatever, you have
protoporphyrin IX, so be it.
07:53
But then you have this enzyme
called ferrochelatase.
07:55
That you’ll want to
memorize for sure.
07:58
We’ll talk more about that
later as you can see here.
08:00
Lead is also going to interfere with
that,
and then what have you formed finally?
Heme.
08:06
Are you done?
No.
08:08
Remember that transferrin
that was bringing the iron?
That iron has to be
incorporated into the heme
so that you can form the heme
component only of hemoglobin.
08:18
Are we clear?
So all we’ve done thus far is form heme.
08:20
What’s left?
The globin.
08:23
Tell me about the globin.
08:25
The globin is the gene.
08:26
Where are you going to get those genes?
G, globin.
08:31
G, gene.
08:33
Obviously inherited.
08:35
Alpha, beta, delta, gamma.
08:36
See that in parenthesis.
08:37
Alpha, beta, delta, gamma.
08:40
Greek letters.
08:41
So you have to know Greek, you have to
know Latin, you have to know medicine.
08:44
I mean really –
It’s endless, isn’t it?
It’s rather interesting.
08:47
So now, you have alpha, beta,
delta, gamma, is that important?
Oh, are you kidding me?
Have I told you anything
that’s not important?
Exactly.
08:55
So here, when you have hemoglobin A,
you have the heme formed
by the porphyria pathway
and the globin in which the genes
have then been given to you.
09:06
In a fetus, what kind of
hemoglobin do you have?
Fetus.
09:10
Hemoglobin F.
09:12
What’s my Greek salad there?
My Greek salad as a fetus
is alpha and gamma, right?
As we’re born and delivered
and such, approximately,
oh, maybe about two to three
maybe maximum of four months,
you convert all of your
hemoglobin F into hemoglobin A.
09:35
What’s your Greek salad
for hemoglobin A?
Alpha and beta.
09:39
Alpha and beta, are we clear?
So as long as all of this
is occurring properly
with the biochemical
pathway in genetics,
boom, they came together
and they form hemoglobin.
09:50
So far, all of the microcytic anemias
that we’ve done have been heme diseases.
09:56
These include, number one, iron deficiency,
anemia of chronic disease, sure,
but it’s dealing with iron
but also chronic diseases.
10:04
And then here, ladies and gentlemen,
welcome to sideroblastic anemia.
10:10
So in sideroblastic anemia,
what’s my problem?
Let’s go back to the beginning.
10:14
So start is on your left.
10:17
The finish of this interesting
porphyria monopoly game
is going to be the hemoglobin.
10:23
Start to finish.
10:24
Left to right.
10:26
So in the beginning,
let’s say that you had a patient who
had night sweats, fever, weight loss.
10:31
On your chest x-ray, you ended up
finding these interesting nodules
or maybe CT that’s showing you nodules.
10:38
With that type of history and the
fact that imaging study of CT,
more likely to have maybe
something like TB, right?
So obviously, you confirm this and you
find acid-fast positive organisms.
10:51
So here’s mycobacteria TB and the
patient now begins on a RIPE regimen.
10:56
What’s RIPE?
R- rifampin.
10:58
I- INH,
a.k.a., isoniazid.
11:03
P- pyrazinamide.
11:04
E- ethambutol.
11:07
Why do have INH here?
Because INH along with the drug,
you have to give pyridoxine.
11:15
What’s another name for pyridoxine?
Oh, yeah, that’s vitamin B6.
11:20
Know both names please.
11:22
Now, point is this,
say that you have a scenario
in which the individual
has not been ordered or instructed,
whatever, to take the B6 with INH.
11:31
What happens?
You become B6 deficient.
11:33
If you become B6 deficient,
then what happens?
My rate limiting enzyme
isn’t working properly.
11:39
Wow!
So if that isn’t working
properly, you’re stuck.
11:43
You can’t even move past your
step of Succinyl-CoA and glycine.
11:47
Can you form heme?
Nope.
11:50
If you can’t form any heme, what
happens to my state of iron?
Too much.
11:56
So what do you think this
iron is going to do?
What is this that
we’re seeing here?
A nucleated RBC.
12:01
So what is this
iron going to do?
It is going to then wrap itself
around your nucleus, isn’t it?
What is that called?
Ring sideroblasts.
12:11
Holy cow! Everything’s
now coming together.
12:14
It’s making sense.
12:16
So therefore is there any
iron deficiency here?
No.
12:20
It’s the fact that
no heme was formed.
12:24
So the iron comes in and it’s lost.
12:26
I don’t know where to go.
12:27
I don’t know where to go
because there’s no heme.
12:30
Are we clear?
So what does it do?
It forms a siderocyte.
12:34
What’s a siderocyte?
It’s just an RBC, which
has too much iron in it.
12:38
A sideroblast, a ringed one, is
one in which around the nucleus,
it forms a beautiful ring.
12:44
And if you do a Prussian blue, obviously,
you’ll find that to be lit up.
12:47
I’ll show you a picture.
12:48
You see that?
So a sideroblastic anemia isn’t specific.
12:52
Is it only one disease?
Is it only one disease?
Sideroblastic is an umbrella of diseases.
12:57
I’ve only given you one, INH.
13:00
Who’s my second one?
Well, my second scenario, let’s
say that there’s a baby.
13:04
And what’s this baby doing?
Well, in the lower socioeconomic
type of environment, unfortunately,
or even like old homes, huh?
Even old homes actually northeast if you go
to the New England area, Boston and such,
the actual communities in which
children are not allowed to live.
13:24
Not because of discrimination or not
because like, “Oh, I don’t like children,
so no children in my community.”
No, no, not because of that.
13:31
It’s the fact that the children are
not allowed in these old homes
because if the paint starts chipping,
what are they going to do?
They put everything in their mouth.
13:39
“Look at that, there’s a –“
Well, they can’t talk to you, right?
They’re going to crawl
over to the paint chip.
13:43
See me crawling?
And you’re going to put a
paint chip in my mouth.
13:46
Uh-oh.
13:47
What happens?
Not good.
13:50
This child is going
to grow not too tall.
13:53
The child’s going to go to
school, not do too well.
13:57
The child gets older and what happens?
Maybe
limp wrist.
14:02
What does that mean?
Something like wrist
drop, maybe foot drop.
14:06
See what I’m getting at?
Maybe that’s neuropathy.
14:08
Uh-oh.
14:09
Later on, adult life, also there might
be issues with increased creatinine.
14:14
What’s that called?
Lead nephropathy.
14:17
That’s what I’m getting at.
14:18
This is all lead poisoning, isn’t it?
So look for –
Even to this day, ladies and gentlemen,
where you find children that unfortunately
might just put anything in their mouth
including lead chips
or paint chips.
14:30
And so therefore, sometimes
if with that type of history,
with maybe lower socioeconomic
type of environment,
where they’re eating old paint,
all they have to do is show
up with abdominal pain,
with that type of history, no doubt,
your patient has lead poisoning.
14:46
What kind of anemia is this?
Good.
14:48
Sideroblastic anemia.
14:50
Most likely here, the MCV is
going to be less than 80,
it doesn’t have to
be at all times.
14:55
But just to make your life a
little bit easier though,
that’s the full history
of your patient.
14:59
They’re not going to go crazy
on the categorization so much
because it could actually
micro or even normal.
15:06
But the history is going to tell
you everything that you need.
15:08
And what about that INH?
Well, that INH, the synthase wasn’t
working properly because there’s no B6.
15:14
So two down.
15:15
Two what?
Two causes of sideroblastic.
15:18
What kind were these?
Acquired, right?
INH, therapy for tuberculosis.
15:24
Number two, lead poisoning.
15:26
Let’s go to the most
common type actually.
15:28
The most common type is one
in which alcohol is involved.
15:31
Just keep it simple, alcohol
is a mitochondrial poison.
15:35
It will damage the mitochondria.
15:37
So therefore, if your mitochondria
isn’t functioning properly,
you’re not able to form heme, are you?
Nope.
15:44
So what do you have?
You have sideroblastic anemia.
15:46
Acquired type.
15:47
“But Dr. Raj, I thought alcohol could cause
non-megaloblastic
anemia, macrocytic?”
It does.
15:53
“I thought, Dr. Raj, alcohol
could consume folate,
may result in megaloblastic
macrocytic anemia?”
Yeah, it does.
15:59
And alcohol may cause
mitochondrial poisoning
and result in sideroblastic anemia.
16:04
So you want to be
very, very careful
with alcohol because it could
be any number of anemias.
16:10
It all depends as to what your questions
and this situation is going for.
16:15
Three down, these were acquired.
16:18
Then, could you then be genetically
deficient of the rate-limiting enzymes?
Sure.
16:23
So you’re genetically deficient of the
rate-limiting enzyme, which one is this?
ALA synthase.
16:29
Wow!
So there is a genetic one
that you want to know?
Yeah.
16:33
You want to know the most common genetic
deficiency causing sideroblastic anemia
and that would be ALA
synthase deficiency.
16:40
And there’s one other that we’ll talk about
a lot more when we get into WBC pathology.
16:45
And that is going to be something
called myelodysplastic syndrome.
16:49
Your myelodysplastic
syndrome, there’s a type of
refractory anemia of
ring sideroblast.
16:55
Rare, but actually we’re finding
more and more about this.
16:59
Hence, it is absolutely
important for you to know.
17:01
So I’ll mention it as we go through here.
17:03
The last little point that I wish to bring
to your attention, ladies and gentlemen,
if you go all the way to the right and to the
top and take a look at the globin chains.
17:12
If you’re missing alpha and
beta, at a later discussion,
we’ll take a look at our fourth and
final type of microcytic anemia,
which is then going to be
dealing with your thalassemias.
17:20
A beautiful picture, ladies and gentlemen,
of really wonderful integration
of biochemistry, your physiology,
your bone marrow issues, obviously
a lot of pathologies here.
17:30
All dealing with what kind of anemia?
Microcytic.
17:33
Which one are we referring
to here specifically?
The sideroblastic anemia’s
an umbrella of etiologies.
17:40
And then just to make sure we’re clear,
take a look at globin in the thalassemias.