Given every three months.
You can also take high doses of oral pure B12
and hope that you just manage to absorb enough.
Now, at the bottom, I've mentioned folate deficiency.
This is not an autoimmune disease but it can also occur when there are excess requirements for folate,
classically, when somebody's pregnant or if they have a hemolytic anemia
and here again, a simple tablet of folic acid will prevent all of the problems.
And folate is used in the same biochemical pathway as B12
which is why these two cause the same effect of megaloblastic anemia.
Let me now turn to another form of anemia, hemolytic anemia.
This is a very interesting condition and we remember that red cells normally live for around 120 days.
But if this is shortened due to hemolysis, destruction of red cells,
then, the bone marrow must be respond to that by producing increased number of red cells.
Interestingly, reticulocytes are slightly larger than red cells.
So, in fact, the mean cell volume within the blood increases.
So, this anemia can be macrocytic in some cases.
Now, the bone marrow can normally cope with a shorter lifespan of red cells until it goes below around 15 days
and then, really, it just cannot keep up and anemia is almost inevitable and that is hemolytic anemia.
Let's look at how that can present in the patient.
Let's start with that figure on the right of somebody who I think you will agree is jaundiced.
You can see the yellowness in the sclera of the eye. That is bilirubin.
Why on earth would somebody with hemolytic anemia become jaundiced?
To understand that, we have to think about how hemoglobin is degraded.
We talked earlier about how it's synthesized and you'll see in the diagram on the left how this occurs.
Degradation of hemoglobin involves firstly the split into haem and globin.
The globin is a protein and that is broken down into constituent amino acids.
We're more interested in the hem.
Again, the iron has to come out and it's recycled but what's left is protoporphyrin
and that's broken down into bilirubin and now you can see why patients may get jaundiced.
That bilirubin's insoluble.
It needs to bind to albumin and it goes to the liver where it can be conjugated and excreted into the gut.
Some of it is actually reabsorbed and can be passed out in urine.
Now, hemolytic anemias should be classified into two large groups.
Disorders which arise because of an inherited abnormality and those which you acquire then later in life.
Now, red cells are relatively simple cells as cells go.
They have a membrane, they have hemoglobin, and they have some enzyme and indeed,
inherited causes of hemolytic anemia can involve those three major components.
Let's look at those three in turn. We now need to just look quickly at the red cell cytoskeleton
because, of course, the shape of a red cell is defined by proteins within the cell that maintain its structure
and you'll see this cross section of a red cell, at the bottom,
we've got proteins called spectrin which form a lattice within the cell.
And spectrin is anchored to the surface of the red cell through ankyrin proteins and proteins
such as band 3 and band 4.1.
So, these are very critical proteins for maintaining red cell's shape.
But what happens if you're born with an abnormality in the gene's coding
for some of these proteins such as spectrin or Ankyrin?
Or one of those disorders is hereditary spherocytosis. Have a look at that film on the right-hand side.
Do you see anything unusual about it?
Well, I think, what you might see is some cells which are very round and darker than normal red cells,
very spherical and those are the cells of hereditary spherocytosis.
Now, these patients often are mildly anemic and it's a very variable disease
depending on the severity of the mutation and how it affects the individual patient.
Folic acid can be useful to maintain and support red cell production
and if the patient is getting symptomatically anemic with a low hemoglobin,
then, you can remove the spleen and splenectomy will solve the problem.
It doesn't change the genetic defect but it stops the spleen
from taking out these slightly different spherical red cells.
But we have to be careful because there are risks associated with taking out the spleen,
particularly, in the children and you have to balance the anemia against this slight
but definite risk of infection following splenectomy.
There are other examples of inherited abnormalities of the red cell membrane,
one of those, I've listed as hereditary elliptocytosis
and, yes, you're right, the red cells do look elliptical in that disorder.
Let's look at another inherited abnormality of the enzymes this time.
One of the important ones is Glucose-6-phosphate dehydrogenase,
a long word and this is more common in people from the Mediterranean and African region, why?
Because what -- a heterozygous disorder can provide some protection against malarial, severe malarial infection.
Now, this is X-linked and patients need to avoid factors that precipitate crisis of acute anemia in this condition.
Sometimes, it's drugs. Bizarrely, sometimes, it's kidney beans, fava beans and that can trigger a crisis.
Just look on the right and you'll see that coming in from the right is what we call oxidant stress.
If drugs, infection of kidney beans lead to oxidation within the red cells,
the lack of sufficient G6PD activity can lead to that oxidation,
damaging and killing the red cell and as you'll work your way down through those -- that column,
you will see that inadequate production of NADPH and glutathione leads to oxidation damage.
Another enzyme disorder is pyruvate kinase deficiency.
Again, a similar but rare disorder.
Finally, the third inherited cause of hemolytic anemia, inherited hemoglobinopathies.
These are very common and we're now pretty sure that they've been selected during evolution
because a heterozygous state, although it's not clinically insignificant in the patient,
it provides protection against severe malaria,
malaria's had a big influence on the genetic makeup of people who live in malarial regions.
But unfortunately, homozygous forms,
a bad gene from your mom and your dad can be very severe disorders.
Let's look particularly at sickle-cell disorders in this case.
Again, on the right, an electrophoretic analysis of globin.
At the top, we have a normal person, hemoglobin A dominating with a small amount of hemoglobin F.
At the bottom, sorry, next one down, sickle-cell anemia, a mutation in the beta chain.
So, there's no normal hemoglobin A.
What we have is hemoglobin S.
I'll show you on the next slide what that does to red cells.
The third one down is sickle-cell trait. This is the heterozygous state.
One normal beta globin gene and one sickle beta globin gene.
And here, we see lower levels of hemoglobin A and some hemoglobin S.
That's largely asymptomatic.
And at the bottom for the aficionados of hemoglobinopathies
is someone who has a sickle beta gene and the hemoglobin C beta gene
and you'll see now, you got hemoglobin C, S, and no normal A.
Sickle-cell anemia is a very severe disease.
In that slide, you'll see a classic sickle-cell, similar to the size that are use for cutting corn.
Now, sickle-cell anemia leads to sickling of red cells during periods of hypoxia
when the blood is deep within capillaries and becomes hypoxic,
the hemoglobin stacks up and leads to sickling of cells.
This can block the blood vessels and that can lead to a range of clinical problems,
largely due to infarction and hypoxia of tissues further down.
Treatment of sickle cell anemia if needed is with red cell transfusions to provide normal blood
or with drugs such as hydroxycarbamide which is shown to be quite effective.
Finally, in the hemolytic anemia, let's consider those disorders which are acquired.
They're not inherited. They've developed in life
and I think, the major one I want to focus on is the autoimmune hemolytic anemias
where the body makes antibodies against the red cell.
Two types of antibodies are made, IgG antibodies which you will know are quite high affinity antibodies.
They bind at 37 degrees and they're sometimes known as warm antibodies.
Look at the top two picture on the right there.
On the left, you will see something we saw similar to you saw a few slides ago, spherocytes.
That's a characteristic feature of autoimmune hemolytic anemia
and you'll notice more reticulocytes as well, slightly bluish cells.
On the right, you will see a stain for reticulocytes
and that's because the body is responding due to the hemolytic anemia.
The second type of antibody that can be produced is IgM.
These are less strongly binding. They often need lower temperatures to act.
Sometimes, known as cold antibodies but they're very powerful at agglutinating red cells.
Look at the slide at the bottom of the picture. You see those clumps of red cells?
They've been agglutinated by these IgM antibodies.
These are sometimes found in older people who have plasma cells in the bone marrow
producing these IgM antibodies and it can be triggered by infection as well.