Now let us look at a range of diseases in
which the anaemia is associated with red cells
of a normal size, normocytic anaemia. One
of the most common that we see in hospitals
now is the anaemia of chronic disease, the
anaemia of chronic inflammation. This is a
very interesting background. Whenever there
is chronic inflammation or infection within
our body, the body sequesters iron within
macrophages. It starts to shut down the flow
of iron within the body. This leads to reduced
iron level in the blood and reduction in haemopoiesis.
You might ask why on earth thus the body do
this, but it is almost certainly physiological
evolutionary selected mechanism to limit the
amount of iron available for pathogens like
bacteria. Iron helps bacteria to divide and
here is a mechanism of hiding it to way from
bacteria. There are two pictures on the right
showing examples of how this may happen.
At the top we have a patient with rheumatoid
arthritis and chronic disorders such as that
are often associated with some form of mild
anaemia and at the bottom you will see a bone
marrow stain iron and the blue there represents the
iron which is present within the reticuloendothelial cells.
It has been taken in because of anaemia
of chronic disease. It is quite a nice illustration
of how iron really has to be very carefully
regulated within our body. Now the treatment
of anaemia of chronic disease is really to
treat the underlying condition, treat Rheumatoid
arthritis or perhaps the malignant disease
or whatever it may be is leading to this condition
and then the rest of the anaemia will sort
Another important cause of normocytic anaemia
is a renal disease because remember that the
kidney produces erythropoietin, the major
regulator of erythropoiesis. You will see
on the right, the chart showing the very beautiful
feedback mechanism for regulating erythropoiesis.
In the bottom in green, the kidney acting
as an oxygen sensor and producing erythropoietin
whenever there is hypoxia releasing that which
leads to increased erythropoiesis and the
correction in the red cell mass. If the kidney
is damaged, it may not be able to make erythropoietin
and anaemia used to be a very severe problem
in patients with chronic kidney disease.
Unfortunately, we know a lot about erythropoietin now
and are being cloned and can be produced as a
molecule for injection and are widely used
for patients with chronic renal failure and
helps to increase that haemoglobin.
Another time where you may see a normocytic
anaemia is when the bone marrow cell is involved
through other diseases. Now in this situation,
you will also see a reduction in white cells
and platelets. The bone marrow simply cannot
produce enough normal cells. This can be due
to a wide range of clinical problems.
I have listed some there, infiltration with leukaemia,
myeloproliferative disease and infiltration
with carcinoma or aplastic anaemia. On the
right, you will see that the fine biopsy of
bone marrow and I do not know if you can recognise
yourself. This is a difficult slide of what
that may be, but in fact, that pink tissue
is metastatic carcinoma not was leading to
anaemia in this patient.
Let us now turn to macrocytic anaemia where
you have large red cells. The major cause
here is a disorder called megaloblastic anaemia
quite a long word again but we can easily
understand it megalo-large, blast-the premature
erythroblast. Look at the right-hand side
and you will see those very large purple erythroblasts
within the bone marrow. Why are they large?
Essentially the vitamin deficiency here is
limiting their ability to divide and replicate.
So they are trying to expand and produce more
molecules ready for division, but they simply
do not make the final division, which is due
to deficiency of vitamin B12 or folate. A
characteristic feature within the blood film
is shown at the bottom and you will see two
white cells, which you will recognise as neutrophils.
Now neutrophils have multilobed nuclei and
you will see the more lobes you would expect
normally after five, but in this condition,
you can see more than that characteristic
feature of megaloblastic anaemia.
Now let us talk a little bit more detail about
how this megaloblastic anaemia can arise.
The most important cause which you need to
know about is pernicious anaemia. This is
now recognised as an autoimmune disease in
which patients makes antibodies to the stomach
to gastric parietal cells and to a protein
called intrinsic factor, which is made within
those cells. Remarkably, while B12 is absorbed
within our food, it has to bind to intrinsic
factor. The complex of B12 and intrinsic is
then absorbed in the terminal ileum. You can
see immediately that if your intrinsic factor
is neutralised with antibodies, you would
not be able to absorb B12 and I have mentioned
that neuropathy can develop and that is certainly
true. This disorder can lead to numbness in
peripheral nerves and if untreated which thankfully
we exceptionally where you see these days
it can lead to very severe problems even blindness
or dementia. I should mention before you the
cause of the pernicious anaemia. This was
a major cause of death of patients over 100
years ago. Treatment is very simple, vitamin
B12 injections given every three months.
You can also take high doses of oral pure B12
and hope you just manage to absorb enough.
On the right, there is a tongue of somebody
with pernicious anaemia is often described
as PA and you can see of certainly is sore
and some more swollen.
Now the bottom I have mentioned folate deficiency.
This is an autoimmune disease, but it can
also occur when there are excess requirements
for folate classically when somebody is pregnant
or if they have a haemolytic anaemia and,
here again, a simple tablet of folic acid
will prevent all of the problems. Folate is
used in the same biochemical pathways B12,
which is why these two causes the same affect
of megaloblastic anaemia. Let me now turn
into another form of anaemia, haemolytic anaemia.
This is a very interesting condition.
We remember that red cells normally live for around 120
days. But if this is shortened due to haemolysis,
destruction of red cells, then the bone marrow
must respond to that by producing increasing
numbers of red cells. Interestingly reticulocytes
were slightly larger than red cells.
So, in fact, the mean cell volume within the blood
increases. So this anaemia can be macrocytic
in some cases. Now the bone marrow can normally
cope with a short lifespan of red cells until
it goes below around 15 days and then really
it just cannot keep up and anaemia is almost
inevitable and that is haemolytic anaemia.
Let us look at how that can present in the
patient. Let us 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 haemolytic
anaemia become jaundiced? To understand that
we have to think about how haemoglobin is
degraded. We talked earlier about how it is
synthesised and you will see the diagram on
the left, how this occurs. The degradation
of haemoglobin involves firstly the split
into haem and globin. The globin is a protein
and that is broken down into constituent amino
acids. We are more interested in the haem.
Again the iron has to come out and is recycled
what is left is protoporphyrin and that is
broken down into bilirubin and now you can
see why patients may get jaundiced.
That bilirubin is insoluble. It needs to bind to albumin
and then 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.
Haemolytic anaemias should be classified into
two large groups. The disorders which arise
because of an inherited abnormality and those
which were required later in life. Red cells
are relatively simple cells. As cells grow,
they have a membrane, they have haemoglobin
and they have some enzymes and indeed inherited
causes of hemolytic anaemia can involve those
three major components. Let us look at those
three in turn. We now need to just look
quickly at the red
cell cytoskeleton because of course the shape
of the red cell is defined by proteins within
the cells that maintain its structure and
you will see this cross section of a red cell
at the bottom we have got proteins called
spectrin, which form ankyrin within the cell
and spectrin is anchored to the surface of
the red cell through anchoring proteins and
protein such as Band 3 and Band 4.1. So these
are very critical proteins for maintaining
red cell shape. What happens if you are born
with an abnormality in the genes coding for
some of these proteins such as spectrin or
ankyrin. 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? 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.
These patients often are mildly anaemic. This
is 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
anaemic with a low haemoglobin, then you can
remove the spleen and splenectomy will solve
the problem. It does not change the genetic
defect, but it stops the spleen from taking
out the slightly different spherical red cells.
We have to be careful because there are always
associated with taking out the spleen particularly
in children and you have to balance the anaemia
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 have
listed as hereditary elliptocytosis and yes
you are right, the red cell does look elliptical
and not disordered. Let us 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 the heterozygous
disorder can provide can protection against
severe malarial infection. This is X-linked
and patients need to avoid factors that precipitate
the crisis of acute anaemia in this condition.
Sometimes it is drugs, bizarrely sometimes
it is kidney beans, fava beans and now it
can trigger a crisis. Just look on the right
of the green boxes there and you will see
that coming in from the right what we call
oxidant stress. If drugs, infection, or fava
beans lead to oxidation within the red cells,
the lack of sufficient G6PD activity can lead
that oxidation damaging and killing of a red
cell and as you work away down through that
dark column you will see that inadequate production
of NADPH and . . . leads to oxidation damage.
Another enzyme disorder is pyruvate kinase
deficiency. Again a similar, but rare disorder.
Finally, the third inherited cause of haemolytic
anaemia inherited haemoglobinopathies.
These are very common. I am pretty sure that they
have been selected during evolution because
heterozygous state although it is not clinically
insignificant in the patient, it provides
protection against severe malaria. Malaria
has 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 us look particularly sickle-cell
disorders in this case. Again on the right,
an electrophoretic analysis of globin.
On the top, we have normal person haemoglobin
a dominating with a small amount of haemoglobin
F. The next one down sickle-cell anaemia,
a mutation in the beta chain. So there is
no normal haemoglobin A. What we have is haemoglobin
S. I will show you on the next slide what
that does to red cells. The third one is a
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 haemoglobin A and some haemoglobin
S. That is largely asymptomatic and at the
bottom for . . . those of haemoglobinopathies
is someone who has a sickle beta gene and
haemoglobin C beta gene and you will see now
you get haemoglobin C as a normal A.
Sickle-cell anaemia is a very severe disease.
In that slide, you will see at the bottom
left a classic sickle-cell similar to the
size that are used for cutting corn. Now sickle-cell
anaemia leads to sickling of red cells during
periods of hypoxia. When the blood is deep
within capillaries and becomes hypoxic, the
haemoglobin 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 anaemia,
if needed, is with red cell transfusions provide
the normal blood or with drugs such as hydroxycarbamide,
which is shown to be quite effective.
Finally in haemolytic anaemia, let us consider
those disorders which are acquired, but not
inherited are developed in life and I think
the major one I want to focus on is the auto-immune
haemolytic anaemias where the body makes antibodies
against the red cells. Two types of antibodies
are made, IgG antibodies, which you will know
a quite high-affinity antibodies. They bind
at 37 degrees and that is sometimes known
as 'warm' antibodies. Look at the top two
pictures on the right. On the left, you will
see something that we saw similar to you saw
a few slides ago, spherocytes. That is the
characteristic feature of autoimmune haemolytic
anaemia and you noticed more reticulocytes
as well, slightly bluish cells. On the right,
you will see a stain for reticulocytes and
that is because the body is responding due
to the haemolytic anaemia.
The second type of antibody they can be produced
is IgM. These are less strongly binding.
They often need lower temperatures to act, sometimes
known as 'cold' antibodies. But that very
powerful at agglutinating red cells look at
the slide at the bottom of the picture, you
see those clumps of red cells they have 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 they can be triggered
by infection as well.