Anemia is a blood disorder where the body doesn't
have enough healthy red blood cells or hemoglobin,
resulting in poorly oxygenated tissues throughout
the body. This condition takes many forms, ranging
from mild to severe depending on the cause.
Anemia in a man is a hemoglobin below 13.5 g/dL
or a hematocrit less than 41%, and in a woman it’s
a hemoglobin below 12.0 g/dL or a hematocrit less
than 36%, but those numbers can differ based on
which guidelines you’re using.
Also, people with chronic respiratory
diseases like emphysema or medical problems
like malnutrition may have symptoms
of anemia even at normal levels
of hemoglobin and hematocrit.
In addition, those living at altitude can have high
levels of hemoglobin and hematocrit to help deal
with the lower oxygen levels. So these guidelines
aren’t appropriate for everyone.
Now, the most common signs and symptoms
of anemia are dyspnea with exertion and at rest,
fatigue, and a hyperdynamic state like bounding
pulses and palpitations.
If someone is anemic, the first thing to look at is the
mean corpuscular volume or MCV.
An MCV of less than 80 is low, so microcytic,
between 80 and 100 is normal, so normocytic, and
above 100 is high, so macrocytic.
Of course, some individuals might have a few types
or causes of anemia mixed together, and that’s
where things get more complicated.
Most microcytic and macrocytic anemias are
caused by a problem in producing either red blood
cells or hemoglobin, and in those situations we can
measure the reticulocyte production index (RPI) or
corrected reticulocyte count (CRC). This number is
the percentage of red blood cells that
are reticulocytes, or immature, and is normally
between 0.5 and 2.5%.
A person with anemia and less than 2% RPI means
that their body is not capable of producing enough
red blood cells.
In certain normocytic anemias that are caused by
the loss or destruction of red blood cells, the RPI is
above 2% because the body increases red blood cell
production to replaced the ones that were lost.
Now, microcytic anemia can be divided into four
main types - iron deficiency anemia, anemia of
inflammation & chronic disease, thalassemias,
and sideroblastic anemia.
To distinguish them, you should check iron studies
which includes the serum iron, which is the free
iron in the blood, the total iron binding capacity or
TIBC, which tells you how much
unbound transferrin is floating around and is
available to bind iron, the ferritin level, which tells
you how much ferritin is floating around and
already bound to iron - effectively storing it, and
a peripheral blood smear.
Iron deficiency anemia is most common and usually
there’s a low serum iron, high TIBC, and a
low ferritin.
Low serum iron means that there’s more
unbound transferrin, so there’s increased total iron
binding capacity, and that there’s less ferritin that’s
already bound to iron and storing it.
This generally occurs in people with chronic slow
bleeding - where the iron in the red blood cells is
lost instead of getting recycled.
This includes women with frequent or
heavy menstruation or patients with colon cancer,
which should be ruled out in older men
through fecal occult blood testing.
Another cause is pregnancy, due to increased iron
requirements for fetal development.
In some settings, iron deficiency anemia can be the
result of not having enough iron in the diet.
Treatment for iron deficiency anemia includes
addressing the cause and giving oral
iron supplements, which can be taken
with orange juice which is slightly acidic and can
help absorption.
Common side effects of oral iron include nausea,
diarrhea, and constipation.
If oral iron isn’t effective, or the side effects can’t
be tolerated, IV iron can be used instead.
Sometimes, the cause of refractory iron
deficiency is a Helicobacter pylori infection,
because the bacteria can sequester iron and it can
cause gastric bleeding, or inflammatory bowel
disease or celiac disease, both of which can
cause malabsorption.
In anemia of chronic disease, there’s low serum
iron, low total iron binding capacity, and
high ferritin. This basically occurs because there’s a
lot of inflammation, and during periods of extended
inflammation the body likes to store away iron.
Anemia of chronic disease often develops in people
with chronic inflammatory diseases, like infections,
autoimmune disorders, and various cancers, and
typically resolves once that underlying condition
resolves.
Next, there’s thalassemia, where everything is
normal - normal serum iron, normal total iron
binding capacity, and normal ferritin. That’s
because the problem has to do with making
the globin chains of hemoglobin.
There are two types of thalassemia: alpha and beta.
In alpha thalassemia, there is a mutation in the
alpha genes that code for alpha globin chains,
which are present in both fetal and adult
hemoglobin, while in beta thalassemia, there is a
mutation in the beta genes that codes for the
beta globin chains, which are only present in adult
hemoglobin.
There are four alpha genes, and two beta genes, so
if more genes are defective, then fewer normal
globins chains are produced, and the more severe
the thalassemia is.
If there’s one defective alpha gene, there’s usually
no symptoms.
If there are 2 defective alpha genes or one defective
beta gene, then half of the genes are gone and there
are mild symptoms.
If three alpha genes or two beta genes are defective,
there’s severe disease.
And if all four alpha genes are defective,
that’s incompatible with life and the fetus dies
in utero, whereas beta thalassemia is not lethal
in utero because the fetal hemoglobin does not
contain beta chains.
To figure out which chains are missing, you can
use hemoglobin electrophoresis.
Usually, patients with mild thalassemia don’t need
treatment, while patients with
severe thalassemia are treated with blood
transfusions, and to prevent iron overload, they’re
also given iron chelating agents that trap some
excess iron and sweep it away through feces or
urine.
In sideroblastic anemia, there’s high serum iron,
low total iron binding capacity, and
high ferritin level.
It is characterized by sideroblasts, which are
basically immature red blood cells found in
the bone marrow.
These erythrocytes cannot utilize iron for the
synthesis of heme, so iron accumulates inside
the mitochondria surrounding their nucleus,
forming a ring.
Eventually, unused iron builds up in the blood and
binds to the transferrin proteins, causing a low total
iron binding capacity.
Increased serum iron also leads to
increased ferritin levels.
Some causes of sideroblastic anemia are congenital,
like genetic mutations, whereas others are acquired
like myelodysplastic syndrome, excessive alcohol
use, copper or vitamin B6 deficiency, or intake of
certain antimicrobial drugs.
Diagnosis is based on bone marrow biopsy, which
shows ringed sideroblasts when stained
with prussian blue, a pigment that binds to iron.
For congenital cases, there might be genetic testing.
Treatment depends on the cause and could include
stopping the use of alcohol or medication, if that’s
the cause.
Some congenital cases respond to vitamin
and mineral supplements, and in the case
of myelodysplastic syndrome, it requires a bone
marrow transplant.
Now, if a person has macrocytic anemia, the next
step is asking for a blood smear to figure out
whether it’s megaloblastic or non-megaloblastic.
Megaloblastic anemia is more common, and it’s
caused by impaired DNA synthesis during red
blood cell production, which leads to continuing
cell growth without division.
On a blood smear there are larger-than-normal red
blood cells and hypersegmented neutrophils, which
means they have 6 or more lobes in their nucleus
when they normally have just three or four.
The two main causes of megaloblastic macrocytic
anemia are vitamin B12 and folate deficiency,
so blood levels of both should be checked to see if
either one is low.
If these two are not informative enough, also
the blood
levels of homocysteine and methylmalonic
acid may be checked.
Homocysteine is generally elevated with either
deficiency, while methylmalonic acid is elevated
when B12 is low, but it’s normal when folate is
low.
B12 is found in animal protein and can be stored for
three to ten years in the liver.
So people who avoid all animal products - like
long time vegans who don’t take B12 supplements -
can get B12 deficiency, that would be a big missed
steak.
And even if someone does eat meat they can still
get B12 deficiency, if they’re not absorbing it
properly.
Normally, meat or dairy are broken down in the
stomach and the B12 is released.
Next a protein made by parietal cells in the stomach
called intrinsic factor binds to the B12.
Then, the B12-intrinsic factor complex moves all
the way through the intestines to the terminal ileum,
where special cells recognize intrinsic factor and
absorb the whole complex.
Now, various things can go wrong with this process,
and that would In pernicious anemia, IgA
antibodies attack intrinsic factor or the parietal cells,
and either way, it interferes with intrinsic factor’s
ability to bind to B12, and subsequently get
absorbed.
In Crohn's disease, often the terminal ileum gets
damaged.
In people that get a gastric bypass, the ingested
food passes through the stomach quickly, so even
if intrinsic factor is produced, it can’t get to the
food to bind B12.
Now, B12 is used throughout the body, so people
with B12 deficiency develop a variety
of neurologic symptoms.
After confirming that there’s a B12 deficiency,
further testing should be carried out to figure out
the cause, for instance by looking for anti-intrinsic
factor antibodies for pernicious anemia, or carrying
out endoscopic or imaging studies in patients that
might have Crohn’s disease.
When the cause of B12 deficiency is a dietary
problem, it’s treated with oral B12 supplement.
When the problem seems to be absorption related, it
could be treated with really high oral B12 doses -
higher than 1000 µg to allow for passive
diffusion in the gut - or with intramuscular B12
injections weekly to get the level back up and then
monthly, and then this can be followed by
oral supplementation if needed.
Now folate, also called vitamin B9, comes
from leafy greens, and nowadays many countries
fortify foods like grains and cereals with folate.
We have up to six week supply of folate in the body,
but this can get used up even quicker during
pregnancy.
So generally, people who get folate deficiency are
pregnant women, or those with an extremely
restricted diet for longer than six weeks.
Unlike B12 deficiency, folate deficiency does not
cause neurological symptoms, but it’s dangerous
for fetal development. For this reason, all pregnant
women must take oral folate supplements.
Non megaloblastic anemia is very rare, and it
presents macrocytosis with increased red cell
membrane surface area, rather than DNA
replication problems.
It’s generally associated with chronic alcohol intake,
but it can also be caused by liver
disease, hypothyroidism, certain drugs like
chemotherapeutic agents or antiretrovirals, and
metabolic inherited diseases.
Another cause is myelodysplastic syndrome, which
is where blood cells in the bone marrow do not
mature, and this can be seen on a bone marrow
biopsy.
Treatment of non megaloblastic anemia involves
dealing with the underlying cause.
Finally, there’s normocytic anemia, which is
generally due to a loss of red blood cells through a
hemorrhage or due to destruction of red blood
cells or hemolysis.
Normally, red blood cells live about 120 days, but
in these situations, they’re lost earlier, so there
is reticulocyte production index of 2% or higher to
try to compensate for this loss.
But in some patients with normocytic anemia,
the reticulocyte production index may be less than
2% due to production problems like in bone
marrow suppression or chronic kidney disease.
Bone marrow suppression is a decrease in
production of cells secondary to bone
marrow malignancy, or some infections or drugs.
So treatment involves dealing with the cause of
suppression.
In chronic kidney disease, kidney cells don’t
produce enough EPO to stimulate red blood cell
production.
To confirm diagnosis, we should look for
elevated creatinine levels. This can be partially
corrected with erythropoiesis- stimulating agents or
ESAs.
Now, a hemorrhage causes anemia only if the blood
loss is severe, but blood tests are usually normal.
External hemorrhage is easy to spot, but internal
hemorrhage can be harder to locate, so imaging
tests can be helpful. The key is to stop the bleeding
and giving IV fluids or blood transfusions, if
needed.
If hemolysis is suspected, then blood tests might
show an elevated lactate dehydrogenase or LDH,
decreased haptoglobin, and in some cases
increased bilirubin, which comes from the
breakdown of hemoglobin and causes the sclera and
skin to look yellow, so jaundice.
Next in hemolysis, a blood smear showing
abnormal red blood cells can give us a clue to the
cause. Causes can be acquired or hereditary. Let’s
go through the most relevant causes.
In autoimmune hemolytic anemia, red blood cells
are attacked by either IgM or IgG antibodies.
IgM antibodies cause cold agglutinin, which
means hemolysis happens in the cool extremities,
and it’s associated with infections
like mycoplasma and mononucleosis.
IgG antibodies cause warm agglutinin, which
means hemolysis happens when it’s warm, and it’s
associated with lupus and drugs
like penicillin and cephalosporin.
In autoimmune hemolytic anemia, the blood
smear shows spherical red blood cells
or spherocytes.
Then the Coombs test is used to detect the presence
of both IgG antibodies and IgM antibodies on the
red blood cells.
IgM positive Coombs means there’s
cold autoimmune hemolytic anemia,
and IgG positive Coombs test means there’s warm
autoimmune hemolytic anemia.
Treatment for IgM positive hemolytic anemia is to
avoid the cold, while IgG positive hemolytic
anemia requires treating the underlying cause, like
stopping a medication that’s causing it, or
using steroids in case of lupus, and
a splenectomy can be done in really severe cases to
limit red blood cell destruction.
Hereditary spherocytosis is a genetic
disorder caused by defects in the structural
proteins ankyrin, spectrin, or band 3.
Without these proteins, the red blood cells can’t
keep their shape and become spherical. This can be
seen in a blood smear, and a Coombs test is done to
rule out autoimmune hemolytic anemia.
The misshapen cells are less flexible than normal
red blood cells and get stuck in the spleen, where
they are destroyed by macrophages.
It is diagnosed by osmotic fragility test, where they
burst when put into water. The treatment is
a splenectomy to prevent hemolysis.
Sickle cell disease is an autosomal recessive
disorder most common among people of African
descent, and it’s caused by a
mutated hemoglobin gene that encodes for an
abnormal adult hemoglobin called hemoglobin
S for sickle.
Sickle cell is usually diagnosed in childhood
with hemoglobin electrophoresis.
When there’s acidosis, hypoxia, or dehydration, the
red blood cells sickle, and that causes
either hemolysis or capillary obstruction
causing ischemia and pain.
These episodes are called sickle cell crisis and can
cause emergencies like vaso-occlusive
crisis, splenic sequestration crisis, acute chest
syndrome, or stroke.
During a sickle cell crisis, a blood smear should be
done to confirm that cell sickling is present.
During a sickle cell crisis, IV fluids, oxygen, and
pain control are used to manage the symptoms.
Occasionally, exchange transfusion is needed if
there is an emergency.
Also regular blood transfusions can be done, and
iron chelating agents may be given to prevent iron
overload.
To prevent these attacks, patients get long
term hydroxyurea, which reactivates the synthesis
of fetal hemoglobin to replace the
abnormal hemoglobin S - so there’s a lower chance
of sickling.
Glucose 6 phosphate dehydrogenase or G6PDD is
an X-linked recessive disorder that results in defects
of the enzyme.
Normally, it protects the red blood cells
from oxidative stress, so in affected individuals,
there’s hemolysis when they’re exposed
to oxidative stressors, like foods like fava
beans, quinine-derived drugs, certain antibiotics,
and infections.
A mild variant of this disease is common in people
of African descent, whereas a more severe variant is
found in people of mediterranean descent.
When there’s oxidative stress, hemoglobin gets
damaged and forms heinz bodies inside the red
blood cell.
Macrophages in the spleen detect the abnormal red
blood cells and try to remove the heinz bodies by
taking out a chunk of the cell, so these red blood
cells looks like something took a bite out of them,
so they are called bite cells. So a blood smear can
show these bite cells and heinz bodies.
During a hemolytic attack, the deficient cells die, so
testing G6PD level acutely isn’t reliable.
So diagnosis is confirmed by a low G6PD level
roughly 8 weeks after an attack.
Treatment of the acute phase of a hemolytic attack
may require blood transfusions.
But to prevent an attack, it’s important to avoid the
triggers, and sometimes those with recurrent
hemolytic attacks will benefit from a splenectomy.
Finally, paroxysmal nocturnal hemoglobinuria is a
disorder caused by a defect in the PIG-A gene.
PIG-A codes for the GPI protein that is normally
found in the cell membrane of red blood cells and it
binds to another protein called DAF.
DAF blocks the complement from attaching to the
cell and destroying it.
Deficiency of GPI means red blood cells can no
longer protect themselves from the complement, so
they get destroyed and release
their hemoglobin into the blood.
This hemoglobin gets into the urine, making it dark.
This is particularly significant during sleep, when
there’s reduced respiratory rate, which leads
to hypoxia and acidosis, and that promotes
complement binding.
Diagnosis is made by flow cytometry, which tests
for the lack of GPI-linked proteins like CD55 on
red blood cells.
Transfusion therapy may be needed for acute
hemolytic attacks, and no chronic treatment is
needed in most cases.
Eculizumab, an antibody against the complement,
could be given to individuals with recurrent attacks
to improve their quality of life.
Summary
All right, as a quick recap, anemia can
be microcytic - due to problems
making hemoglobin, normocytic - due to bleeding
or hemolysis, and macrocytic - due to
deficient DNA production.
Microcytic anemias include iron deficiency, chronic
inflammation, thalassemias, and sideroblastic
anemia.
To distinguish, you can check serum iron, total iron
binding capacity, and ferritin.
In normocytic anemia, red blood cells are lost, so
there’s a reticulocyte production index of over 2%
to try to compensate.
However, in some patients with production
problems like bone marrow suppression or chronic
kidney disease, the reticulocyte production index is
below 2%.
Finally, macrocytic anemia can be megaloblastic -
due to low vitamin B12 or folate - or
non megaloblastic, which may be due to
chronic alcohol intake, liver
disease, hypothyroidism, certain medications,
metabolic inherited diseases, or myelodysplastic
syndrome.