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Transcript of Anaemia

- to be able define anaemia

- to be able to discuss the differences between normocytic, macrocytic and microcytic anaemias on blood results

- to be able to list the principal causes of the different subtypes

- to be able to differentiate between the main causes of anaemia given a clinical setting

- A clinical overview
Anaemia is too few red blood cells (RBCs) in the circulation, as defined by WHO as:
< 130g/l for men
< 120g/l for women
< 110g/l if pregnant
The principal tests when considering anaemia are:
Haemoglobin count (Hb)
A measurement of the concentration of RBCs in the blood, this allows us to ascertain if the patient has anaemia
Volume (MCV)
A measurement of the average size of RBCs, this allows us to ascertain which category of anaemia it falls into
A self directed learning module by 652610
Please press the left and right arrow keys to navigate, and double click on an area to zoom in
In microcytic anaemia the RBCs are smaller than average, primarily due to a failure of haemoglobin synthesis which results in erythroblasts in the marrow overdividing
In normocytic anaemia, whilst total Hb is low, the average size of the cells remains normal
Other major causes include
anaemia of chronic disease (though more usually presents as normocytic anemia)

The principal causes of this are:
A decreased production
eg. anaemia of chronic disease, aplastic anaemia
An increased loss or destruction of RBCs
eg. acute blood loss, Sickle Cell Disease (and many other haemolytic anaemias such as G6PD deficiency)
In macrocytic anaemia, a failure of DNA replication leads to what is also termed macrocytosis (larger than normal RBCs)
The 3 main causes are:
Folate insufficiency
Vitamin B12 insufficiency
Chronic excessive alcohol intake (even in the absence of vitamin insufficiencies)
Iron Deficiency Anaemia
Iron is the major constituent of haem, and a daily absorption of 0.1-0.2 mg is needed to maintain adequate levels (at equilibrium roughly 10% of dietary intake is absorbed).
Absorbed in duodenum
Thus anything that increases loss or decreases intake will cause iron deficiency anaemia
Clinical Assessment
In the developing world malnutrition and pregnancy are the principal causes
In the developed world, gastrointestinal bleeding is the key consideration
As such
and bleeding per rectum are key clinical signs
N.B. Bleeding is 3 times more likely in the upper gastrointestinal tract than colon
Bleeding causes decreased transit time of food in the gut, and thus decreased absorption
Due to the potential dangerous causes of the bleed (eg. colonic cancer, peptic ulcers) it is essential to effectively investigate unexplained iron deficient anaemia
Other key causes of iron deficiency include:
Coeliac disease
Heavy menstrual bleeding
Principal clinical signs are:

Glossitis (redness of the tongue and loss of papillae) - you also get this in Vitamin B12 deficiency
Koilonychia (spoon-shaped nails)
Angular stomatitis (inflammation of the corners of the mouth)
Learning Outcomes
The main symptoms & signs are:
lethargy & tiredness
shortness of breath
pallor (best seen in the conjunctiva)
To recap, the main symptoms
of anaemia are...

Additional blood tests results used to diagnose iron deficiency anaemia are:

Low serum iron
Frequently raised serum transferrin levels
Low serum ferritin levels (reflects stores of iron in the body)
There are many other blood tests to further differentiate between the different causes, but the above two allow one to give a clinical division of...
Microcytic anaemia
Normocytic anaemia
Macrocytic anaemia
Iron deficiency anaemia is by far the principal cause
primarily due to malnutrition, but also caused by malabsorption in the GI tract
Definition of anaemia and principal symptoms
Key blood tests used
Subtypes of anaemia
an overview of the most common causes of the different subtypes
Iron deficiency anaemia & Thalessaemia Major
Anaemia of chronic disease & Sickle Cell Disease
A recapping quiz to reinforce the learning
This self-directed learning tool should take the user between 20 and 40 minutes.
- research anything you are unsure of as you progress, either via books or online
- suggestions for further reading to expand upon the context will be provided at the end
Dependent on the cause
Give ferrous sulphate tablets unless contraindicated
N.B. It is essential to warn patients that stools may turn black
If GI bleeding, investigate cause further and treat
If patient fails to respond
reconsider diagnosis and/or consider the potential of multiple aneamic pathologies at play
Clinical case 1
A GP suspects that a malnourished child child of 4 years is anaemic. The child's Hb result comes back as 90g/L.

In terms of RBC size, what category of anaemia would this most likely fall into?
Answer = Microcytic
The child has mild anaemia, which is most likely due to malabsorption of iron secondary to poor dietary intake.
Remember, microcytic anaemia is where the MCV is <82fl, and the main cause is iron deficiency anaemia
Nearly 25% of the world's population suffers from this, and due to the non-specific symptoms and its prevalence, it is thus crucial for any medical student to understand how to effectively analyze blood results - and through this offer effective management
Clinical case 2
Anaemia of Chronic Disease
Folate deficiency
Vitamin B12 deficiency
N.B. Microcytic anaemia can also be diagnosed based on mean cell haemoglobin (MCH) of <27 pg
Thus the term hypochromic anaemia is also used, as on a blood film the RBCs appear paler
Particularly common in hospital patients, and increasing in prevalence with age,
the principal management here is treating the underlying disease
Thalassaemia major
The most severe subtype of Thalassaemia, an autosomal recessive disorder mostly found in African, Mediterranean, south-east Asian, and sub-continental populations
A type of hereditary haemolytic anaemia (wherein RBC life span reduces due to increased destruction)
Clinical presentation
Depending on severity, usually presents as severe anaemia in 2nd-12th month of life, or moderate anaemia from year 1
Principal signs are
(due to increased destruction of RBCs)
frontal bossing
(due to bone marrow expansion to increased RBC production)
Additional blood tests will show:
variation in RBC size and shape on blood film
raised reticulocyte count
Major diseases commonly associated with anaemia of chronic disease include:
renal failure
Many inflammatory diseases, such as:
systemic lupus erythematosus
inflammatory bowel disease
Management primarily revolves around blood transfusions
as such iron overloading is a significant long term complication
Either due to:
increased utilization, e.g.
malignant diseases associated with increased cell turnover
chronic haemolytic anaemias (such as Thalassaemia)
decreased absorption, e.g.
coeliac disease
small bowel surgery
poor intake
Antifolate drugs, e.g.
Folate is central to the DNA synthesis of RBCs, and, as such, deficiency can lead to macrocytic anaemia
it is primarily absorbed in the duodenum or jejunum
Presentation and tests
Folate deficiency presents as a non-specific anaemia.
Serum folate levels or RBC folate levels are the primary investigations
Daily folic acid
if organic causes suspected, investigate appropriately
given prophylactically in chronic haematological disorders where there is rapid cell turnover
The main investigation to differentiate between normocytic anaemias is the reticulocyte count
This is a measurement of the proportion of RBCs still in their immature form and thus allows us to ascertain the rate of production of RBCs
Reticulocyte count will be high if increased destruction is the cause, as the bone marrow tries to compensate for the increased turnover
Reticulocyte count will be low if the anaemia is due to a failure of production
Primarily due to pernicious anaemia
Vitamin B12 is first bound by intrinsic factor in the stomach, and any disease affecting its production by the parietal cells will thus affect it levels in the body
primarily an auto-immune mediated disease, but can also be due to H.Pylori gastric infection & Zollinger-Ellison syndrome

Like folate, vitamin B12 is key to the DNA synthesis of RBCs
absorbed in the terminal ileum
Also caused by poor dietary intake, such as in veganism
Clinical signs & tests
Slowly developing, and can include
glossitis (most common sign aside from pallor)
vague GI disturbance
can be accompanied by vitamin B12 neuropathy - including peripheral neuritis
serum B12 will be low
Vitamin B12 intramuscular injections
Also investigate and treat the cause
And the principal classification, as divided by mean corpuscular volume (MCV) is...
Microcytic anaemia
Primarily caused by iron deficiency anaemia
Normocytic anaemia
Primarily caused by anaemia of chronic disease and many haemolytic anaemias

Further classified by the reticulocyte count
Macrocytic anaemia
Primarily caused by one of:
Folate deficiency
Vitamin B12 deficiency
Chronic excessive alcohol intake
Other symptoms & presentations may include:
Dizziness & fainting
Palpitations & increased heart rate
Chest pain & myocardial infarction
Cold extremities
Change in stool colour
Jaundice (if due to severe haemolytic anaemia)
Alcohol & Anaemia
Advice on diet should be given to the parents, as should iron tablets (with instructions to keep the container out of reach of children)
A 17 year old girl with Crohn's Disease presents with increasing pallor & shortness of breath 2 years after having her terminal ileum resected due to the complications of her disease. Blood tests show her to be anaemic, with a MCV of 104fl, whilst her tongue shows signs of glossitis.

What is the most likely cause of her anaemia?
How have these come about?
Answer = Vitamin B12 deficiency
B12 is absorbed in the terminal ileum, and without it the girl is likely to need to need life long B12 injections
Glossitis is a non-specific sign (it can also be present in iron deficient anaemia)
N.B. Inflammatory bowel disease often leads to normocytic anaemia due to anaemia of chronic disease, whilst if affecting the duodenum and/or jejunum, iron and/or folate intake can also be deficient
Clinical case 3
N.B. - blood results in a clinical setting will come with the normal ranges. The key point is to remember that anaemia with an MCV less than the normal range (82-100fl) is microcytic, more than the normal range is macrocytic
35% of individuals consuming an average of 30 units of alcohol a day will develop macrocytosis
Whilst dietary insufficiency means that some alcoholics will have folate related anaemia, alcohol itself also causes a high MCV
the toxic role of acetaldehyde on erythroblasts (as ethyropoiesis is usually normoblastic)
If alcohol is suspected as the cause, liver function tests, and a neurological examination are essential to assess its effects elsewhere
Microcytic Anaemia
Normocytic anaemia
Macrocytic anaemia
MCV < 82fl
MCV > 82fl MCV < 100fl
MCV > 100fl
Sickle Cell Anaemia
One last recapping quiz
Vitamin B12 deficiency anaemia is primarily due to?
Pernicious Anaemia
primarily an auto-immune mediated disease, but can also be due to H.Pylori gastric infection & Zollinger-Ellison syndrome
treatment is via B12 intramuscular injections
Where is folate absorbed?
In the duodenum & jejunum
as such, any disease affecting this section of small bowel can result in macrocytosis due to folate deficiency
percentage of alcoholics will suffer from macrocytic anaemia?
N.B. if alcohol is the suspected cause, detailed alcohol related investigations and examinations must be performed.
A recap quiz of normocytic anaemia
What blood test
is commonly used to differentiate between these two overarching processes?
Normocytic anaemia is primarily due to which two overarching processes?
Increased RBC destruction,
and failure of RBC production
Can you explain the process behind hand and foot syndrome in Sickle Cell Disease?
Sickle shaped RBCs cause vascular obstruction due to their shape. Hand & foot syndrome is a common presentation of this.
Reticulocyte count (this measures the percentage of immature RBCs in the serum)
in increased RBC destruction it will be raised
in a failure of RBC production it will be decreased
A 39 year old woman, who has taken repeated courses of Trimethoprim for recurrent urinary tract infections, is shown to have an Hb of 90g/l on a routine blood test.

What is the most likely process at play in her anaemia?
What classification of anaemia will this fall into?
Answer = folate deficiency causing macrocytic anaemia
Trimethoprim is an anti-folate drug, and as such can lead to folate deficiency, a major cause of macrocytosis
N.B. A thorough drug history is key in ascertaining the cause of anaemia

If unsure as to the side-effect profile of drugs, always consult the BNF
Now to bring it all together...a few clinical cases
But remember - clinical presentations of anaemia can be confusing, with often multiple causes at play, and as such, always keep an open mind as to the working diagnosis.
Now for a recap quiz of microcytic anaemia
What is the most common cause of microcytic anaemia?
Iron deficiency anaemia
Remember that this is primarily due to dietary insufficiency, but more sinister pathologies of the GI tract must always be considered
Apart from generalised signs of anaemia, name the three clinical principal signs of iron deficient anaemia?
Signs can include:
angular stomatis
What are the principal differentiating signs of Thalassaemia Major?
Splenomegaly (due to increased destruction of RBCs by the spleen)
Frontal bossing (due to expansion of the bone marrow in attempts to increase RBC production to compensate for the anaemia)
Remember that serum iron, serum transferrin and serum ferritin levels are all important to check when considering this diagnosis
Primarily found in Sub-Saharan African populations, but also in pockets where malaria is endemic.
This is an autosomal recessive genetic disease that results in classically 'sickle' shaped RBCs due to mutations of the haemoglobin.
Like Thalassaemia Major, another hereditary haemolytic anaemia.
Clinical presentations
These are numerous and varied, but when most severe can include:
vascular-occlusive crisis
wherein the sickle shape of RBCs causes obstruction
eg. hand and foot syndrome (painful swelling)
splenic sequestrating syndrome (acute painful splenomegaly due to obstruction)
Haeomlytic crisis
sudden drop in Hb due to increased break down.
Aplastic crisis
normally due to paravirus infection, and leads to a crisis in bone marrow production.
Management includes:

Hib and meningococcal vaccinations due to increased rate of infection
daily folic acid
active treatment of bacterial infections
blood transfusion in severe circumstances (eg. an aplastic crisis)
Diagnosis centres around blood films to show the sickled RBCs, as well as genetic testing.
Anaemia is rarely the sole issue at hand with a patient, and interlinks with whole range of medical areas such as obstetrics, oncology and neonatology, to name just a few.
Further reading and references
For a slightly
more in depth overview see:
Provan D. ABC of clinical haematology [Internet]. 3rd ed. London: Blackwell; 2007
For more detail as well as more on the underlying physiology see:
Moore GW, Knight G, Blann A. Haematology. Oxford: Oxford University Press; 2010
Whilst for those
learners who prefer solid text, see the excellent:
And two good
book to have whilst on the wards are:
As such, once you feel you have a grasp of the basics outlined in this SDL it is crucial to read around the subject to fully place it within its medical context.
Mehta AB, Hoffbrand AV. Haematology at a glance. 4th ed. S.l.: John Wiley & Sons Inc; 2013
The below books have all been used in the production of this SDL, but all serve varying purposes for the reader. Please click through to see them.
Hoffbrand AV, Moss PAH. Essential haematology. 6th ed. Chichester ; Malden, Mass: Wiley-Blackwell; 2011
Hughes-Jones NC, Wickramasinghe SN, Hatton C. Lecture notes : Haematology. 8th ed. Oxford: Wiley-Blackwell; 2009
N.B. A blood film is a key haematological investigation where blood is smeared on a piece of glass and inspected with a microscope
Provan D. Oxford handbook of clinical haematology. 3rd ed. Oxford: Oxford University Press; 2009
Longmore JM. Oxford handbook of clinical medicine. 8th ed. Oxford: Oxford University Press; 2010
N.B. splenic sequestration syndrome is another presentation of this, and remember:

- Sickle Cell Disease commonly presents due to:
a vascular obstructive crisis
a haemolytic crisis
an aplastic crisis
This is because there is too little DNA for the optimum number of divisions to occur during erythropoiesis.
Thus the RBCs mature before they have divided to their normal physiological size.
You have now
come to the end of this self directed learning module.

Thank you for using it.
Online resources...
Though not specifically used in compiling this SDL, useful clinically orientated reference websites include:
conjunctiva yellowing & pallor
skin pallor, yellowing and coldness
heart palpitations, chest pain and increased heart rate
shortness of breath
muscle weakness
change in stool colour
fatigue, dizziness and fainting
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