Sie sind auf Seite 1von 43

Classification of Anaemia:

Microcytic Hypochromic Anaemia


Chapter 2
Prepared by Noor Izzah Abd Rahman

Classification of Anaemia
Microcytic &
Hypochromic

Normochromic
& Normocytic

MCV within RR
MCH within RR

MCV<RR
MCH<RR

Defects in
haem
synthesis

Iron
deficiency
ACD
Sideroblastic
(congenital)

Macrocytic

Defects in
globin
synthesis

Thalassaemia
Haemoglobinopathies

Acute blood loss


Haemolysis
ACD
Marrow infiltration

MCV>RR

Megaloblastic

B12/Folate deficiency

Non-megaloblastic

Liver
disease
Drug
induced
MDS

Iron Regulation

Normal Iron Absorption and


Metabolism

Ferritin
Iron storage protein
Produced by all living organisms including bacteria, algae, &
higher plants and animals
In humans, it acts as a buffer against iron deficiency and
iron overload
Consists of:
Apoferritin protein component
Core- ferric, hydroxyl ions and oxygen

Largest amount of ferritin-bound iron is found in:


Liver hepatocytes (majority of the stores)
BM
Spleen

Excess dietary iron induces increased ferritin production


Partially digested ferritin= HAEMOSIDERIN- insoluble and
can be detected in tissues (hepatocytes) using Perls
Prussian blue stain

Transferrin (Tf)

Transports iron from palsma to erythroblast


Mainly synthesized in the liver
Fe3+ (ferric) couples to Tf
Apotransferrin = Tf without iron
Contains sites for max 2 iron molecules
The amount of diferric Tf changes with iron status
Levels decreased when cellular iron demand is
increased
Increased levels lead to increase hepcidin production
that decreases iron absorption

Transferrin Receptor (TfR)


Provides transferrin- bound iron access into cell
Control of TfR synthesis is one of major
mechanisms for regulation of iron metabolism
Cells maintain appropriate iron levels by altering TfR
expression and synthesis
Increased by iron deficiency

Located on all cells except mature RBC


Can bind up to 2 Tf
apoTf is not recognized by TfR

Ferroportin
Transmembrane protein
Found on the surface of most cells:
Enterocytes
Hepatocytes
RE system

Regulates iron release from those tissues (iron


exporter)
Hepcidin receptor

Hepcidin
Is an antimicrobial peptide produced in the liver
Act as a negative regulator of intestinal iron absorption
& release from macrophages
Hepcidin binds to the ferroportin receptor & cause
degradation of ferroportin, resulting in trapping of iron
in the intestinal cells
As a result, iron absorption & mobilization of storage
iron from the liver & macrophage are lowered
Increased synthesis of hepcidin occurs when transferrin
saturation is high and decreased synthesis when iron
saturation is low

Causes of Iron deficiency


Blood loss:
GIT
Urinary

Malabsorption

Increased demand:
Growth
Pregnancy

Major causes of
IDA in Western
Society

Haemolysis

Major causes of IDA


in developing
countries

Parasitic infection

Malnutrition

Inadequate intake
Infants
vegetarian

Iron sequestration at
inaccessible sites (pulmonary
haemosiderosis)

Symptoms of Iron Deficiency


Mainly attributed to anaemia

Fatigue
Pallor
Shortness of breath
Tachycardia
Failure to thrive

More specific features (only apparent in severe


IDA ):
Koilonychia
Glossitis
Unusual dietary cravings (pica)

Stages of Iron Deficiency


3 stages
Stage 1
Characterized by a progressive loss of storage
iron
Bodys reserve iron is sufficient to maintain
transport and functional compartments through
this phase, so RBC development is normal
No evidence of iron deficiency in peripheral blood
and patient experiences no symptoms

Stage 2
Defined by exhaustion of the storage pool of
iron
For a time, RBC production is normal relying
on the iron available in transport
compartment
Anaemia may not be present but Hb level
starts to drop
Serum iron, ferritin and Tf saturation
decreased
Increased TIBC, Tf and TfR

Stage 3
Microcytic hypochromic anaemia
Having thoroughly depleted storage iron and
diminished transport iron, developing RBCs
are unable to develop normally
The result is first smaller cells with adequate
[Hb], although these cannot be filled with Hb
leading to cells becoming microcytic &
hypochromic
FBE parameters & iron studies all outside RR

Diagnosis - FBE

Hb or borderline
RBC
Hct/PCV
MCV
MCH
MCHC
RDW
+/- thrombocytosis
Elongated cells
Target cells (severe IDA)

Diagnosis- Iron studies


Ferritin

Results in
IDA

Serum
Iron

Transferrin

Tf
Saturation

TIBC

TfR

Differential diagnoses
Thalassaemias/ Haemoglobinopathies
Not all hbpathies are microcytic and hypochromic

Anaemia of chronic disease


Congenital sideroblastic anaemia

Treatment of Iron Deficiency


Treatment of underlying cause (ulcers)
Dietary supplementation
Oral supplements

Transfusion
If anaemia is symptomatic and life threatening
No prompt response to treatment

Dimorphic blood film is present in treated IDA


With oral supplements-newly produced cells are
normochromic normocytic
Transfused cells are normochromic and normocytic

Anaemia of Chronic Disease


Anaemia of chronic inflammation
Usually normochromic normocytic; microcytosis &
hypochromia develop as the disease progress
Iron stores abundant, but iron is NOT available for
erythropoiesis
There are several proposed mechanism for abnormal
iron haemostasis in ACD:
Lactoferrin competes with transferrin for iron
RBC dont have lactoferrin receptors

Ferritin increases
Cytokines inhibit erythropoieis
HEPCIDIN

ACD- Role of Hepcidin


Increase in hepcidin:
Levels can be increased up to 100 times in ACD
Release from liver after stimulation by IL-6
Acute phase reactant

Binds to ferroportin
Decreases iron absorption and export from cells

Diagnosis & Treatment


Identification of the disease
CRP & IL 6
Measurement of hepcidin levels via ELISA, HPLC
or LCMS
Iron studies to distinguish from IDA
Failure to respond to iron supplementation
Tx:
Maintaining normal Hb is challenging
EPO administration + IV iron
Anti-inflammatory therapy

Sideroblastic anaemia
Can either be inherited or acquired
Rare condition
Most common mutation is in ALA synthase gene
(ALAS2) located on X chromosome
Abnormal haem synthesis & presence of ringed
sideroblasts in erythroid precursors (visible if
stained with Perls Prussian Blue)
Microcytic hypochromic anaemia
Ineffective erythropoiesis
Systemic iron overload

STRUCTURE OF HAEMOGLOBIN

Polypeptides are made up of 2a chains and 2B chains, a2B2. Haem groups bind
oxygen.

STRUCTURE OF HAEM

Haem structure: the iron (Fe)at the centre


enables oxygen to bind

Development of Haemoglobin

Stages of Haemoglobin Development


Embryonic haemoglobin
Hb Gower 1 z2e2
Hb Portland a2g2
Hb Gower 2 a2e2

Foetal Haemoglobin
Hb F a2g2 Foetus 100%

Adult haemoglobins

Adult <1%

Hb A2 a2d2
Adult 1.8-3.6%
Hb A a2b2
Adult 96-98%
The globin genes are arranged on the chromosomes in order of
expression

Inherited defects of globin sythesis


These are due to:
1. Synthesis of an abnormal haemoglobin eg
haemoglobinopathies
2. Reduced rate of synthesis of or chains:
thalassaemia

- Thalassaemia
Caused by defective B globin chain synthesis
Due to mutations in the B globin gene
The unpaired chain precipitate in the
developing cells leading to damage to the RBCs
surface ~ leading to removal of RBCc by
macrophages
Leads to ineffective erythopoiesis
The more chain in excess, the more haemolysis
occurs
Can be divided into B-thal minor and B-thal major

B-thal minor
Results when 1 of the 2 gene that produces Bchain is defective (heterozygous)
Usually present as a mild asymptomatic
anaemia
Hepatomegaly and splenomegaly are seen in
some patients

B-thal major
Characterized by severe anaemia first
detected in early childhood as to switch
takes place
Patient
presents
with
jaundice,
hepatosplenomegaly, marked bone changes
(frontal bossing)

thalassaemia
Due to large deletions in the globin genes
Notation for the normal gene complex or
haplotype is expressed as , signifying 2
normal genes on chr 11
There are 4 clinical syndromes of
thalassaemias;
silent
carrier,
-thal
minor/trait,
HbH
disease
(due
to
accumulation of unpaired B chain,
homozygous -thal (hydrops foetalis)

Signs & Symptoms of Thalassaemia


Severe anaemia first detected in early
chilhood
Jaundice, hepatosplenomegaly, marked bone
changes (frontal bossing)
Microcytic hypochromic anaemia

Laboratory Findings

Most thalassaemias are microcytic & hypochromic


Hb and PCV, MCV
RCC
Poikilocytosis, target cells, elliptocytes, polychromasia,
nRBCs, basophilic stippling
Bone marrow hypercellylar with extreme erythroid
hyperplasia
Electrophoresis- decresead % of Hb A
Supravital stain to detect thalassaemia major (HbH)

Treatment
1.
2.
3.
4.

Transfusion
Iron chelation therapy- desferrioxamine
BM transplantation
Hydroxyurea- to increase Hb F levels enough to
eliminate transfusion requirements for patients
with thalassaemia major

Hb
107 120160g/L
RCC 5.50 3.805.401012/L
MCV 61
80-100 fL
MCH 19.5 27-32 pg
Hb A2 5.0 1.8-3.5 %
Hb F <0.1 0.0-1.0 %

Comparison of a normal blood film


with b-thal major

Normal Blood Film


Bain B. Blood Cells. A practical guide2006

Intermittently transfused b-thal


HbF>90%
Free a chains form Heinz bodies and inclusions
Marked haemolysis
reticulocytosis
Basophilic stippling and Pappenheimer bodies

HbH Disease

Study Questions
What are the main causes of IDA?
Draw a diagram that explains how iron
haemostasis is maintained in the body
Discuss different stages of development of IDA
How would you differentiate between
different microcytic and hypochromic
anaemia?
Explain the involvement of iron regulatory
proteins in ACD

Study Questions

Describe how you would approach the investigation of a patient who has been
diagnosed with mild microcytic hypochromic anaemia. In your answer include the
tests, expected results and how they would help you differentiate the disorders to
make a final diagnosis.
Are thalassaemias & haemoglobinpathies the same? Why?
Why do patients with iron deficiency and a suspected thalassaemia need to
receive iron replacement therapy before Hb electrophoresis and HPLC can be
performed? How does iron deficiency influence these tests and the results
obtained?
Describing the principle and rationale, explain why Hb electrophoresis and HPLC
can be used to diagnose these disorders. Are there any analytical errors that could
lead to inaccurate results?
What role does prenatal diagnosis & genetic counseling have in this group of
disorders?