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Chapter 3 notes

Hypochromic anaemias
Iron deficiency anaemia is the most common cause of anaemia
The storage forms of iron, ferritin and haemosiderin, constitute about 13% of total body
iron.
The small peptide hepcidin plays a key role in iron metabolism and absorption
Iron is contained in:

Haemoglobin

the reticuloendothelial system (as ferritin and haemosiderin)

muscle (myoglobin)

plasma (bound to transferrin)

cellular enzymes (e.g. cytochromes, catalase, succinic dehydrogenase)

Reticuloendothelial cells (macrophages) gain iron from the haemoglobin of effete red cells and
release it to plasma transferrin which transports iron to bone marrow and other tissues with
transferrin receptors (TfRs).

Characteristics of storage proteins:

Solubility
Molecular weight
Structure

Iron weight
Light microscopy
Stain

Ferritin
Water-soluble
465000
Outer protein shell
apoferritin
22 subunits
iron-phosphatehydroxide core
20%
X

Haemosiderin
Insoluble
Derivative of ferritin
aggregates (via lysosomal
digestion)

37%

Perls reaction (Prussian


Blue)

Transport and storage is mediated by 3 proteins:


1) Transferrin (small proteins that come from dietary iron; delivers iron to the tissues that
has TfRs particularly erythroblasts)
2) Transferin Receptor (TfR1)
3) Ferritin

Regulation of Ferritin and TfR1 synthesis:

Hepcidin:

synthesized by the liver cells that controls iron absorption and circulation

major hormonal regulator of iron homeostasis

regulator of ferroportin concentration

It lowers cell levels of ferroportin (protein that allows iron entry into the portal
circulation; transmembrane iron exporter) by accelerating degradation of ferroportin
mRNA

Hepcidin therefore reduces both iron absorption and iron release from macrophages (and
intestinal epithelial cells) to transferrin

Hepcidin synthesis is controlled by various proteins, e.g. HFE, hemojuvelin (HJV) and
the minor transferrin receptor TfR2. Mutation of any of these lowers hepcidin secretion
and causes excess iron absorption

Inflammation increases hepcidin synthesis through increased levels of IL-6.

Increased iron stores stimulate hepcidin synthesis while iron deficiency reduces it.
Increased erythropoiesis lowers hepcidin synthesisbecause of a protein GDF15 released
from erythroblasts.

Iron absorption:

Absorbed as haem and partly broken down in


the gut to inorganic iron

Inorganic iron absorbed through duodenum

Absorption is regulated by DMT-1 at the


villous tip and ferroportin (controlled by
hepcidin) at the basolateral surface of the
enterocyte

At the luminal surface iron is reduced to the


Fe2+ state and on entry to portal plasma reoxidized to Fe3+. It then binds to transferrin.

Causes of iron deficiency:

Laboratory findings:
Hypochromic microcytic anaemia.
Raised platelet count.
Blood film appearances include
hypochromic/microcytic cells,
anisocytosis/poikilocytosis, target cells and
pencil cells.
Bone marrow not needed for diagnosis:
erythroblasts show ragged irregular cytoplasm;
absence of iron from stores and erythroblasts
(detected by Perls stain).
Serum ferritin reduced, serum iron low with
raised transferrin and reduced saturation of
iron-binding capacity

Treatment
Oral iron ferrous sulfate is best (200 mg, 67 mg iron per tablet) before meals three times
daily.
A reticulocyte response begins in 7 days, but treatment should be continued for 46 months to
replenish stores.
Side effects (e.g. abdominal pain, diarrhoea or constipation) require a lower dose, taking iron
with food, or a different preparation (e.g. ferrous gluconate 300 mg, 37 mg iron per tablet).
Poor response may be because of continued bleeding, incorrect diagnosis, malabsorption or
poor compliance.
Oral iron, often combined with folic acid, is given for iron deficiency in pregnancy.
Intravenous iron is used in patients with malabsorption or who are unable to take oral iron.
Ferric hydroxyide sucrose (Venofer), iron dextran (Cosmofer), ferric carboxymaltose (Ferinject)

and iron isomaltoside (Monofer) are useful to treat iron deficiency anaemia and replenish iron
stores. In the United States ferumoxytol (Feraheme) is also used.

Other investigations

History (especially for blood loss, diet, malabsorption)

Tests for cause (especially in males and postmenopausal females) include occult blood
tests, upper and lower gastrointestinal endoscopy, capsule (camera) endoscopy, tests for
hookworm, malabsorption and urine haemosiderin.

Haemoglobin high performance liquid chromatography (HPLC) or and/or globin gene


DNA analysis to exclude thalassaemia trait or other haemoglobin defect causing a
microcytic hypochromic blood picture

Tests for transglutaminase antibodies and duodenal biopsy

Other frequent causes of a hypochromic,


microcytic anaemia are the anaemia of
chronic disordes which occurs in
patients with chronic inflammatory or
malignant diseases, or
thalassaemia. Less frequent cases
include sideroblastoc anaemia and
lead poisoning
Sideroblastic anaemia

a refractory anaemia in which the marrow shows iron present as granules arranged in a
ring around the nucleus in developing erythroblasts (ringed sideroblasts)

At least 15% of erythroblasts show this in the primary forms.

A defect of haem synthesis is present

Most frequent is a subtype of myelodysplasia

Classification:
In hereditary forms the anaemia is characterized by

A hypochromic and microcytic blood film

An X-linked genetic defect in haem synthesis (eg. ALA-S gene mutations on the X
chromosome, ataxia mitochondrial defects, thiamine-responsive and other autosomal
defects)

These occur predominantly in males.

In the primary acquired type (a type of myelodysplasia), which is the most common, the
anaemia is characterized by

ringed sideroblasts (less than 15%) may also occur with other haematological disorders
and with alcohol, isoniazid therapy and lead poisoning.

Treatment:

Pyridoxine therapy

Erythropoietin (primary acquired)

Repeated blood transfusion and iron chelation are often required (severe cases)

Lead poisoning

Inhibits haem and globin synthesis at several points

Disrupts RNA breakdown by inhibiting 5nucleotidase. Leads to accumulation of


denatured RNA in cell

blood film shows basophilia stippling in Rowansky stain (blue staining dots is
undegraded RNA)

hypochromic or haemolytic

marrow may show ringed sideroblasts

Free erythrocyte protoporhyrin increased

Anemia of Chronic Disorders

A common normochromic or mildly hypochromic anaemia, occurring in patients with


different inflammatory and malignant diseases

Reduced serum iron and total iron-binding capacity

Normal or raised serum ferritin with adequate iron stores in the bone marrow but
stainable iron absent from erythroblasts.

Characteristics:
1) Normochromic, normocytic or mildly hypochromic red cells

MCV rarely <75 fL

2) Mild, non progressive anaemia

Haemoglobin rarely <9.0fL

3) Reduced serum iron and TICB (total iron binding capacity)


4) Serum ferritin normal or raised
5) Erythroblast iron reduced; bone marrow iron normal
Causes:
Chronic inflammatory diseases

Infections (eg. Pulmonary abscess, tuberculosis, osteomyelitis, pneumonia, bacterial


endocarditis)

Non-infectious (eg. Rheumatoid arthritis, systemic lupus erythematosus and other


connective tissue diseases, sarcoidosis, Chrons disease, Gauchers disease)

Malignant disease

Carcinoma, lymphoma, sarcoma

Pathogenesis
Related to reduce iron absorption and iron release by macrophages into plasma due to

raised hepcidin levels

Reduced red cell lifespan

Inadequate erythropoietin response caused by IL-1 cytokin and TNF on erythropoiesis