The thalassaemias and

related
disorders

DR.YASEEN M. TAHER

The thalassaemias are the commonest single - gene

disorders. Thalassaemia was first recognized by Cooley
and Lee in 1925 as a form of severe anaemia associated
with splenomegaly and bone changes in children.
The term thalassaemia is derived from the Greek
(meaning the sea ) since many of
the early cases came from the Mediterranean region

Definition and
classification

The thalassaemias are classifi

ed into

,,,
, , and
thalassaemias according to the
type of globin chain(s) that is
produced in reduced amounts
The two major categories
are the and
thalassaemias while the rare
forms include the , and
thalassaemias.

Functionally, some thalassaemia mutations

cause a complete absence of globin chain
synthesis, and these are called 0 or 0
thalassaemias; in others, the globin chain is
produced at a reduced rate and these are
designated + or + thalassaemias.
The thalassaemias are subdivided in
the same way

Clinically, the thalassaemias are classified according to their severity

into major, intermediate and minor forms.
Thalassaemia major is a severe and transfusion - dependent
disorder.
Thalassaemia minor is the symptomless trait or carrier state.
Thalassaemia intermedia is characterized by anaemia (with or
without splenomegaly), though not of such severity as to require
regular transfusion. In practice, thalassaemia intermedia
encompasses a wide spectrum of clinical severities intermediate
between the two extremes of thalassaemia major and trait

The thalassaemias
The thalassaemias pose by far the most
important public health problems because they are
common and usually produce severe anaemia in
their homozygous and compound heterozygous
states.

Pathophysiology
The molecular defects in
thalassaemia result in
absent or reduced - chain
production while - chain
synthesis is unaffected.
The imbalance in globin
chain production leads to an
excess of - chains. The
free - globin chains are
highly
unstable
and
precipitate in red cell
precursors,forming
intracellular inclusions that
interfere with red cell
maturation

Clinical findings in severe thalassaemia

Severe thalassaemia usually presents in the first
year of life. Typically there is failure to thrive, with poor
weight gain and growth with developmental delay.
The parents may have noticed that the infant is pale
and jaundiced, with a protruding abdomen. There may
be a family history of severe anaemia,

Examination confirms the pallor and

jaundice, with palpable hepatosplenomegaly.
There may be evidence of marked erythroid
hyperplasia, with signs of the typical
thalassaemic facies including expansion of
the skull vault and maxillary bones.
The symptoms and signs are not specifi c
and
differential
diagnoses
include
gastrointestinal or hepatic disease, and
malignancy.

Laboratory diagnosis of severe thalassaemia

The full blood count shows a low haemoglobin, usually
less than 5 g/dL. Mean corpuscular haemoglobin (MCH)
and mean corpuscular volume (MCV) are low, with a very
wide red cell distribution width. The nucleated cell count
may be very high due to the presence of large numbers of
nucleated red cells.

A blood film shows marked anisopoikilocytosis, with

basophilic stippling and small red cell fragments

The reticulocyte count is elevated but less than

expected for the degree of anaemia, in keeping with the
ineffective erythropoiesis.
Renal function is normal, but liver function tests
show elevation of bilirubin, aspartate aminotransferase
and lactate dehydrogenase, with a normal alanine
aminotransferase.
Erythropoietin levels will be high, with soluble
transferrin receptor levels up to 30 time greater than
normal. White cell and platelet counts should be normal
unless there is hypersplenism.

A bone marrow aspirate is not essential to

make the diagnosis, but if performed shows very
marked erythroid hyperplasia, with
dyserythropoiesis.
Immunoelectron microscopy confirms that the
inclusions in thalassaemia consist of
precipitated - globin chains

Haemoglobin analysis is needed to confi rm the

diagnosis, typically using either electrophoretic or
chromatographic techniques.
This will usually show an increased amount of HbA 2 ,
with the vast majority of the remainder consisting of HbF;
small amounts of HbA may be present depending on
the globin mutation, the age of the child and whether
the child has been transfused. Absence of HbA
confirms a diagnosis of 0 thalassaemia, while
presence of HbA (pre - transfusion sample) confirms
+ thalassaemia.

Management of severe thalassaemia

Blood transfusions

The aim of regular transfusions is to correct anaemia

and suppress the abnormal erythroid hyperplasia.
Correcting anaemia improves oxygen delivery to the
tissues and facilitates normal growth and development.
Suppression of erythropoiesis stops bony distortion,
limits excessive iron absorption and reduces
extramedullary haemopoiesis.

The current recommended practice is to use red

cell units that have not been stored more than 2
weeks.
In general, the transfusion rate is 5 to
6/ml/kg/hour. In the case of patients with cardiac
failure, blood should be infused at a slower rate (no
more than 3 to 4 ml/Kg/h), and the administration of
diuretics before transfusion is advised.

The recommended interval between

transfusions should take into account the
patient's practical needs, as long as a
pretransfusional Hb ranging between 9 and
10.5 g/dl is maintained.
It is important to keep an accurate record of
the amount transfused, in order to calculate
the iron intake of the patient.

Iron overload
Iron overload inevitably complicates regular blood
transfusions and is the source of many serious
complications. Each unit of transfused blood contains
about 200 250 mg iron, compared with the 1 mg iron
normally absorbed each day.
Despite the increased iron, serum hepcidin remains
inappropriately low, which further contributes to iron
loading through increased intestinal iron absorption .

The body has no mechanism for excreting iron and iron

-chelating drugs are necessary to avoid toxic iron
accumulation.
Iron chelation is usually started after about 1 year of
monthly blood transfusions. Ideally, children delay
starting chelation until they are 3 years old, as drug
toxicity is thought to be highest in the young; it is usually
necessary to start chelation earlier in children who start
transfusions in the fi rst year of life, although in general
low doses are used.

After only a few years of transfusion, however,

transferrin is completely saturated in the majority
of patients. In thalassemia major, serum ferritin
has, in general, been found to correlate well with
iron stores, as measured by phlebotomy, and with
liver iron, either measured directly by liver biopsy
or by MRI.

Serial measurements of serum ferritin

remain a reliable means, and the easiest one,
to evaluate iron overload and efficacy of
chelation therapy.

Chelation
Currently, three drugs are used
for
iron
chelation:
desferrioxamine, deferiprone and
deferasirox.

Splenectomy

Splenectomy, associated with sporadic blood

transfusions, has for many years represented the
mainstay of therapy in thalassemia. It was often
performed shortly after diagnosis because the
spleen soon reached an enormous size and
caused severe hypersplenism, frequently leading
to profound neutropenia and thrombocytopenia.

The thalassaemias

Normal individuals have

four - globin genes
arranged as linked pairs,
2 and 1, at the tip of
each chromosome 16,
the normal genotype
being represented as
/