Download Anemia - Shanyar

Anemias
Thalassemias
Professor Nasir Allawi
Definition of Thalassemia
• A group of inherited
disorders of
Hemoglobin synthesis, characterized by
reduced or absent synthesis of one or more
of the globin chains of Hemoglobin.
• They are labeled  thalassemias, if it
is the alpha chain that is affected,
and  thalassaemias, if it is the Beta.
β- Thalassaemia
• β-Thalassaemias are inherited defects in the rate of
synthesis of β-globin chains of hemoglobin, which are
widely distributed throughout the world, with considerable
frequencies
in
certain
areas
particularly
the
Mediterranean and Middle Eastern countries, including
Kurdistan and Iraq.
• β-Thalassaemia major is an important health problem
throughout Iraq, including Kurdistan , where there are
more than 800 registered patients in Sulaimani, in
a population of about 1500000 .
Iraq
Global Distribution of Hb- Disorders
Types of normal Hemoglobins
• All Normal Hemoglobins consists of two
pairs of globin chains, at the centre of
each is one heme group.
• Hb A ( Adult Hb) : 2 2 (~96%).
• Hb F (Fetal Hb) :
2 2 (<1.0%).
• Hb A2 (minor Adult Hb) :
3.5%).
2 2
(1.8-
Types of Normal Hb
hemoglobin molecule
four -globin genes
two -globin genes
two  chains
two  chains
 Thalassaemia
• This is one of the most common inherited
hematological disorders in Iraq.
• It was estimated that around 4.4-6.5% of
the population of the country carry
thalassemia genes (Baghdad : 4.4%, Basra :
4.6%, Mousel : 6.5%, Duhuk 3.7%,
Sulaimani 4.1%).
Genetics of  thalassemia
• There is one β- globin gene on each chromosome 11 in
human genome.
• This form of thalassaemia is mostly caused by point
mutations involving various points in and around the beta
globin gene.
• The inheritance of this disorder is autosomal recessive, so
that heterozygous are usually symptomless, while
homozygotes are severely or moderately affected.
• β0 denotes absent β chain synthesis, while β+ means
reduced synthesis of β chain .
Clinically β thalassaemia could be
classified into :
• β Thalassaemia Major :
Severe clinical manifestations presenting before the age of 2
years, usually transfusion dependent. Due usually to
homozygosity to β thalassemic gene defect (β0 β0, β+ β+, β0
β+) .
• β Thalassaemia minor :
Mild or no clinical manifestations, usually does not require
specific management. Due usually to heterozygosity to β
thalassemia gene defect(β0β or β+ β) .
• β Thalassaemia Intermediate :
Moderate manifestations, intermediate between major and
minor.
Simplified diagram of types of Beta thal.
Genetic defect & relevance of Beta chain Normal  chain production
production
Normal  gene
+thal. Gene defect
reduced  chain production
o thal. Gene defect
No  chain production
Defective  gene

Chr 11

Chr 11
Normal
beta genes
Normal  gene

Chr 11

Chr 11
Heterozygous to
beta thalassaemia
genetic defect
Thalassamia
Minor
Homozygous to
beta thalassaemia
genetic defect
Thalassamia
Major

Chr 11

Chr 11
Clinical features of β thalassaemia Major
• First diagnosis between age of 6 months and 2 years.
• Presentation usually with pallor, poor feeding, failure to
thrive , abdominal swelling (due to hepato-splenomegaly)
and sometimes Jaundice.
- Deformities in the skull due to bone marrow expansion
(Bossing , and mongoloid facies; hair-on-end appearance
on skull X-ray).
- Also dental problems and inadequate drainage of sinuses
and middle ear, leading to chronic sinusitis and deafness
- Increased frequency of infections.
Clinical features – thal. major
Bossing of the skull- thal. major
Hair-on-end sign on skull X ray in thal. major
Widening of Diploic
space – Skull
Blood Picture in Thalassaemia major
• Complete Blood Picture (CBP)
• Hemoglobin is usually 3-7 g/dl.
• Moderate to sever hypochromic microcytic anemia, with
marked anisopoikylocytosis.
• PCV is evidently reduced.
• MCV and MCH are both reduced.
• Leucocytes : Maybe normal or increased.
• Plateletes : may be normal or increased.
• Reticulocytes : usually range 2-8%.
• Hb electrophoresis:increased Hb F 10-98%. Hb A2 is
variable.
Blood film in Thalassaemia major
Iron Overload
Prognosis in thal major
• If no Transfusions, death usually occurs in the first few
years of life.
• If iron overload is allowed to occur then death in 2nd or
early third decade, most commonly due to progressive
cardiac damage due to iron deposition, with heart failure
or arrhythmias, often precipitated by infections.
• However if measures to prevent Iron overload by Iron
Chelation are instituted early on, with the transfusion, Iron
overload consequences may be limited, although delayed
puberty and stunted growth may still be encountered, but
otherwise patients may develop normally.
Blood Picture of thal. minor
• Hemoglobin is usually reduced 1-2 g/dl less than normal for
age and sex.
• MCH and MCV are reduced.
• RBC count is > 5 x 1012/L in 85% of cases.
• Reticulocyte count is slightly increased or normal.
• Blood film : slight hypochromia, anisocytosis, poikiocytosis,
microcytosis, tear drop cells and target cells.
Diagnostic tests in  thal minor:
• Increase in Hb A2 : Normal range of Hb A2
is 1.8-3.5%, in Beta thalassemia minor it is
increased to 4-7% .
• Increased Hb A2 is considered diagnostic of
Beta thalassemia minor.
• S. Transferrin saturation(S.Iron/TIBC) is
usually normal or upper normal.
Blood Film in thal minor
Thals. Major
Normal blood film
Thalassemia minor
Normal blood film
Alpha thalassaemias
• Much less common in our country than Beta
thalassemias, and of much less clinical
significance.
• Due to reduced or absent synthesis of alpha ()
globin chains of hemoglobin.
• (Alpha () chains are constituents of all three
normal Hb A, A2 and F).
Genetics of Alpha thalassemias
• There are two  genes on each of chromosome 16, so there
is a total of 4  genes in the human genome.
• The defects leading to alpha thalassemias are usually
deletions removing one or both alpha genes.
• o defects : if both  genes are deleted so no
alpha chain production by chr. 16.
• + defect : if only one of the  genes is deleted,
so the production of  chains is reduced.
An over-Simplified diagramatic representation of
the + and o thalassaemia genetic defects
 
Normal
 genome
+
Normal  chain production
Two  genes

One  gene
reduced  chain production
o
No Alpha chain production
No  genes
Normal  gene
Deleted  gene
Clinical Phenotypes of Alpha thalassaemia (relevant to number of alpha genes remaining):
No alpha
genes
o
o
Incompatible with life
One
Alpha
gene
+
o
Thalassaemia
intermedia phenotype
No alpha
chains
1. Hb Barts Hydropes Fetalis
Markedly reduced
alpha chain
production
2. Hb H disease
Two
alpha
genes
+
Moderately
reduced Alpha
chains

+
3.  Thalassemia minor
Normal
Three
Alpha
genes
+
 genes
Minimally
reduced Alpha
chains
4. Silent  thal. carrier state
Hb Bart’s Hydrops Fetalis
• Common only in SEA.
• Genetics :
Due to inheritance of o defect from both parents, so
(--/--). So no Hb F but 4 (Hb Barts) which is
ineffective as an Oxygen carrier.
• Clinical :
Death in utero, or within hours of birth.
CBP
Sever
hypochromic
anemia
with
anisopoikylocytosis.
Hb electrophoresis;
• Electrophoresis :
~ 80% Hb Barts (4),
marked
Hb Bart’s Hydrops Fetalis
Hemoglobin H disease
• Common in South East Asia, less so
Mediterranean countries. Sporadic in Iraq.
in
• The only clinical phenotype of alpha thalassaemia
of clinical significance.
• Due to deletion of three of the four normal alpha
genes… so only one functional alpha gene is left
with associated marked reduction in alpha chain
production.
Blood film in Hb H disease
Clinical Features
•
•
•
•
Very variable, variable pallor.
Variable degrees of splenomegaly.
Sometimes Jaundice.
Most unusual to see severe thalassaemic skeletal changes
or growth retardation.
• Usually survive to adult life.
• Anemia aggravated by infections, oxidant drugs.
CBP
Sever hypochromic anemia with marked anisopoikylocytosis.
Hb electrophoresis;
• Electrophoresis :
~ Shows Hb A with 5-40% Hb H.
• On modification of the retics stain : characteristic Hb H
inclusions could be seen in RBCs( Golf ball appearance).
Hb H preparation
Hemoglobin H disease
Alpha thalassemia minor
• Due to deletion of two alpha genes, leaving only two alpha
genes, so only moderate reduction of alpha chain
production.
• Clinical and blood picture, exactly the same as beta
thalassaemia minor.
• Hb electrophoresis shows Hb A, with normal or reduced
Hb A2 and normal Hb F.
Normal blood film
Iron Deficiency Anemia
Blood Film in thal minor
Normal blood film
Thalassemia minor