Types and Causes of Thalassemias Explained

The Thalassemias
Prof. Dr. Saad S Al Ani
Senior Pediatric Consultant
Head of Pediatric Department
Khorfakkan Hospital
Sharjah ,UAE
saadsalani@yahoo.com

The Thalassemias

Are a group of inherited hematologic disorders
caused by defects in the synthesis of one or
more of the hemoglobin chains.

The Thalassemias Prof. Dr. Saad S Al Ani Khorfakkan Hospital ,Sharjah
5 March 2013
,UAE
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Cont.
•Alpha thalassemia is caused by reduced or
absent synthesis of alpha globin chains.

• Beta thalassemia is caused by reduced or
absent synthesis of beta globin chains.

5 March 2013 The Thalassemias Prof. Dr. Saad S Al Ani Khorfakkan Hospital ,Sharjah
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Epidemiology
 Approximately 5 percent of the world's
population has a globin variant, but only 1.7
percent has alpha or beta thalassemia trait

•Thalassemia affects men and women equally and
occurs in approximately 4.4 of every10,000 live
births
Rund D, Rachmilewitz E. Beta-
thalassemia.
N Engl J Med. 2005;353(11):1135–
1146.
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Cont.

•Alpha thalassemia occurs most often in persons of
African and Southeast Asian descent

•Beta thalassemia is most common in persons of
Mediterranean, African, and Southeast Asian
descent
•Thalassemia trait affects 5 to 30 percent of
persons in these ethnic groups.
Rund D, Rachmilewitz E. Beta-
thalassemia.
N Engl J Med. 2005;353(11):1135–
5 March 2013 ,UAE 1146. 5

Geographical distribution of
Thalassemias

The Thalassemias Prof. Dr. Saad S Al Ani Khorfakkan Hospital
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Pathophysiology
 Hemoglobin consists of an iron-containing heme ring
and four globin chains: two alpha and two nonalpha.

•The composition of the four globin chains
determines the hemoglobin type.

Structure of human hemoglobin.
• The proteins' α and β subunits
are in red and blue, and the
iron-containing heme groups
in green.

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Normal hemoglobin

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Site of synthesis of globin

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Cont.
At birth, Hgb F accounts for approximately 80
percent of hemoglobin and Hgb A accounts for
20 percent.

The transition from gamma globin synthesis
(Hgb F) to beta globin synthesis (Hgb A)begins
before birth.

By approximately six months of age, healthy
infants will have transitioned to mostly Hgb A,
a small amount of Hgb A2, and negligible Hgb F.
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Cont.
•Fetal hemoglobin (Hgb F) has two alpha and two
gamma chains (alpha2 gamma2).

http://en.wikipedia.org

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Cont.
•Adult hemoglobin A (Hgb A) has two alpha and
two beta chains (alpha2 beta2)

http://shamelesslyatheist.wordpress.c
om
5 March 2013
The Thalassemias Prof. Dr. Saad S Al Ani Khorfakkan Hospital ,Sharjah ,UAE
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Cont.
•Hemoglobin A2 (HgbA2) has two alpha and two
delta chains (alpha2delta2).

http://en.wikipedia.org
5 March 2013 ,UAE
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Alpha Thalassemia
 Alpha thalassemia is the result of deficient or
absent synthesis of alpha globin chains, leading
to excess beta globin chains.

•Alpha globin chain production is controlled by
two genes on each chromosome 16

•Each of the four alpha globin
genes contribute to the
synthesis of the alpha globin
protein.

The Thalassemias Prof. Dr. Saad S Al
Ani Khorfakkan Hospital ,Sharjah
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5 March 2013 ,UAE

Prototypical Forms of Alpha
Thalassemia
Variant of alpha
thalassemia Chromosome 16 Signs and symptoms
Silent carrier One of four gene Asymptomatic
deletions
Trait Two of four gene Asymptomatic
deletions
Hgb Constant Spring Reduced output of alpha Silent or mildly
globin symptomatic
Intermedia with significant Three of four gene •Moderate to severe
Hgb H (Hgb H disease) deletions hemolytic anemia
• Modest degree of
ineffective
erythropoiesis
• Splenomegaly
• Variable bone changes
Major with significant Four of four gene Causes nonimmune
Hgb Bart's deletions hydrops fetalis, usually
The Thalassemias Prof. Dr. Saad S Al fatal
Ani Khorfakkan Hospital
,Sharjah ,UAE 15
5 March 2013

Chromosome 16gene deletions

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5 March 2013

www.nhlbi.nih.gov

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Beta Thalassemia
 Beta thalassemia is the result of deficient or
absent synthesis of beta globin chains, leading
to excess alpha chains.

•Beta globin synthesis is controlled by one gene on
each chromosome 11
•The two gamma globin
genes are active during
fetal growth and produce
Hgb F.
•The "adult" gene, beta, takes
over after birth.
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CONT
.
•Beta thalassemia occurs from any of more than
200 point mutations and (rarely) deletions of the
two genes.

 Beta globin chain production can range from
near normal to completely absent, leading to
varying degrees of excess alpha globin to beta
globin chain production.

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Prototypical Forms of Beta
Thalassemia
Variant of Beta
thalassemia Chromosome 11 Signs and Symptoms
Trait One gene defect Asymptomatic
Intermedia Two genes defective (mild to Variable degrees of
moderate decrease in beta severity of symptoms
globin synthesis) of thalassemia major
Major Two genes defective (severe •Abdominal swelling
decrease in beta globin • Growth retardation
synthesis) •Irritability
• Jaundice, pallor
•Skeletal abnormalities
• Splenomegaly
• Requires lifelong
blood
transfusions

The Thalassemias Prof. Dr. Saad S Al Ani Khorfakkan Hospital ,Sharjah ,UAE 21
5 March 2013

Chromosome 11 gene defect

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Severity of β-Thalassemia

5 March 2013
The Thalassemias Prof. Dr. Saad S Al Ani Khorfakkan Hospital ,Sharjah ,UAE 23

Beta Thalassemia –bone changes

surgerypicts.blogspot.com


Anteroposterior radiograph of the lumbar spine.
Osteopenia is present; striated appearance of the vertebral bodies resulting
from preservation and thickening of the vertical trabeculae.
Clips from a previous cholecystectomy are present.

5 March 2013 The Thalassemias Prof. Dr. Saad S Al Ani Khorfakkan Hospital
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Lateral skull radiograph.
Widening of the calvarium is present;
-The outer table overlying the frontal region is obliterated
- New bone formation can be seen in the diploë, producing a "hair-on-end“
appearance.

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Anteroposterior of the hands.
. A generalized loss of bone density is observed.
-The cortex is thinned
-The trabeculae are coarsened
- Outline localized lucency.
. Widening of the medullary cavity has resulted in squaring of the metacarpals
- The enlarged nutrient foramina in the middle phalanges.

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Anteroposterior radiograph of the forearm.
A fracture is noted in the distal radius.
Evidence of medullary expansion and cortical thinning is observed.

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Radiograph of the ribs.
Erosions of the inferior cortical margins of the third, fourth, and fifth ribs are
noted.

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Other β-Thalassemia
Syndromes
The β-thalassemia syndromes are
broken into six groups:
1. β-thalassemia
2. δβ- Thalassemias
3. γ- Thalassemias
4. δ-thalassemias
5. ϵγδβ- Thalassemias
6. the HPFH syndrome.
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Pathogenesis of Beta Thalassemia

medicinembbs.blogspot.co
The Thalassemias
m
Prof. Dr. Saad S Al Ani Khorfakkan Hospital ,Sharjah
,UAE 31
5 March 2013

CONT.
 The one gene defect, beta thalassemia trait
(minor) is asymptomatic and results in
microcytosis and mild anemia.

•If the synthesis from both genes is severely
reduced or absent, the person has beta
thalassemia major, also known as Cooley
anemia.

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CONT
.
•If the synthesis of beta chains is less severely
reduced , the person has beta thalassemia
intermedia.
 Persons with beta thalassemia major are almost
never symptomatic at birth because of the presence
of Hgb F, but symptoms begin to develop by six
months of age.

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Diagnosis
 Most persons with thalassemia trait are found
incidentally when their complete blood count
shows a mild microcytic anemia

•Microcytic anemia can be caused by:
1. Iron deficiency
2.Thalassemia
3. Lead poisoning
4.Sideroblastic anemia
5.Anemia of chronic disease.

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CONT.
 To exclude some of these etiologies , the
followings can help:
- Mean corpuscular volume (MCV)
- Red blood cell distribution width (RDW)
- Patient's history

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Hematologic Indices of Iron
Deficiency and Alpha and Beta
Thalassemia
Test Iron deficiency Beta thalassemia Alpha thalassemia
MCV (abnormal if Low Low Low
• < 70 fl in children six
months to six years of
age
• < 76 fl in children
seven
to 12 years of age)
Red blood cell High Normal; Normal
distribution width(RDW) occasionally high
Ferritin Low Normal Normal
Mentzer index for > 13 < 13 < 13
children (MCV/red blood
cell count)
Hgb electrophoresis Normal (may •↑ Hgb A2 Newborns: may
have↓ HbA2) • ↓ Hgb A have Hgb H or Hgb
Bart's
•Probably↑ Hgb F

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Use of RDW Values in the
Diagnosis of Thalassemia
Microcytic Anemia
Children 6 months -6 years of age: MCV <70fl
Children 7 to 12 years of age: MCV <76fl
↓
RDW
↓ ↓
Normal Elevated (>15)
↓ ↓
Favors Ferritin level
Thalassemia
↓ ↓
Normal(>100ng/m Low(<10ng/mL)
L)
↓ ↓
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Supplemental tests
 Include:
- Serum ferritin
- The peripheral smear
- Hemoglobin electrophoresis
- Serum lead level
- Rarely bone marrow aspirate

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The peripheral smear of
Thalassemia major

www.wardelab.com

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Cont.
 The hemoglobin electrophoresis with beta thalassemia
trait usually has:
- Reduced or absent Hgb A
- Elevated levels of Hgb A2
- Increased Hgb F

•A normal concentration of HbA2 does not rule
out beta thalassemia trait, especially if there
was coexistent iron deficiency

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The hemoglobin electrophoresis

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Time of complications of
Thalassemia

www.nyas.org

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Treatment

 Blood Transfusions
 Iron Chelation Therapy
 Splenectomy
 Bone Marrow Transplant

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Cont.
 Beginning transfusion and chelation
therapy are difficult challenges for parents
to face early in their child's life.

• Blood products that are leukoreduced and
phenotypically matched for the Rh and
Kell antigens are required for transfusion

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Cont.
 If a bone marrow transplant is a
possibility, the blood for transfusion
should be negative for cytomegalovirus

•Hematopoietic stem cell transplantation
has cured >1,000 patients who have β-
thalassemia major.

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Cont.
 Most success has been in children
1. younger than 15 yr of age
2. without excessive iron stores and
hepatomegaly
3. who undergo sibling HLA-matched
allogeneic transplantation.

•All children who have an HLA-matched
sibling should be offered the option of
bone marrow transplantation

Prevention
 Blood tests and family genetic studies can
show whether an individual has
thalassemia or is a carrier.

•A genetic counselor can detail the family
background, discuss risks, and give you
information on available testing.

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Summary
1. Imbalances of globin chains cause:
- Hemolysis
- Impair erythropoiesis

2.Silent carriers of alpha thalassemia and
persons with alpha or beta thalassemia trait
are asymptomatic and require no treatment.

3.Alpha thalassemia intermedia, or hemoglobin H
disease, causes hemolytic anemia.
http://www.aafp.org

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Cont.
4.Alpha thalassemia major with hemoglobin
Bart's usually results in fatal hydrops fetalis

5.Beta thalassemia major causes:
- Hemolytic anemia
- Poor growth
- Skeletal abnormalities during infancy
6.Affected children will require regular lifelong
blood transfusions.

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Cont.
7.Beta thalassemia intermedia is less severe
than beta thalassemia major and may
require episodic blood transfusions

8.Transfusion-dependent patients will develop
iron overload and require chelation therapy to
remove the excess iron

http://www.aafp.org

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Cont.
10.Bone marrow transplants can be curative for
some children with beta thalassemia major

11.Persons with the thalassemia trait have a
normal life expectancy.

12.Persons with beta thalassemia major often
die from cardiac complications of iron
overload by 30 years of age.

http://www.aafp.org

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When this picture will disappear?

http://soulverses.org/

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Types and Causes of Thalassemias Explained

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Types and Causes of Thalassemias Explained