The Thalassemias

The Thalassemias

Prof. Dr. Saad S Al Ani

Senior Pediatric Consultant

Head of Pediatric Department

Khorfakkan Hospital

Sharjah ,UAE

[email protected]

mailto:[email protected]

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The Thalassemias

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

April 12, 2023The Thalassemias Prof. Dr. Saad S Al Ani Khorfakkan Hospital ,Sharjah ,UAE

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Cont.

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

•Alpha thalassemia is caused by reduced or absent synthesis of alpha globin chains.

April 12, 2023 The Thalassemias Prof. Dr. Saad S Al Ani Khorfakkan Hospital ,Sharjah ,UAE

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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):1135–1146.April 12, 2023

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

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Geographical distribution of Thalassemias


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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.com


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Cont.•Hemoglobin A2 (HgbA2) has two alpha and two delta chains (alpha2delta2).

http://en.wikipedia.org


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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.

Alpha Thalassemia

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Prototypical Forms of Alpha ThalassemiaVariant of alpha thalassemia Chromosome 16 Signs and symptoms Silent carrier One of four gene

deletionsAsymptomatic

Trait Two of four gene deletions

Asymptomatic

Hgb Constant Spring Reduced output of alpha globin

Silent or mildly symptomatic

Intermedia with significant Hgb H (Hgb H disease)

Three of four gene deletions

•Moderate to severe hemolytic anemia• Modest degree of ineffective erythropoiesis• Splenomegaly• Variable bone changes

Major with significant Hgb Bart's

Four of four gene deletions

Causes nonimmune hydrops fetalis, usually fatal

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Chromosome 16gene deletions

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www.nhlbi.nih.gov

April 12, 2023


http://www.nhlbi.nih.gov/

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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.

Beta Thalassemia

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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.

•Beta thalassemia occurs from any of more than 200 point mutations and (rarely) deletions of the two genes.

CONT.


20April 12, 2023 The Thalassemias Prof. Dr. Saad S Al Ani Khorfakkan

Hospital ,Sharjah ,UAE

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Prototypical Forms of Beta ThalassemiaVariant of Beta thalassemia Chromosome 11 Signs and SymptomsTrait One gene defect Asymptomatic

Intermedia Two genes defective (mild to moderate decrease in beta globin synthesis)

Variable degrees of severity of symptoms of thalassemia major

Major Two genes defective (severe decrease in beta globin synthesis)

•Abdominal swelling• Growth retardation•Irritability• Jaundice, pallor•Skeletal abnormalities• Splenomegaly• Requires lifelong blood transfusions

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Chromosome 11 gene defect


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Severity of β-Thalassemia


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Beta Thalassemia –bone changes

surgerypicts.blogspot.com


https://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&docid=KxErcjyps8eODM&tbnid=5yd-nFjyqtRqnM:&ved=0CAQQjB0&url=http://surgerypicts.blogspot.com/2013/01/thalessemia.html&ei=IzsnUYezCZDomAWk74GQAg&bvm=bv.42768644,d.bmk&psig=AFQjCNGXktDSDkWovFth-s2J3SZDfNAoUA&ust=1361611789488600

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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.


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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.

April 12, 2023


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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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medicinembbs.blogspot.com

Pathogenesis of Beta Thalassemia

April 12, 2023


https://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&docid=fWC9S3YrLWGaYM&tbnid=O3hk5j0NoW3C_M:&ved=0CAQQjB0&url=http://medicinembbs.blogspot.com/2011/01/thalassemia.html&ei=BzwnUd_PHJCKmQX-zYGICw&bvm=bv.42768644,d.bmk&psig=AFQjCNGXktDSDkWovFth-s2J3SZDfNAoUA&ust=1361611789488600

https://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&docid=fWC9S3YrLWGaYM&tbnid=O3hk5j0NoW3C_M:&ved=0CAQQjB0&url=http://medicinembbs.blogspot.com/2011/01/thalassemia.html&ei=BzwnUd_PHJCKmQX-zYGICw&bvm=bv.42768644,d.bmk&psig=AFQjCNGXktDSDkWovFth-s2J3SZDfNAoUA&ust=1361611789488600

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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.

CONT.


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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.

CONT.

•If the synthesis of beta chains is less severely reduced , the person has beta thalassemia intermedia.


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

CONT.


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Hematologic Indices of Iron Deficiency and Alpha and Beta ThalassemiaTest Iron deficiency Beta thalassemia Alpha thalassemiaMCV (abnormal if• < 70 fl in children six months to six years of age• < 76 fl in children seven to 12 years of age)

Low Low Low

Red blood cell distribution width(RDW)

High Normal; occasionally high

Normal

Ferritin Low Normal Normal

Mentzer index for children (MCV/red blood cell count)

> 13 < 13 < 13

Hgb electrophoresis Normal (may have↓ HbA2)

•↑ Hgb A2

• ↓ Hgb A•Probably↑ Hgb F

Newborns: may have Hgb H or Hgb Bart's


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Use of RDW Values in the Diagnosis of ThalassemiaMicrocytic Anemia

Children 6 months -6 years of age: MCV <70flChildren 7 to 12 years of age: MCV <76fl

↓

RDW

↓ ↓

Normal Elevated (>15)

↓ ↓

Favors Thalassemia

Ferritin level

↓ ↓

Normal(>100ng/mL)

Low(<10ng/mL)

↓ ↓

Favors Thalassemia

Favors Iron Deficiency anemiaApril 12, 2023


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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


http://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


http://www.nyas.org/

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Treatment

Blood TransfusionsIron Chelation TherapySplenectomyBone 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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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

Cont.


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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

http://www.aafp.org

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.

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

http://www.aafp.org

Cont.

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


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

http://www.aafp.org

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.

Cont.


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When this picture will disappear?

http://soulverses.org/


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Health & Medicine

The Thalassemias