thalassemia

Faculty of pharmacy-mansoura university department of bio chemistery

thalassemiasupervisor :prof-Dr :Mamdouh el-sheshtawy

Students:

1-ebtsam hamed

2-ebthal gamal

3-abrar alaa

4-abrar labeb

5-ehsan elsheshtawy

Normal adult hemoglobin (HbA) consists of a tetramer made up of two alpha-globin and two beta-globin subunits.

The alpha globin gene is found on chromosome 16 and is duplicated, which means that each somatic cell with its pair of homologous chromosomes contains 4 copies of the alpha chain gene.

The gene encoding beta globin only has two copies, one present on each of the pair of chromosome 11.

Thalassemia is an inherited disease which results when mutations affecting the genes involved in Hb biosynthesis lead to decreased Hb production. The clinical phenotype results from both the diminished amount of the particular globin chain as well as from the resultant chain imbalance that occurs because of normal production of the other globin chain.

Alpha

thalassemia

Beta

thalassemia

thalassemia

•Many mutations can affect the alpha globin gene, but the most common

•are gene deletions

•there are 4 copies of the alpha gene in each somatic cell. Thus, phenotypes increase in severity as the number of functional alpha genes decreases

•Silent carrier: refers to patients with one alpha gene deletion, they are clinically asymptomatic)

•Alpha thalassemia trait: these patients have two alpha gene deletions, and very mild phenotypes. Gene deletions can both be present on the same chromosome, or divided between the two chromosomes which has relevance for the patients offspring.

•Hemoglobin H disease: named reflecting the presence of the beta tetramer HbH (B4) found in red cells. Causes moderately severe anemia. Occurs with three alpha chain deletions

•Hydrops fetalis: the most severe form, caused by 4 alpha gene deletions

•Red cells contain gamma-globin tetramers (Hb Bart) which are ineffective at delivering oxygen to tissues, causing anoxia, edema, hepatosplenomegaly. Historically was not compatible with life, but aggressive in-utero and lifelong transfusions may save individuals with this condition

mutations on chromosome 11

hundreds of mutations possible in the beta

globin gene, therefore beta thalassemia is

more diverse

results in excess of alpha globins

Beta Thalassemia Trait slight lack of beta globin

smaller red blood cells that are lighter in

colour due to lack of hemoglobin

no major symptoms except slight anemia

lack of beta globin is more significantbony deformities due to bone marrow trying to make more blood cells to replace defective onescauses late development, exercise intolerance, and high levels of iron in blood due to reabsorption in the GI tractif unable to maintain hemoglobin levels between 6 gm/dl – 7 gm/dl, transfusion or splenectomy is recommended

complete absence of beta globinenlarged spleen, lightly coloured blood cellssevere anemiachronic transfusions required, in conjunction with chelation therapy to reduce iron (desferoxamine)

signsymptom

Mechanism(s)

Shortness of breath,fatigue,

and weakness(anemia)

Secondary to anemiaDeficient synthesis of the beta chain of hemoglobin causes red cells have low HbA levels, thus explaining their phenotype and

impaired ability to transport oxygenimbalance between alpha and beta globin production leads to a

precipitation of the relatively overabundant alpha globin cha in . within the RBCs their precursors

Hepatomegaly Ineffective erythropoiesis leads to activation of extramedullaryerythropoiesis in areas such as the spleen, liver, lymph nodes, and the thorax.Hepatomegaly can result from a number of mechanisms; extramedullary erthyropoiesis, hepatitis due to chronic transfusion associated infections, and iron overload.

Bone pain and fragility fractures

Caused by two major mechanisms:•Destruction of the cortex leading to weakening of the bone

•Secondary to Osteopenia/osteoporosis (mechanism above)

Cardiac failure and arrhythmias

Secondary to anemia and iron overload

SplenomegalySecondary to extramedullary hemotopoiesisCan also be due to extravascular hemolysis causing a hypertropicresponse in the spleen.

Gallstones Bilirubin stones•Lifelong hemolytic state causes increased bilirubin deposition in the

gallbladder

Malnutrition Rapidly growing erythrocyte precursors compete for nutrients and can cause malnutrition

Bronze skin

How Are Thalassemias Treated

Treatments for thalassemias depend on the type and severity of the disorder.

Patients with thalassemia minor usually do not require any specific treatment. People with β-thalassemia trait should be warned that their condition can be misdiagnosed as the more common iron deficiency anemia. They should avoid routine use of iron supplements; iron deficiency can develop, though, during pregnancy or from chronic bleeding

Doctors use three standard treatments for moderate and severe forms of thalassemia. These treatments include blood transfusions, iron chelation (ke-LAY-shun) therapy, and folic acid supplements. Other treatments have been developed or are being tested.

Standard Treatments :-

A) Blood Transfusion :

Transfusions of red blood cells are the main treatment for people who have

moderate or severe thalassemias. This treatment gives you healthy red blood cells

with normal hemoglobin.During a blood transfusion, a needle is used to insert an

intravenous (IV) line into one of your blood vessels. Through this line, you receive

healthy blood. The procedure usually takes 1 to 4 hours.Red blood cells live only

for about 120 days. So, you may need repeated transfusions to maintain a healthy

supply of red blood cells.If you have hemoglobin H disease or beta thalassemia

intermedia, you may need blood transfusions on occasion. For example, you may

have transfusions when you have an infection or other illness, or when your

anemia is severe enough to cause tiredness.If you have beta thalassemia major

(Cooley's anemia), you’ll likely need regular blood transfusions (often every 2 to 4

weeks). These transfusions will help you maintain normal hemoglobin and red

blood cell levels, but it's expensive and carries a risk of transmitting infections and

viruses (for example, hepatitis). However, the risk is very low in the United States

because of careful blood screening.

B) Iron Chelation Therapy :

The hemoglobin in red blood cells is an iron-rich protein. Thus, regular blood

transfusions can lead to iron overload in the blood and this will damage the liver,

heart, and other parts of the body.

To prevent this damage, doctors use iron chelation therapy to remove excess iron

from the body. Two medicines are used for iron chelation therapy.

1-Deferoxamine is a liquid medicine that's given slowly under the skin, usually

with a small portable pump used overnight. This therapy takes time and can be

mildly painful.

Side effects include problems with vision and hearing.

2-Deferasirox is a pill taken once daily.

Side effects include headache, nausea (feeling sick to the stomach), vomiting,

diarrhea, joint pain, and tiredness

C)Folic Acid Supplements :

Folic acid is a B vitamin that helps the body make new red blood cells . Your doctor

may recommend folic acid supplements in addition to treatment with blood

transfusions and/or iron chelation therapy

Other Treatments

Other treatments for thalassemias have been developed or are being tested, but

they're used much less often :

In Beta thalassemia

-Physicians often use splenectomy to decrease transfusion requirements and

the resultant iron overload.

Because postsplenectomy sepsis is possible, defer this procedure until the patient is

older than 6-7 years. In addition, to minimize the risk of postsplenectomy sepsis

,Administer penicillin prophylaxis to children after splenectomy.

Cholecystectomy

Patients with thalassemia minor may have bilirubin stones in their gallbladder

and, if symptomatic, may require treatment. Perform a cholecystectomy using a

laparoscope or carry out the procedure at the same time as the splenectomy.

Blood and Marrow Stem Cell Transplant :

the only cure for thalassemia is a procedure called a bone marrow transplant.

Bone marrow, which is found inside bones, produces blood cells. In a bone

marrow transplant, a person is first given high doses of radiation or drugs to

destroy the defective bone marrow. The bone marrow is then replaced with cells

from a compatible donor, usually a healthy sibling or other relative. Bone marrow

transplants carry many risks, so they usually are done only in the most severe

cases of thalassemia.