Download Beta- Thalassemia

Assistant Professor
Dr. Akrem Atrushi
Two B -globin genes are present in diploid
cells, one on each chromosome 11.
Some B-thalassemia genes produce no βglobin chains and are termed β0thalassemia.
Other β-globin genes produce some βglobin, but in diminished quantities, and
are termed β+thalassemia
There is an excess of α-globin chains relative
to β- and γ-globin chains; α-globin
tetramers (α4) are formed, and these
inclusions interact with the red cell
membrane and shorten red cell survival,
leading to anemia and increased erythroid
production.
The γ-globin chains are produced in normal
amounts, leading to an elevated Hb F
(α2γ2).
The δ-globin chains are also produced in
normal amounts, leading to an elevated Hb
A2 (α2δ2) in β-thalassemia.
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These children usually become symptomatic
from progressive hemolytic anemia with
profound weakness and cardiac
decompensation during the second 6 mo of
life with fatigue, poor appetite, and lethargy
severe thalassemic facies, pathologic
fractures, marked hepatosplenomegaly,
cachexia , splenomegaly causing
mechanical discomfort and secondary
hypersplenism, greenish brown complexion
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Complications of iron overload:
in the liver, fibrosis and cirrhosis;
in the beta cells of the pancreas, diabetes
mellitus;
in the pituitary, testis, and ovaries, growth
retardation and hypogonadotropic
hypogonadism;
in the parathyroid, hypocalcemia and
osteoporosis;
in the heart, arrhythmias, myocarditis, and
intractable cardiac failure.
CBC:
*a decreased MCV with or without mild
anemia.
*moderately raised reticulocyte count but the
reticulocyte index is normal to decreased
*The peripheral blood smear typically shows
hypochromia, target cells, and sometimes
basophilic stippling
*nucleated red blood cells often exceed the
number of circulating white blood cells
Hemoglobin electrophoresis performed after
6–12 months of age is usually diagnostic
when levels of hemoglobin A2, hemoglobin
F, or both are elevated.
The unconjugated serum bilirubin level is
usually elevated
Serum ferritin and saturation of the
transferrin are elevated
Skull X-ray has typical ‘hair-on-end’
appearance due to medullary expansion
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Chronic transfusion with iron chelation is
generally targeted to maintain a nadir
hemoglobin level of 9–10 g/dL. This
approach gives increased vigor and wellbeing, improved growth, and fewer overall
complications.
Iron chelation with desferrioxamine usually
given by subcutaneous infusion over several
hours daily 5-6 days a week .
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Small doses of supplemental ascorbic acid
may enhance the efficacy of iron chelation.
Splenectomy to reduce transfusion
requirements, and hence iron loading
preceded by pneumococcal vaccine and
prophylactic penicillin
Bone marrow or umbilical cord blood
transplantation with cure rate greater than
90% when transplantation is performed
prior to the development of hepatomegaly
or portal fibrosis.
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Thalassemia intermedia can be any
combination of β-thalassemia mutations
(β0/β+, β0/βvariant, E/β0)
Phenotype of microcytic anemia with
hemoglobin of about 7 g/dL.
There is controversy about whether to
transfuse these children.
They will certainly develop a degree of
medullary hyperplasia and nutritional
hemosiderosis.
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Extramedullary hematopoiesis can occur in
the vertebral canal, compressing the spinal
cord and causing neurologic symptoms
requiring immediate local radiation therapy
to halt erythropoiesis.
Transfusion will alleviate the thalassemic
manifestations and hasten the need for
chelation.
A splenectomy puts the child at risk for
infection and pulmonary hypertension.
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Thalassemia trait is frequently misdiagnosed as
iron deficiency in children because the two are
similar hematologically and iron deficiency is much
more prevalent.
A short course of iron and re-evaluation is all that
is required to separate those children who will
need further evaluation.
Children who have β-thalassemia trait will have a
persistent red cell distribution width, and on
hemoglobin electrophoresis they will have an
elevated Hb F and diagnostically elevated Hb A2.
There are "silent" forms of thalassemia trait, and if
the family history is suggestive, further studies
may be indicated.
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A 5 years old girl presents recurrently with
attacks of severe pain in the back, abdomen,
upper limbs and lower limbs that last for
several days every time and mandate hospital
admission. She is not well thriving, pale and
jaundiced.
What lab test is needed for making the
diagnosis?
What is the daignosis?
How can you explain the presence of such
attacks?
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Hb S is the result of a single base-pair
change, thymine for adenine, at the sixth
codon of the β gene.
This change encodes valine instead of
glutamine in the sixth position on the βglobin molecule.
The charge at this site is altered and allows
for polymerization of hemoglobin under
conditions of hypoxia
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Polymerization of sickle hemoglobin
distorts erythrocyte morphology, decreases
red cell deformability, causes a marked
reduction in red cell life span
Because of the disruption of the red cell
membrane, the increased adhesiveness of
sickle reticulocytes, and the increased
leukocyte count there is a thrombotic
coagulopathy associated with sickle cell
anemia that contributes to the severity of
the disease
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Moderate-to-severe anemia is poorly manifested,
since they readily adjust by increasing heart rate
and stroke volume; however, there is decreased
stamina, which may be noted on the playground or
when participating in physical education class.
Splenic sequestration is an anemic crisis. Although
hypofunctional at an early age, the spleen has an
anatomic structure that responds to certain stimuli,
usually febrile illnesses. It suddenly becomes
enlargedand traps blood cells. Hemoglobin levels
dramatically drop from baseline values and the
reticulocyte count is elevated. The platelet count
often is slightly decreased, and hypovolemic shock
occurs if a large volume of blood is trapped or
sequestered.
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Aplastic crisis is also an anemic crisis. Most
commonly, it is caused by infections with
parvovirus, which results in the rapid onset
of severe anemia. Reticulocyte count is very
low,
Functional asplenia results in extreme
susceptibility to infection especially
encapsulated respiratory bacteria,
particularly Streptococcus pneumoniae,
osteomyelitis due to Staphylococcus or
Salmonella , meningitis and urinary tract
infection leading to bacteremia
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Chest syndrome caused by infection in young
children or infarction in the older. It is the
combination of respiratory symptoms, new lung
infiltrates, and fever.
Bone marrow embolism with severe pain
Bone pain often is due to bone marrow infarction.
During the first 18 months of life, the metatarsals
and metacarpals can be involved, presenting as
dactylitis or hand-foot syndrome. long bones of
the extremities in the older. Proximity to the joints
and occasional sympathetic effusions lead to the
belief that the pain the joints. As marrow activity
recedes further during adolescence, pain involves
the vertebral bodies, especially in the lumbar
region.
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Abdominal pain can result from referred
pain from other sites or intra-abdominal
solid organ or soft tissue infarction.
Reactive ileus leads to intestinal distention
and pain
Stroke occurs in approximately 11% of
patients with hemiparesis or other deficits
may be found, depending on the location of
the infarct. Convulsions frequently are
associated with stroke.
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Cholecystitis due to chronic hemolysis leading to
cholelithiasis
Avascular necrosis of the femoral or humeral head
Priapism with severe pain if erection persists longer
than 3 hours.
Renal function is progressively impaired by diffuse
glomerular and tubular fibrosis leading to
hyposthenuria with polyuria and enuresis in
patients older than 5 yr. Renal papillary necrosis
and nephrotic syndrome also develop occasionally
Poor growth and delayed maturation associated
with Zinc deficiency
Skin ulcers may also develop in adolescence
Retinopathy may develop and hyphema is a medical
emergency
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CBC :
Baseline hemoglobin level of 7–10 g/dL.
The baseline reticulocyte count is elevated markedly.
The anemia is usually normocytic or macrocytic, and the peripheral
blood smear typically shows the characteristic sickle cells, target
cells, poikilocytes, hypochromasia, nucleated RBCs, and Howell-Jolly
bodies.
Hemoglobin electrophoresis. Children with sickle cell anemia and
with sickle β 0-thalassemia have only hemoglobins S and F. Persons
with sickle β +-thalassemia have a preponderance of hemoglobin S
with a lesser amount of hemoglobin A. Persons with sickle
hemoglobin C disease have equal amounts of hemoglobins S and C
Radiologic studies may reveal characteristic bony findings of sickle
cell disease in the vertebral bodies, mild expansion of the marrow
cavities, osteoporosis, and possibly sclerosis of the long bones and
femoral heads
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Babies should receive penicillin daily initiated by
age 2 months and continued at least until age 5
years and be immunised against Streptococcus
pneumoniae, Haemophilus influenzae type b, and
Neisseria meningitidis.
Because of the thrombotic nature of the sickle
hemoglobins and the high red cell turnover, folate
supplementation is recommended.
Parents should be warned to seek medical advice
on any suspicion of infection.
Painful crises should be managed with adequate
analgesics, hydration, oxygen and correction of
acidosis if present, .
The patient should be observed carefully for a
source of infection and a drop in haemoglobin
concentration.
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Strokes should be treated with a transfusion; there is good
evidence now that they can be prevented by regular
surveillance of cerebral blood flow by Doppler examination
and prophylactic transfusion.
Blood transfusion is indicated for acute chest syndrome,
stroke, stroke prevention, severe anemia, and splenic
sequestration and before general surgery Simple or partial
exchange transfusion to reduce the percentage of circulating
sickle cells is indicated for some severe acute vaso-occlusive
events and may be lifesaving
Bone marrow transplantation is the only cure for sickle cell
disease, but it is only an option for children younger than 16
yr of age who have an HLA-matched sibling
Daily administration of oral hydroxyurea increases levels of
fetal hemoglobin, decreases hemolysis, and reduces by 50%
episodes of pain in severely affected patients
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The most commonly occurring sickle syndromes
besides Hb SS are Hb SC and Sβ0-thalassemia and
Sβ+-thalassemia.
Sβ0-thalassemia is a severe sickle cell anemia.
Hb SC does not polymerize like Hb SS, but the
presence of crystals of Hb C interact with the
membrane ion transport dehydrating the cell,
inducing sickling. Children who have Hb SC disease
can experience the same symptoms and
complications as those with severe Hb SS disease,
but the frequency is less.
These children have an increased hemoglobin
concentration and better growth.
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However, they have more fat in their bone
marrow, and this can lead to more severe
acute chest syndrome and organ failure
caused by fat emboli from bone necrosis.
There is also an increased incidence of
retinopathy and chronic hypersplenism.
Despite a well-developed appearance, these
children may develop all the chronic
complications of sickle cell disease.
Sβ+-thalassemia is a less severe form of
sickle cell disease with a much lower
frequency of the severe manifestations.