61441633 thalassemia case report
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CASE REPORT
THALASSEMIA β MAJOR
Presenter : Gracelia R. E. Damanik
Sam Raj Rayan
Day/Date : Tuesday, 22nd of June 2010
Supervisor : dr. Lily Irsa, Sp.A(K)
INTRODUCTION
Thalassemias are genetic disorders in globin chain production, inherited
autosomal recessive blood disease. In thalassemia, the genetic defect results in
reduced rate of synthesis of one of the globin chains that make up hemoglobin.
Reduced synthesis of one of the globin chains causes the formation of abnormal
hemoglobin molecules, and this in turn causes the anemia which is the
characteristic presenting symptom of the thalassemias.1,2
Thalassemia was first defined in 1925 when Dr. Thomas B. Cooley
described five young children with severe anemia, splenomegaly, and unusual
bone abnormalities and called the disorder erythroblastic or Mediterranean anemia
because of circulating nucleated red blood cells and because all of his patients
were of Italian or Greek ethnicity. In 1932 Whipple and Bradford coined the term
thalassemia from the Greek word thalassa, which means the sea (Mediterranean)
to describe this entity. Somewhat later, a mild microcytic anemia was described in
families of Cooley anemia patients, and it was soon realized that this disorder was
caused by heterozygous inheritance of abnormal genes that, when homozygous,
produced severe Cooley anemia.2,3
In Europe, Riette described Italian children with unexplained mild
hypochromic and microcytic anemia in the same year Cooley reported the severe
form of anemia later named after him. In addition, Wintrobe and coworkers in the
United States reported a mild anemia in both parents of a child with Cooley
anemia. This anemia was similar to the one that Riette described in Italy. Only
then was Cooley's severe anemia recognized as the homozygous form of the mild
2
hypochromic and microcytic anemia that Riette and Wintrobe described. This
severe form was then labeled as thalassemia major and the mild form as
thalassemia minor. These initial patients are now recognized to have been
afflicted with β thalassemia. In the following few years, different types of
thalassemia that involved polypeptide chains other than β chains were recognized
and described in detail. In recent years, the molecular biology and genetics of the
thalassemia syndromes have been described in detail, revealing the wide range of
mutations encountered in each type of thalassemia.2,4
EPIDEMIOLOGY
Certain types of thalassemia are more common in specific parts of the
world. β thalassemia is much more common in Mediterranean countries such as
Greece, Italy, and Spain. Many Mediterranean islands, including Cyprus,
Sardinia, and Malta, have a significantly high incidence of severe β thalassemia,
constituting a major public health problem. For instance, in Cyprus, 1 in 7
individuals carries the gene, which translates into 1 in 49 marriages between
carriers and 1 in 158 newborns expected to have b thalassemia major. As a result,
preventive measures established and enforced by public health authorities have
been very effective in decreasing the incidence among their populations. b
thalassemia is also common in North Africa, the Middle East, India, and Eastern
Europe. Conversely, α thalassemia is more common in Southeast Asia, India, the
Middle East, and Africa. Worldwide, 15 million people have clinically apparent
thalassemic disorders. Reportedly, disorders worldwide, and people who carry
thalassemia in India alone number approximately 30 million. These facts confirm
that thalassemias are among the most common genetic disorders in humans; they
are encountered among all ethnic groups and in almost every country around the
world.2,4,5
Although β-thalassemia has >200 mutations, most are rare. Approximately
20 common alleles constitute 80% of the known thalassemias worldwide; 3% of
the world's population carries genes for β-thalassemia, and in Southeast Asia, 5–
10% of the population carries genes for α-thalassemia. In a particular area there
3
are fewer common alleles. In the U.S., an estimated 2,000 individuals have β-
thalassemia.1
ETIOLOGY
Thalassemia syndromes are characterized by varying degrees of ineffective
hematopoiesis and increased hemolysis. Clinical syndromes are divided into α-
and β-thalassemias, each with varying numbers of their respective globin genes
mutated. There is a wide array of genetic defects and a corresponding diversity of
clinical syndromes. Most β-thalassemias are due to point mutations in one or both
of the two β-globin genes (chromosome 11), which can affect every step in the
pathway of β-globin expression from initiation of transcription to messenger RNA
synthesis to translation and post translation modification. Picture below shows the
organization of the genes (i.e., ε and γ, which are active in embryonic and fetal
life, respectively) and activation of the genes in the locus control region (LCR),
which promote transcription of the β-globin gene. There are four genes for α-
globin synthesis (two on each chromosome 16). Most α-thalassemia syndromes
are due to deletion of one or more of the α-globin genes rather than to point
mutations. Mutations of β-globin genes occur predominantly in children of
Mediterranean, Southern, and Southeast Asian ancestry. Those of α-globin are
most common in those of Southeast Asian and African ancestry.6
(source: Manual of Pediatric Hematology and Oncology)
Major deletions in β thalassemia are unusual (in contrast to α thalassemia),
and most of the encountered mutations are single base changes, small deletions, or
insertions of 1-2 bases at a critical site along the gene, as in the image below.
4
(source: Thalassemia, Emedicine Multimedia)
CLASSIFICATION
The thalassemias can be defined as a heterogeneous group of genetic
disorders of hemoglobin synthesis, all of which result from a reduced rate of
production of one or more of the globin chains of hemoglobin. This basic defect
results in imbalanced globin chain synthesis, which is the hallmark of all forms of
thalassemia. The thalassemias can be classified at different levels. Clinically, it is
useful to divide them into three groups: the severe transfusion-dependent (major)
varieties; the symptomless carrier states (minor) varieties; and a group of
conditions of intermediate severity that fall under the loose heading thalassemia
intermedia”. This classification is retained because it has implications for both
diagnosis and management.4
β-THALASSEMIA2,8
5
The β-thalassemia syndromes are caused by abnormalities of the b-gene
complex on chromosome 11. More than 150 different mutations have been
described, and most of these are small nucleotide substitutions within the b gene
complex. Deletions and mutations that result in abnormal cleavage or splicing of
β-globin RNA may also result in thalassemia characterized by absent (β0) or
reduced (β+) production of β-globin chains.2,7
THALASSEMIA MINOR (THALASSEMIA TRAIT)
Heterozygosity for a b-thalassemia gene results in a mild reduction of b-
chain synthesis and, therefore, a reduction in HbA and mild anemia. Hemoglobin
levels are 10 to 20 g/L lower than that of normal persons of the same age and
gender, but the anemia may worsen during pregnancy. This mild anemia usually
produces no symptoms, and longevity is normal. Thalassemia trait is almost
always accompanied by familial microcytosis and hypochromia of the red blood
cells. Target cells, elliptocytes, and basophilic stippling are seen on the peripheral
blood smear. Almost all individuals with b-thalassemia trait have MCVs less than
75 fL, and mean MCV is 68 fL. In thalassemia trait the MCV is disproportionately
low for the degree of anemia because of a red blood cell count that is normal or
increased. The RDW is normal in thalassemia trait. The ratio of MCV/RBC
(Mentzer index) is <11 in thalassemia trait but >12 in iron deficiency. Iron studies
are normal. In an individual with microcytic red blood cells, a diagnosis of b-
thalassemia trait is confirmed by an elevated HbA2 (α2δ2) level. The normal level
of HbA2 is 1.5 to 3.4%, and HbA2 >3.5% is diagnostic of the most common form
of β-thalassemia trait. Levels of HbF (α2γ2) are normal (<2.0%) in about half of
individuals with classical thalassemia trait and moderately elevated (2.0 to 7%) in
the rest.
Less common forms of β-thalassemia trait include βδ-thalassemia trait,
characterized by familial microcytosis, normal levels of HbA2, and elevated levels
of HbF (5-15%), and Lepore hemoglobin trait, characterized by the presence of 5
to 10% HbLepore, a hemoglobin that migrates electrophoretically in the position of
HbS. Lepore hemoglobin is a fusion product resulting from an unequal crossover
between b and d genes and associated with decreased b-chain synthesis.
Occasionally a silent carrier is identified on the basis of being a parent of a child
6
with severe thalassemia but slight or no microcytosis or elevations of HbA2 or
HbF.
The importance of establishing a diagnosis of β-thalassemia trait is to avoid
unnecessary treatment with medicinal iron and to provide genetic counseling.
Two individuals with b-thalassemia trait face a 25% risk with each pregnancy of
having a child with homozygous β-thalassemia. Populations with a high
prevalence of thalassemia trait can be screened to provide genetic counseling. In
at-risk pregnancies, prenatal diagnosis can be performed as early as 10 to 12
weeks of gestation using fetal DNA obtained by chorionic villus biopsy.
HOMOZYGOUS β-THALASSEMIA (THALASSEMIA MAJOR,
COOLEY ANEMIA)
Homozygosity for β-thalassemia genes is usually associated with severe
anemia because of a marked reduction of synthesis of the b-globin chains of HbA.
However, reduction of HbA synthesis does not explain the hemolysis and
ineffective erythropoiesis that are a consequence of unbalanced globin chain
synthesis. In homozygous β-thalassemia, α-globin chains are produced in normal
amounts and accumulate, denature, and precipitate in the RBC precursors in the
bone marrow and circulating RBC. These precipitated α-globin chains damage the
RBC membrane, resulting in destruction within the bone marrow (ineffective
erythropoiesis) and in the peripheral blood.
The fetus and the newborn infant with homozygous β-thalassemia are
clinically and hematologically normal. In vitro measurements demonstrate
reduced or absent β-chain synthesis. Increasingly, homozygous β-thalassemia is
being diagnosed in the United States by neonatal electrophoretic hemoglobin
screening that shows only HbF and no HbA Symptoms of β-thalassemia major
develop gradually in the first 6 to 12 months after birth, when the normal
postnatal switchover from γ-chains to β-chains results in a decreased level of
HbF). By the age of 6 to 12 months, most affected infants show pallor, irritability,
growth retardation, jaundice, and hepatosplenomegaly as a result of
extramedullary hematopoiesis. By 2 years of age, 90% of infants are symptomatic,
and progressive changes in the facial and cranial bones develop. The hemoglobin
level may be as low as 30 to 50 g/L at the time of diagnosis.
7
Other varian of β-thalassemia are:6
Silent carrier β thalassemia: Similar to patients who silently carry α
thalassemia, these patients have no symptoms, except for possible low
RBC indices. The mutation that causes the thalassemia is very mild and
represents a β+ thalassemia.
Thalassemia intermedia: This condition is usually due to a compound
heterozygous state, resulting in anemia of intermediate severity, which
typically does not require regular blood transfusions.
β thalassemia associated with β chain structural variants: The most
significant condition in this group of thalassemic syndromes is the Hb E/β
thalassemia, which may vary in its clinical severity from as mild as
thalassemia intermedia to as severe as β thalassemia major.
α-THALASSEMIA2,9
The a-thalassemia syndromes are prevalent in people from Southeast Asia
and usually result from deletion of one or more of the four α-globin genes on
chromosome 16. In general, the severity is proportional to the number of α-globin
genes deleted which can be quantitated by DNA analysis.1,6
SILENT CARRIER (α2-THALASSEMIA TRAIT, - α/αα) Individuals
with a single α-globin gene deletion are clinically and hematologically normal,
but they may be identified at birth by the presence of small amounts (1-3%) of the
fast-migrating Barts hemoglobin (γ4) by neonatal hemoglobin electrophoresis. In
later life, the diagnosis can be established only by determining the number of a-
globin genes by DNA analysis.
α1-THALASSEMIA TRAIT (-α/-α OR --/αα) Individuals in whom two of
four α-globin genes are deleted have mild microcytic anemia. At birth, relative
microcytosis with 5 to 8% of HbBarts is present. Barts hemoglobin disappears by 3
to 6 months of age, and the hemoglobin electrophoresis becomes normal. After
the newborn period, a definitive diagnosis may be impractical in this mild
disorder, and the diagnosis is usually suspected when other causes of microcytic
anemia, such as β-thalassemia trait or iron deficiency, are ruled out.
8
α1-Thalassemia trait can occur in two ways: a cis-deletion in which the two
deleted a genes are on the same chromosome 16, and a trans-deletion in which
one a-gene is deleted from each of the 16 chromosomes. The cis-deletion is usual
in Southeast Asian populations, whereas the trans-deletions are usual in people of
African ethnicity. Thus, although α-thalassemia commonly occurs in African
people, a maximum of only two genes can be deleted in any individual because of
the trans-configuration. Consequently, the more severe α-thalassemia syndromes
associated with three and four α-deletions are not seen.
HEMOGLOBIN H DISEASE (--/-α) Three α-globin gene deletions result
in hemoglobin H disease, which is associated with a marked imbalance between a-
and β-globin chain synthesis. Excess free β chains accumulate and combine to
form an abnormal hemoglobin, a tetramer of β chains (β4) called HbH. HbH is
unstable and precipitates within red blood cells, leading to chronic microcytic,
hemolytic anemia. Laboratory findings include a moderately severe microcytosic
anemia (Hb 60-100 g/L with evidence of hemolysis). Precipitated HbH can be
demonstrated in the red blood cells with supravital stains. On hemoglobin
electrophoresis, HbH has a fast mobility and accounts for 10 to 15% of the total
hemoglobin.
FETAL HYDROPS SYNDROME (--/--) Deletion of all four a-globin
genes results in a syndrome of hydrops fetalis with stillbirth or immediate
postnatal death. In the absence of α-chain synthesis, such fetuses are incapable of
synthesizing embryonic hemoglobins. At birth, hemoglobin electrophoresis shows
predominantly Barts hemoglobin (γ4) and small amounts hemoglobin H (β4) as
well as embryonic hemoglobins. The high oxygen affinity of Barts hemoglobin
makes it oxygen transport ineffective, leading to the intrauterine manifestations of
severe hypoxia, out of proportion to the degree of anemia. A number of infants
with this syndrome who have been identified prenatally and treated with
intrauterine and postnatal transfusions have survived. These infants are
transfusion dependent, but some are developing normally. As in thalassemia
major, the only curative therapy is bone marrow transplantation. Termination of
the pregnancy is often recommended because of a high frequency of severe
maternal toxemia associated with a hydropic fetus.
9
Thalassemias can also be classified at the genetic level into the α, β, δβ or
εγδβ thalassemias, according to which globin chain is produced in reduced
amounts. In some thalassemias, no globin chain is synthesized at all, and hence
they are called α0 or β0 thalassemias, whereas in others some globin chain is
produced but at a reduced rate; these are designated α+ or β+ thalassemias. The δβ
thalassemias, in which there is defective δ and β chain synthesis, can be
subdivided in the same way, i.e., into (δβ)+ and (δβ)0 varieties.4
(source: Pediatric Hematology)
PATHOPHYSIOLOGY2,4,6,9
The basic defect in all types of thalassemia is imbalanced globin chain
synthesis. However, the consequences of accumulation of the excessive globin
chains in the various types of thalassemia are different. In β thalassemia,
excessive α chains, unable to form Hb tetramers, precipitate in the RBC
10
precursors and, in one way or another, produce most of the manifestations
encountered in all of the β thalassemia syndromes; this is not the situation in α
thalassemia.
The excessive chains in α thalassemia are γ chains earlier in life and β chains
later in life. Because such chains are relatively soluble, they are able to form
homotetramers that, although relatively unstable, nevertheless remain viable and
able to produce soluble Hb molecules such as Hb Bart (4 γ chains) and Hb H (4 β
chains). These basic differences in the 2 main types of thalassemia are responsible
for the major differences in their clinical manifestations and severity.
α chains that accumulate in the RBC precursors are insoluble, precipitate in
the cell, interact with the membrane (causing significant damage), and interfere
with cell division. This leads to excessive intramedullary destruction of the RBC
precursors. In addition, the surviving cells that arrive in the peripheral blood with
intracellular inclusion bodies (excess chains) are subject to hemolysis; this means
that both hemolysis and ineffective erythropoiesis cause anemia in the person with
β thalassemia.
The ability of some RBCs to maintain the production of γ chains, which are
capable of pairing with some of the excessive α chains to produce Hb F, is
advantageous. Binding some of the excess a chains undoubtedly reduces the
symptoms of the disease and provides additional Hb with oxygen-carrying ability.
Furthermore, increased production of Hb F, in response to severe anemia,
adds another mechanism to protect the RBCs in persons with β thalassemia. The
elevated Hb F level increases oxygen affinity, leading to hypoxia, which, together
with the profound anemia, stimulates the production of erythropoietin. As a result,
severe expansion of the ineffective erythroid mass leads to severe bone expansion
and deformities. Both iron absorption and metabolic rate increase, adding more
symptoms to the clinical and laboratory manifestations of the disease. The large
numbers of abnormal RBCs processed by the spleen, together with its
hematopoietic response to the anemia if untreated, results in massive
splenomegaly, leading to manifestations of hypersplenism.
If the chronic anemia in these patients is corrected with regular blood
transfusions, the severe expansion of the ineffective marrow is reversed. Adding a
11
second source of iron would theoretically result in more harm to the patient.
However, this is not the case because iron absorption is regulated by 2 major
factors: ineffective erythropoiesis and iron status in the patient.
Ineffective erythropoiesis results in increased absorption of iron because of
downregulation of the HAMP gene, which produces a liver hormone called
hepcidin. Hepcidin regulates dietary iron absorption, plasma iron concentration,
and tissue iron distribution and is the major regulator of iron. It acts by causing
degradation of its receptor, the cellular iron exporter ferroportin. When ferroportin
is degraded, it decreases iron flow into the plasma from the gut, from
macrophages, and from hepatocytes, leading to a low plasma iron concentration.
In severe hepcidin deficiency, iron absorption is increased and macrophages are
usually iron depleted, such as is observed in patients with thalassemia intermedia.
Malfunctions of the hepcidin-ferroportin axis contribute to the etiology of
different anemias, such as is seen in thalassemia, anemia of inflammation, and
chronic renal diseases. Improvement and availability of hepcidin assays facilitates
diagnosis of such conditions. The development of hepcidin agonists and
antagonists may enhance the treatment of such anemias.
By administering blood transfusions, the ineffective erythropoiesis is
reversed, and the hepcidin level is increased; thus, iron absorption is decreased
and macrophages retain iron.
Iron status is another important factor that influences iron absorption. In
patients with iron overload (eg, hemochromatosis), the iron absorption decreases
because of an increased hepcidin level. However, this is not the case in patients
with severe β thalassemia because a putative plasma factor overrides such
mechanisms and prevents the production of hepcidin. Thus, iron absorption
continues despite the iron overload status.
As mentioned above, the effect of hepcidin on iron recycling is carried
through its receptor "ferroportin," which exports iron from enterocytes and
macrophages to the plasma and exports iron from the placenta to the fetus.
Ferroportin is upregulated by iron stores and downregulated by hepcidin. This
relationship may also explain why patients with β thalassemia who have similar
12
iron loads have different ferritin levels based on whether or not they receive
regular blood transfusions.
For example, patients with β thalassemia intermedia who are not receiving
blood transfusions have lower ferritin levels than those with β thalassemia major
who are receiving regular transfusion regimens, despite a similar iron overload. In
the latter group, hepcidin allows recycling of the iron from the macrophages,
releasing high amounts of ferritin. In patients with β thalassemia intermedia, in
whom the macrophages are depleted despite iron overload, lower amounts of
ferritin are released, resulting in a lower ferritin level.
Most nonheme iron in healthy individuals is bound tightly to its carrier
protein, transferrin. In iron overload conditions, such as severe thalassemia, the
transferrin becomes saturated, and free iron is found in the plasma. This iron is
harmful since it provides the material for the production of hydroxyl radicals and
additionally accumulates in various organs, such as the heart, endocrine glands,
and liver, resulting in significant damage to these organs.
CLINICAL MANIFESTATIONS
History
Thalassemia minor usually presents as an asymptomatic mild microcytic
anemia and is detected through routine blood tests. Thalassemia major is a severe
anemia that presents during the first few months after birth. Thalassemia minor
(beta thalassemia trait) usually is asymptomatic, and it typically is identified
during routine blood count evaluation. Thalassemia major (homozygous beta
thalassemia) is detected during the first few months of life, when the patient's
level of fetal Hb decreases.
Physical Examination
Patients with the beta thalassemia trait generally have no unusual physical
findings. The physical findings are related to severe anemia, ineffective
erythropoiesis, extramedullary hematopoiesis, and iron overload resulting from
transfusion and increased iron absorption. Skin may show pallor from anemia and
jaundice from hyperbilirubinemia. The skull and other bones may be deformed
13
secondary to erythroid hyperplasia with intramedullary expansion and cortical
bone thinning. Heart examination may reveal findings of cardiac failure and
arrhythmia, related to either severe anemia or iron overload. Abdominal
examination may reveal changes in the liver, gall bladder, and spleen.1,2,5
Hepatomegaly related to significant extramedullary hematopoiesis typically
is observed. Patients who have received blood transfusions may have
hepatomegaly or chronic hepatitis due to iron overload; transfusion-associated
viral hepatitis resulting in cirrhosis or portal hypertension also may be seen. The
gall bladder may contain bilirubin stones formed as a result of the patient's life-
long hemolytic state. Splenomegaly typically is observed as part of the
extramedullary hematopoiesis or as a hypertrophic response related to the
extravascular hemolysis. Extremities may demonstrate skin ulceration. Iron
overload also may cause endocrine dysfunction, especially affecting the pancreas,
testes, and thyroid.11
Laboratory Findings2,10,12
The CBC count and peripheral blood film examination results are usually
sufficient to suspect the diagnosis. Hemoglobin (Hb) evaluation confirms the
diagnosis in β thalassemia, Hb H disease, and Hb E/b thalassemia.
In the severe forms of thalassemia, the Hb level ranges from 2-8 g/dL.
Mean corpuscular volume (MCV) and mean corpuscular Hb (MCH) are
significantly low, but, unlike thalassemia trait, thalassemia major is associated
with a markedly elevated RDW, reflecting the extreme anisocytosis.
The WBC count is usually elevated in β thalassemia major; this is due, in
part, to miscounting the many nucleated RBCs as leukocytes. Leukocytosis is
usually present, even after excluding the nucleated RBCs. A shift to the left is also
encountered, reflecting the hemolytic process.
Platelet count is usually normal, unless the spleen is markedly enlarged.
Peripheral blood film examination reveals marked hypochromasia and
microcytosis, hypochromic macrocytes that represent the polychromatophilic
cells, nucleated RBCs, basophilic stippling, and occasional immature leukocytes,
as shown below.
14
(source: Color Atlas of Hematology)
The diagnosis of beta thalassemia minor usually is suggested by the
presence of an isolated, mild microcytic anemia, target cells on the peripheral
blood smear, and a normal red blood cell count. Hb electrophoresis usually
reveals an elevated Hb F fraction, which is distributed heterogeneously in the
15
RBCs of patients with β thalassemia, Hb H in patients with Hb H disease, and Hb
Bart in newborns with a thalassemia trait. In β0 thalassemia, no Hb A is usually
present; only Hb A2 and Hb F are found. An elevation of Hb A2 (2 alpha-globin
chains complexed with 2 delta-globin chains) demonstrated by electrophoresis or
column chromatography confirms the diagnosis of beta thalassemia trait. The Hb
A2 level in these patients usually is approximately 4-6%. In rare cases of
concurrent severe iron deficiency, the increased Hb A2 level may not be observed,
although it becomes evident with iron repletion. The increased Hb A2 level also is
not observed in patients with the rare delta-beta thalassemia trait.2,5
Iron studies (iron, transferrin, ferritin) are useful in excluding iron
deficiency and the anemia of chronic disorders as the cause of the patient's
anemia. (talasemia beta) Serum iron level is elevated, with saturation reaching as
high as 80%.
The serum ferritin level, which is frequently used to monitor the status of
iron overload, is also elevated. However, an assessment using serum ferritin levels
may underestimate the iron concentration in the liver of a transfusion-independent
patient with thalassemia.2,13
Complete RBC phenotype, hepatitis screen, folic acid level, and human
leukocyte antigen (HLA) typing are recommended before initiation of blood
transfusion therapy.2
Patients may require a bone marrow examination to exclude certain other
causes of microcytic anemia. Physicians must perform an iron stain (Prussian blue
stain) to diagnose sideroblastic anemia (ringed sideroblasts).
Radiologic Examinations
The skeletal abnormalities observed in patients with thalassemia major
include an expanded bone marrow space, resulting in the thinning of the bone
cortex. These changes are particularly dramatic in the skull, which may show the
characteristic hair-on-end appearance. Bone changes also can be observed in the
long bones, vertebrae, and pelvis.2,5,8
Skeletal survey and other imaging studies reveal classic changes of the
bones that are usually encountered in patients who are not regularly transfused.
16
The striking expansion of the erythroid marrow widens the marrow spaces,
thinning the cortex and causing osteoporosis. These changes, which result from
the expanding marrow spaces, usually disappear when marrow activity is halted
by regular transfusions. Osteoporosis and osteopenia may cause fractures, even in
patients whose conditions are well-controlled.
In addition to the classic "hair on end" appearance of the skull, shown
below, which results from widening of the diploic spaces and observed on plain
radiographs, the maxilla may overgrow, which results in maxillary overbite,
prominence of the upper incisors, and separation of the orbit. These changes
contribute to the classic "chipmunk facies observed in patients with thalassemia
major.
Other bony structures, such as ribs, long bones, and flat bones, may also be
sites of major deformities. Plain radiographs of the long bones may reveal a lacy
trabecular pattern. Changes in the pelvis, skull, and spine become more evident
during the second decade of life, when the marrow in the peripheral bones
becomes inactive while more activity occurs in the central bones.
Compression fractures and paravertebral expansion of extramedullary
masses, which could behave clinically like tumors, more frequently occur during
the second decade of life.2
The liver and biliary tract of patients with thalassemia major may show
evidence of extramedullary hematopoiesis and damage secondary to iron overload
resulting from multiple transfusion therapy. Transfusion also may result in
infection with the hepatitis virus, which leads to cirrhosis and portal hypertension.
Gallbladder images may show the presence of bilirubin stones.
The heart is a major organ that is affected by iron overload and anemia.
Cardiac dysfunction in patients with thalassemia major includes conduction
system defects, decreased myocardial function, and fibrosis. Some patients also
develop pericarditis.
DIFFERENTIAL DIAGNOSIS
17
The differential diagnosis of the thalassemia syndromes are other microcytic
anemias.6
(source: Manual of Pediatric Hematology and Oncology)
MANAGEMENT 6,13
Hypertransfusion Protocol
The hypertransfusion protocol is used to maintain a
pretransfusion hemoglobin between 10.5 and 11.0 g/dL at all
times using 15 cc/kg leukocyte-depleted crossmatched packed
red cells. Post-transfusion hemoglobin falls roughly 1 gram per
week, necessitating transfusions every 3–4 weeks. Transfusion
therapy should be started when a diagnosis is made and the
hemoglobin level falls below 7 g/dL.
Hypertransfusion results in:
1. Maximizing growth and development
2. Minimizing extramedullary hematopoiesis and decreasing
facial and skeletal abnormalities
18
3. Reducing excessive iron absorption from gut
4. Retarding the development of splenomegaly and
hypersplenism by reducing the number of red cells containing
-chain precipitates that reach the spleen
5. Reducing and/or delaying the onset of complications (e.g.,
cardiac)
Chelation Therapy
The objectives of chelation therapy are:
1. To bind free extracellular iron
2. To remove excess intracellular iron
3. To attain a negative iron balance (i.e., iron excretion > iron input).
Iron overload results from:
1. Ongoing transfusion therapy
2. Increased gut absorption of iron
3. Chronic hemolysis.
Chelation using desferrioxamine (Desferal) is recommended as follows:
1. Chelation should be instituted when the ferritin level is greater than 1000
ng/mL and adequate iron is excreted into the urine with the
desferrioxamine challenge.
2. The desferrioxamine challenge is performed as follows:
A 24-hour urine collection is started.
Desferrioxamine 40 mg/kg is infused IV over 8 hours, starting at the
beginning of the collection.
The urine collection continues for 16 more hours, and the urine is assayed
for total iron content.
If the 24-hour urinary iron excretion is greater than or equal to 50% of the
daily iron overload, the patient is ready for chelation.
Daily iron load is calculated using roughly 1 mg iron/1 mL packed red
blood cells (PRBCs). For example, if a patient receives 210 cc PRBCs
every 21 days, the daily iron load is 10 mg. If the patient excretes 5 mg
iron with the 24-hour challenge, chelation should be started.
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3. Desferrioxamine, 40–60 mg/kg/day, is infused subcutaneously over 8–10
hours nightly via a portable electronic pump 4–6 nights per week,
depending on iron overload.
4. In selected cases, with severe iron overload, desferrioxamine is
administered IV in a high dose, maximum 10 g/day. This may be done
immediately posttransfusion to bind transiently increased free serum iron.
5. The aim is to maintain the serum ferritin level close to 1000 ng/mL. The
ferritin level should be monitored every 3–6 months.
The complications of desferrioxamine administration include:
Swelling at infusion site
Local reactions: pruritus, rash, and hyperemia (add hydrocortisone 2
mg/mL to the desferrioxamine solution)
Anaphylactoid reactions (treat by desensitization)
Toxic effects on the eye; cataracts, reduction of visual fields and visual
acuity, and night blindness; occurs with prolonged or high-dose therapy or
if desferrioxamine is used without sufficient iron overload
Hearing impairment with prolonged or high-dose therapy, typically
without sufficient iron overload
Metaphyseal dysplasias
Desferrioxamine toxicity exacerbated when there is insufficient excretable
iron relative to the amount of desferrioxamine given.
Splenectomy
1. Splenectomy reduces the transfusion requirements in
patients with hypersplenism. It is usually performed in
adolescents when transfusion requirements have increased
secondary to hypersplenism.
2. Two weeks prior to splenectomy, a polyvalent
pneumococcal and meningococcal vaccine should be given.
If the patient has not received a Haemophilus influenzae
vaccine, this should also be given. Following splenectomy,
20
prophylactic penicillin 250 mg bid is given to reduce the
risk of overwhelming postsplenectomy infection.
3. Indications for splenectomy include:
Persistent increase in blood transfusion requirements by
50% or more over initial needs for more than 6 months
Annual packed cell transfusion requirements in excess of
250 mL/kg/year in the face of uncontrolled iron overload
(ferritin greater than 1500 ng/mL or increased hepatic iron
concentration)
Evidence of severe leukopenia and/or thrombocytopenia.
Supportive Care
1. Folic acid is not necessary in hypertransfused patients; 1
mg daily orally is given to patients on low transfusion
regimens.
2. Hepatitis B vaccination should be given to all patients.
3. Appropriate inotropic, antihypertensive, and antiarrhythmic
drugs should be administered when indicated for cardiac
dysfunction.
4. Endocrine intervention (i.e., thyroxine, growth hormone,
estrogen, testosterone) should be implemented when
indicated.
5. Cholecystectomy should be performed if gallstones are
present.
6. Patients with high viral loads of hepatitis C that are not
spontaneously decreasing should be treated with PEG-
interferon and ribavirin. Ribavirin increases hemolysis and
transfusion requirements typically increase during therapy.
7. HIV-positive patients should be treated with the
appropriate antiviral medications.
21
8. Genetic counseling and antenatal diagnosis (when
indicated) should be carried out using chorionic villus
sampling or amniocentesis.
9. Management of osteoporosis includes:
Periodic screening and prevention through early hormonal
replacement.
Yearly screening of adolescents with bone densitometry
and gonadal hormone evaluation.
Early in adolescence, patients should receive
estrogen/progesterone or testosterone replacement to
prevent gonadal insufficiency–induced bone loss, which
may result in a decreased adult height due to fusion of the
epiphyses. The possible increased risk of breast cancer
with hormonal replacement therapy should be explained to
female patients.
Two new agents are available to treat osteoporosis: (1)
Calcitonin prevents trabecular bone loss by inhibiting
osteoclastic activity. Parenteral and intranasal preparations
are available. Miacalcin is the intranasal preparation. The
dose is 1 spray into alternating nostrils daily. Miacalcin
should be taken with calcium carbonate 1500 mg daily and
vitamin D 400 units daily. (2) Bisphosphonates
(alendronate sodium) also inhibit osteoclast-mediated bone
resorption. The usual dose of Fosamax is 10 mg orally
taken daily with a full glass of water 30 minutes before
breakfast.
Hematopoietic Stem Cell Transplantation 6,13
1. Stem cell transplantation from an HLA-identical sibling is a curative mode
of therapy.
2. The greater the degree of hepatomegaly, hemosiderosis, and portal fibrosis
of the liver prior to transplant, the worse the outcome.
22
3. Stem cell transplantation is a controversial mode of therapy because its
risks must be weighed against the fact that patients who are least
symptomatic have the best transplant results.
The following information is available about transplantation:
Results are better among patients less than 3 years of age who have
received few transfusions and are without significant complications.
GVHD occurs less frequently in younger patients.
The refinement of methods of preparation for transplantation has brought
about a drastic reduction in morbidity and mortality.
Gene Therapy 14,15
Research is under way on methods of inserting a normal β-globin gene into
mammalian cells. Ultimately, the aim is to insert the gene into stem cells and
utilize these for stem cell transplant.
FOLLOW-UP 2,6
Follow-up of patients with thalassemia includes:
Monthly: Measure the pretransfusion hemoglobin.
Every 3 months: Measure height and weight; measure ferritin; perform
complete blood chemistry, including liver function tests.
Every 6 months: Complete physical examination and dental examination.
Every year: Evaluate growth and development; evaluate iron balance;
complete evaluation of cardiac function (echocardiograph, ECG, Holter
monitor as indicated); endocrine function (TFTs, PTH, FSH/LH,
testosterone/estradiol, IGF-1, fasting cortisol); visual and auditory acuity;
viral serologies (HAV, HBV panel, HCV [or if HCV+, quantitative HCV
RNA PCR], HIV); bone densitometry; ongoing psychosocial support.
Every 1–2 years: Evaluation of tissue iron burden: SQUID
(superconducting quantum interference device) measurement of liver iron;
T2-star measurement of cardiac iron (in select patients with cardiac
disease); liver biopsy for iron concentration and histology.
23
PREVENTIONS
Screening and prevention includes the following:
In persons with β thalassemia trait, confirming the diagnosis is usually
easy. In such situations, genetic counseling is necessary, and, if both
parents are carriers, a detailed discussion with the couple should include
all possible outcomes. These include the 1 in 4 chance of having a severely
affected or completely healthy child and a 1 in 2 chance of having a child
with heterozygous thalassemia.8
For α thalassemia carriers, confirmation is not that simple. Hemoglobin
(Hb) electrophoresis is usually not informative. For this reason, more
sophisticated studies are warranted if confirmation is critical. Genetic
counseling should be provided for patients with b thalassemia if a sibling
or a family member is known to be affected.9
Prenatal DNA testing has been available for several years. The decision to
perform prenatal diagnosis in parents known to be at risk for having a child with
thalassemia is complex and is usually influenced by several factors, such as
religion, culture, education, and the number of children in the family. Genetic
counseling by professionals that addresses the details of both the genetic risks and
the testing risks involved is expected to help the parents make an informed and
intelligent decision concerning the procedure. 2,6
Screening of children, pregnant women, and individuals visiting public
health facilities is effective in identifying individuals at risk who require further
testing. A simple CBC count, with emphasis on the RBC counts and indices,
including the mean corpuscular volume (MCV), mean corpuscular Hb (MCH),
and RBC distribution width (RDW), is the main component of such screening
processes. Persons suspected to be positive for thalassemia are checked for
elevated levels of Hb A2, Hb F, or both for confirmation. In some situations, this
simple method is not adequate, and further testing, including analyses of globin
chain synthesis, must be performed to reach a final diagnosis.6,11,13
Prenatal diagnosis includes the following:
24
Globin chain synthesis, which was once used in postnatal diagnosis, was
also used on fetal cells obtained by fetoscopy to screen the fetus. This test
reveals imbalanced production of certain globin chains that are diagnostic
of thalassemia.
Since polymerase chain reaction (PCR) techniques have become available,
several new methods are now in use to identify affected babies or carrier
individuals accurately and quickly. The DNA material is obtained by
chorionic villus sampling (CVS), and mutations that change restriction
enzyme cutting sites can be identified.
COMPLICATIONS 5,6
Complications include the following:
Iron overload
Traditionally, ferritin level assessment has been the most commonly used
test for indirect evaluation of body iron stores, even though it reflects only 1% of
the total iron storage pool. The test is not perfect or accurate, as various conditions
complicate the interpretation of its values. For this reason, reliance on serum
ferritin assessment alone can lead to an inaccurate assessment of body iron stores
in patients with iron overload who have been transfused heavily and who have
levels in excess of the upper limit for the physiologic ferritin synthesis (400
mcg/L). At high levels, the test loses its clinical relevance since ferritin can be
released from damaged cells in certain pathologic conditions.
Furthermore, certain drugs and clinical conditions such as ascorbate
deficiency, fever, acute and chronic infections, and hemolysis may influence the
ferritin level, producing misleading values. Despite its deficiencies, and for lack
of a better practical, noninvasive test, ferritin assessment continues to be the most
commonly used tool to diagnose and to monitor iron overload. MRI or CT
scanning is used to assess liver iron levels as a measure of total body iron load.
Liver biopsy may be performed to assess liver iron concentration, which is
considered the most sensitive method to assess body iron burden. Again, this
procedure is an invasive one and not without complications. Furthermore, because
iron distribution in the thalassemic liver is uneven and could be affected by
25
fibrosis, one can expect conflicting and inaccurate results in some patients.
Grading of stainable iron or measuring parenchymal iron by atomic absorption
spectroscopy has been helpful in measuring tissue iron levels, with good
correlation to calculated body iron burden.
Cardiac complications
Most deaths in patients with thalassemia are due to cardiac involvement.
These complications range from constrictive pericarditis to heart failure and
arrhythmias.
Transfusional hemosiderosis has been classified into 3 stages based on the number
of blood units given. The higher the number of packed red blood cell (PRBC)
units given, the more advanced the stage. Advanced stage is associated with more
severe clinical symptoms and more abnormal findings on cardiac function studies.
Cardiac hemosiderosis does not occur without significant accumulation of
iron in other tissues. Chelation therapy has shown promising results in patients
with cardiac symptoms due to iron overload. Ventricular myocardium is the first
site of cardiac iron deposition, while the conduction system is usually the last to
be affected. The value of endomyocardial biopsy, which has been used to evaluate
iron deposits in the heart, has been questioned. Iron has been reported as absent
from the right ventricular subendocardium in some patients with cardiac iron
overload. Echocardiography, radionuclide cineangiography, and 24-hour ECG are
to be used to monitor these patients.
Hepatic complications
Patients who have received regular blood transfusions for some time
develop liver enlargement due to swelling of the phagocytic and parenchymal
cells from the deposition of hemosiderin.Liver enzyme levels are not typically
elevated unless hemosiderin deposition is associated with hepatitis. Chelation
therapy may prevent or delay progressive liver disease, which may end in
cirrhosis.
Long-term therapy complications
26
Because of improved medical care, patients with thalassemia are surviving
their disease longer and reaching old age. With this longer survival comes new
issues related to complications that need to be addressed.
Hepatitis C virus (HCV) has emerged as the paramount risk in patients who
have been receiving blood transfusions all their lives. Unfortunately, a high
incidence rate of HCV continues in developing countries, leading to an increased
incidence of fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), especially in
the presence of a second risk factor such as iron overload. For this reason, many
centers advocate screening patients with HCV every 6 months by obtaining a
fetoprotein (AFP) and an ultrasound of the liver. Two-thirds of patients with β
thalassemia major have multiple calcified bilirubin stones by age 15 years.
Hematologic complications
Thrombosis was encountered in relatively significant numbers of patients
with thalassemia. Short-term antithrombotic therapy, both perioperatively and in
the presence of thrombotic risk factors, is recommended. Patients who have
undergone splenectomy and have a platelet count in excess of 600,000/µL receive
low-dose daily aspirin
Pulmonary hypertension as a result of small pulmonary thrombi represents a
significant indication of the increased risk for clotting in such patients. This
complication is emerging as major cause of morbidity and mortality in patients
with chronic hemolytic anemia. The incidence in such population was estimated at
10%. According to one study, endothelial dysfunction due to lack of
bioavailability of NO is one of the main reasons for developing such
complications. Free plasma Hb resulting from hemolysis directly consumes NO,
and the presence of arginase in the hemolysate depletes arginine, which is the
substrate for NO synthetase, thus preventing generation of such product. The
presence of excessive oxygen radicals in patients with chronic hemolytic anemia
who are on regular packed RBC (PRBC) transfusions adds to the problem by
causing rapid consumption of NO. Studies have showed that treatment with
hydroxyurea may improve or prevent this complication.
27
Silent cerebral infarction (SCI) was diagnosed by MRI in 24% of patients
with β -thalassemia/Hb E disease in a study conducted in Thailand. A Cambodian
child who also has β -thalassemia/Hb E disease has also been described.
Increasing reports addressing the issue of thrombotic tendency in patients with
thalassemia have revealed that such tendency is indeed seen in all types of chronic
hemolytic anemia and is not limited to thalassemia intermedia as suggested
earlier. Numerous factors for the thrombotic complications in this patients
population were reported by many authors. A study conducted on patients with
thalassemia has shown that the patients platelets, as well as their RBCs when
mixed individually with normal RBCs or normal platelets, have resulted in
increased platelets adhesions; this was not noticed when control cells were used in
both instances. This finding may suggest that both platelets and RBCs in
thalassemia could induce increased platelets adhesion which may predispose to
thrombotic events.
Based on these reports and several others which confirm the presence of
hypercoagulable state in patients with chronic hemolysis such as thalassemia and
sickle cell disease, one should seriously reconsider the role of splenectomy in such
conditions to avoid further risk for thrombotic events in this population of
patients.
Endocrine complications
People with thalassemia major frequently exhibit features of diabetes
mellitus; 50% or more exhibit clinical or subclinical diabetes. This is believed to
be due to defective pancreatic production of insulin, but insulin resistance also has
been implicated.
Glucose intolerance encountered in these patients usually correlates with the
numbers of transfusions received and the patient's age and genetic background.
Thus, the underlying disease may modulate iron-related endocrine injury.
Growth retardation
Growth retardation is frequently severe in patients with thalassemia (30%).
This retardation is caused, in part, by the diversion of caloric resources for
28
erythropoiesis, as well as by the chronic anemia because hypertransfusion usually
restores normal growth. Unless chelation therapy is initiated early in life, patients
rarely grow normally. Excessive chelation with DFO may also cause growth
retardation.
The direct cause of growth retardation in these patients is thought to be an
impaired growth hormone production or deficiency in production of somatomedin
by the hemosiderotic liver. This has been questioned by a report that suggested
GHD does not correlate with the efficacy of transfusional or chelation therapy.
Other factors are thought to be involved.
Involvement of the adrenal glands or the thyroid gland may also contribute
to growth failure.
Fertility and pregnancy complications
The survival of patients with thalassemia major has improved significantly.
Since the introduction of effective transfusion and chelation regimens. Patients are
now reaching their adulthood, and the questions regarding fertility becomes
relevant. Adult patients with thalassemia major have low fertility; this was
thought to be related to endocrine toxicity as a consequence to iron overload.
Patients with abnormal semen parameters were noticed to have low ferritin
level, whereas those with high ferritin had normal sperms parameters.
This is an interesting observation that is not fully understood; however, it raises
the question whether the abnormal sperm parameters are related to a negative
effect of intensive chelation therapy.
Females are frequently oligomenorrheic or amenorrheic. Pregnancy
complications are also seen frequently and are likely due to endocrinologic and
cardiac complications. Case reports demonstrated, however, that successful
pregnancy and delivery of healthy babies is possible in women with thalassemia
major. Gonadal dysfunction that results in arrested or delayed puberty is reported
in females with thalassemia major receiving transfusion and chelation therapy.36
A small uterus was noted in all women with delayed or arrested puberty. The size
may improve with hormonal replacement therapy (HRT).
29
Adequate transfusion to keep Hb at normal or near normal level at all times,
effective chelation and early intervention with hormonal therapy may prevent
permanent damage and help to preserve fertility.
PROGNOSIS 1,2,16
The prognosis depends on the type and severity of thalassemia. As stated
above, the clinical course of thalassemia varies greatly from mild or even
asymptomatic to severe and life threatening.
CASE REPORT
AH, 10 year-old boy, body weight 25 kg, body length 123 cm was admitted to H.
Adam Malik General Hospital on 3rd June 2010.
Main complaint is paleness for the last a week.
History of nausea, vomiting, icteric were not found.
Defecation and urination were positive and normal.
History of immunization was complete (BCG scar in right deltoid was
positive.
Os was diagnosed with Thalassemia Major from the result of Hb
electrophoresis that was done when the patient was 1 year old.
History of any family members having the same type of problem or having
Thalassemia was negative.
Os was the former patient of Non-Infection Unit/ Hemato-Oncology Unit
HAM General Hospital and given PRC transfusion regularly.
PHYSICAL EXAMINATION
Consciousness was alert, body weight 25 kg, body temperature 37,4oC. There
were anemi. Ichteric eyes, cyanosis, edema and dyspnoe were not confirmed.
Head : Eye : light reflexes (+/+), isochoric pupil, pale inferior palpebra
conjunctiva (+/+)
E/N/M : normal
Neck : Lymph node enlargement (-)
30
Chest : Symmetrical fusiform, no retraction
HR : 96 bpm, regular, no murmur
RR : 28 tpm, regular, no rales
Abdominal : Soepel, peristaltic was normal
Hepar : Palpable 5 cm below right costal arc
Lien : Palpable Schuffner II
Extremities : Pulse 96 tpm, regular, pressure/ volume normal
LABORATORY FINDINGS
Hematology
Complete Blood Count (CBC)
Hemoglobine (HGB) : 5.70 gr%
Erythrocyte : 2.50 x 106/ mm3
Leucocyte : 6.41 x 103 / mm3
Hematocrite : 18.20 %
Thrombocyte : 114 x 103 /mm3
MCV : 72.80 fL
MCH : 22.80 pg
MCHC : 31.30 gr%
RDW : 18.80 %
Diftel
Neutrophil : 41.10 %
Lymphocyte : 49.60 %
Monocyte : 6.10 %
Eosinophil : 3.00 %
Basophil : 0.20 %
Morphology
Erythrocyte : anisocytosis, hypochromic microcyter
Leucocyte : normal
31
Thrombocyte : normal
Conclusion : anemia hypochromic microcyter + thrombocytopenia
Liver Function Test
Total Bilirubin : 0.83 mg/dl
Direct Bilirubin : 0.28 mg/dl
Alkaline phosphatase : 140 U/L
AST/SGOT : 154 U/L
ALT/SGPT : 146 U/L
Renal Function Test
Ureum : 16.70 mg/dl
Creatinine : 0.49 mg/dl
Uric Acid : 4.7 mg/dl
Working diagnosis is Thalassemia β Major.
Treatments were given :
PRC transfusion as needed
Transfusion requirement : Δ Hb x 4 x BB : (10-5,7) x 4 x 23 : 395,6 cc
: ≈ 2 ½ bags
Transfusion ability : 5cc/kgBW : 5 x 23 : 115 cc : ¾ bag
Folic Acid 1 x 1 mg
Vitamine E 1 X 100 UI
Diet MB 1500 kcal with 50 grams protein
Nutritional Status was normal (normoweight) with 108%.
FOLLOW UP 3RD OF JUNE 2010 (15.00 WIB)
Consciousness was alert, body weight 25 kg, BB/TB : 103%, body temperature
36oC. There was paleness. Ichteric eyes, cyanosis, edema and dyspnoe were not
confirmed.
32
Head : Eye : light reflexes (+/+), isochoric pupil, pale inferior palpebra
conjunctiva (+/+)
E/N/M : normal
Neck : Lymph node enlargement (-)
Chest : Symmetrical fusiform, no retraction
HR : 92 bpm, regular, no murmur
RR : 32 tpm, regular, no rales
Abdominal : Soepel, peristaltic was normal
Hepar : Palpable 5 cm below right costal arc
Lien : Palpable Schuffner II
Extremities : Pulse 92 tpm, regular, pressure/ volume normal
Working diagnosis is Thalassemia β Major
Treatments:
PRC transfusion as needed
IVFD D5% NaCl 0,45% 10 gtt/i micro
Folic Acid 1 x 1 mg
Vitamine E 1 X 100 UI
Diet MB 1500 kcal with 50 grams protein
Transfusion requirement : Δ Hb x 4 x BB : (10-5,7) x 4 x 23 : 395,6 cc : ≈
2 ½ bags
Transfusion ability : 5cc/kgBW : 5 x 23 : 115 cc : ¾ bag
FOLLOW UP 4TH OF JUNE 2010 (06.00 WIB)
Consciousness was alert, body weight 25 kg, BB/TB : 103%, body temperature
36,8oC. There was paleness. Ichteric eyes, cyanosis, edema and dyspnoe were not
confirmed.
Head : Eye : light reflexes (+/+), isochoric pupil, pale inferior palpebra
conjunctiva (+/+)
E/N/M : normal
Neck : Lymph node enlargement (-)
Chest : Symmetrical fusiform, no retraction
33
HR : 106 bpm, regular, no murmur
RR : 32 tpm, regular, no rales
Abdominal : Soepel, peristaltic was normal
Hepar : Palpable 5 cm below right costal arc
Lien : Palpable Schuffner II
Extremities : Pulse 96 tpm, regular, pressure/ volume normal
BP : 105/75 mmHg
Working diagnosis is Thalassemia β Major
Treatments:
IVFD D5% NaCl 0,45% 10 gtt/i micro
Folic Acid 1 x 1 mg
Vitamine E 1 X 100 UI
Diet MB 1500 kcal with 50 grams protein
Further Prescription :
Disferal (20-50 mg/kgBW/day) = 20-50 (25) = 500-1250 mg/day
≈ 1000 mg/day ( 3 days )
PRC transfusion (day 2)
FOLLOW UP 4TH OF JUNE 2010 (16.00 WIB)
Consciousness was alert, body weight 25 kg, BB/TB : 103%, body temperature
36,3oC. There was paleness. Ichteric eyes, cyanosis, edema and dyspnoe were not
confirmed.
Head : Eye : light reflexes (+/+), isochoric pupil, pale inferior palpebra
conjunctiva (+/+)
E/N/M : normal
Neck : Lymph node enlargement (-)
Chest : Symmetrical fusiform, no retraction
HR : 92 bpm, regular, no murmur
RR : 30 tpm, regular, no rales
Abdominal : Soepel, peristaltic was normal
Hepar : Palpable 5 cm below right costal arc
Lien : Palpable Schuffner II
34
Extremities : Pulse 92 tpm, regular, pressure/ volume normal
Working diagnosis is Thalassemia β Major
Treatments:
IVFD D5% NaCl 0,45% 10 gtt/i micro
Folic Acid 1 x 1 mg
Vitamine E 1 X 100 UI
PRC transfusion (day 3, last transfusion)
Diet MB 1500 kcal with 50 grams protein
Infusion Desferal 1000 mg in 250 cc NaCl 0.9 % for 6 hours
(13.10-19.10 WIB)
Modul Hemato-Oncology
Futher Prescription :
Desferal 1000 mg ( day 2 )
Routine Blood Analysis
Ferriprox 1 x 1 tablet
FOLLOW UP 5TH OF JUNE 2010 (06.00 WIB)
Consciousness was alert, body weight 25 kg, BB/TB : 103%, body temperature
37oC. There was not anemi. Ichteric eyes, cyanosis, edema and dyspnoe were not
confirmed.
Head : Eye : light reflexes (+/+), isochoric pupil, pale inferior palpebra
conjunctiva (-/-)
E/N/M : normal
Neck : Lymph node enlargement (-)
Chest : Symmetrical fusiform, no retraction
HR : 96 bpm, regular, no murmur
RR : 28 tpm, regular, no rales
Abdominal : Soepel, peristaltic was normal
Hepar : Palpable 5 cm below right costal arc
Lien : Palpable Schuffner II
Extremities : Pulse 92 tpm, regular, pressure/ volume normal
Working diagnosis is Thalassemia β Major
35
Treatments:
IVFD D5% NaCl 0,45% 10 gtt/i micro
Folic Acid 1 x 1 mg
Vitamine E 1 X 100 UI
Diet MB 1500 kcal with 50 grams protein
Infusion Desferal 1000 mg in 250 cc NaCl 0.9 % for 6 hours ( day 2 )
Modul Hemato-Oncology
Futher Prescription : Routine Blood Analysis post transfusion
The patient was discharged in 5th of June 2010, with Hb > 10 gr/dl, no paleness,
and the PRC transfusion had been finished.
DISCUSSION
There is family history of Thalassemia of patient with Thalassemia.
Symptoms of β-thalassemia major develop gradually in the first 6 to 12 months
after birth. By the age of 6 to 12 months, most affected infants show pallor,
irritability, growth retardation, jaundice, and hepatosplenomegaly as a result of
extramedullary hematopoiesis.17,18 Patient did not have family history of
Thalassemia. This patient was diagnosed Thalassemia β Major in 1 year of life.
This patient had pallor before diagnosed with Thalasemia and did not have growth
retardation (nutritional status of patient patient was normoweight). There was
hepatosplenomegali on physical diagnostic.
In the severe forms of thalassemia, the Hb level ranges from 2-8 g/dL. Mean
corpuscular volume (MCV) and mean corpuscular Hb (MCH) are significantly
low, reflecting anemia hypochromic microcyter. Thalassemia major is associated
with a markedly elevated RDW, reflecting the extreme anisocytosis. Platelet count
is usually normal, unless the spleen is markedly enlarged.1,6 Patient had 5.70 gr%
of Hb value, so that he had severe anemia, that indicated patient had to get RBC
transfusion. In hematology laboratory findings, there was declining of MCV,
MCH, and MCHC value, but not significantly, that described the type of anemia
hypochromic microcyter. There was inclining of RDW value significantly that
36
reflects the morphology of RBC is anisocytosis. There was thrombocytopenia,
unless there was enlarging of spleen.
Liver involvement is common in those who undergo long-term transfusions.
Early cirrhotic changes can be observed as early as age 7 years in some people
with thalassemia. Upregulation of the transport of NTBI is observed in cultured
hepatocytes and is likely to occur in vivo. Once cirrhosis develops, the risk of
hepatocellular carcinoma (HCC) is increased. There was augmentation of SGOT
and SGPT that indicated there was damage process of hepatocyte, as the initial
sign of cirrhocis due to iron overload.
Transfusion therapy should be started when a diagnosis is made and the
hemoglobin level falls below 7 g/dL. The hypertransfusion protocol is used to
maintain a pretransfusion hemoglobin between 10.5 and 11.0 g/dL at all times
using 15 cc/kg leukocyte-depleted cross matched packed red cells. The primary
treatment for iron overload in thalassemia is chelation. 6,13,19 The transfusion had
started. The formula for finding amount of transfusion requirement was not 15
cc/kgBW. It was used formula : Transfusion requirement : Δ Hb x 4 x BB.
Desferal IV was administered to patient after transfusion.
Nutritional deficiencies are common in thalassemia, due to hemolytic
anemia, increased nutritional requirements. Patients should be evaluated annually
by a registered dietitian regarding adequate dietary intake of calcium, vitamin D,
folate, trace minerals (copper, zinc, and selenium) and antioxidant vitamins (E and
C). Energy and protein intake for 10 years old boy: Energy à 75 kcal/kgBW/day
and Protein à 1.2 gr/kgBW/day. Dietary intake for this patien is MB (makanan
biasa “usual meal”) with energy amount 1500kcal and protein 50 grams.20
SUMMARY
It has been reported a case of a boy, 10 years old with Thalassemia β
Major. The diagnosis was established based on anamnesis, clinical sign,
symptoms, and physical examination. The prognostic of this patient was not good,
due to continuous transfusion. This patient should remain controlled as an
outpatient to prevent complication of continuous transfusion. This patient also
37
needed chelation to reduce the accumulation of iron, along with other nutrient
(calcium, vitamin D, folate, trace minerals (copper, zinc, and selenium) and
antioxidant vitamins (E and C)).
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