Pediatr Clin N Am 49 (2002) 1165 – 1191

Thalassemia: current approach to an old disease

Louise Lo, MD, Sylvia Titi Singer, MD*
Children’s Hospital and Research Center at Oakland, Department of Hematology/Oncology,
747 52nd Street, Oakland, CA 94069, USA

The thalassemias, a group of inherited disorders of hemoglobin synthesis, are

the most common single gene disease worldwide. Only in the 1930s and 1940s did
it become apparent that this disease, first described as severe anemia, bone
changes, and splenomegaly, results from a defective synthesis of one of the two
globin chains, alpha (a) or beta (b), that constitute adult hemoglobin [1]. Most
forms are inherited in a Mendelian recessive fashion from asymptomatic parents
who are the gene carriers, and who have a one in four chance of having an affected
child. The disease has tremendous variation, ranging from silent, asymptomatic
carriers to transfusion dependency for survival, sometimes referred to as ‘‘Cooley
anemia’’ and used to describe the severe form of the b-globin deficiency.
More than 100,000 affected infants and several million heterozygotes are born
annually. The highest incidence is in the ‘‘malaria belt,’’ around the equator, as it
reflects an advantage of the heterozygous form against Plasmodium falciparum
malaria [2– 4]. In the countries surrounding the Mediterranean Sea and the Middle
and Far East, thalassemia is becoming an increasing public health problem;
however, because of population migration, it is found throughout the world [5,6].
Over the last two decades broader understanding of the disease pathophysiology
led to successful prenatal diagnosis, improved supportive care that resulted in
decreased morbidity, and prolonged life expectancy. Thalassemia is an example of
a best studied disease of a known molecular mechanism, one of the first human
genes cloned and sequenced. This to research aimed at understanding the defects
in gene function and their effect on disease expression [7], and to efforts at curing
or ameliorating the disease severity by gene manipulation. Thalassemia is also one
of the first genetic diseases treated and cured with bone marrow transplantation,
a field offering constant therapeutic advances for this patient population [8,9].
In the early twenty-first century, these major advances in the disease diagnosis
and therapy are in widespread use, yet the medical system still struggles with the

* Corresponding author.
E-mail address: tsinger@mail.cho.org (S.T. Singer)

0031-3955/02/$ – see front matter D 2002, Elsevier Science (USA). All rights reserved.
PII: S 0 0 3 1 - 3 9 5 5 ( 0 2 ) 0 0 0 8 8 - 3
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issues of optimal care for the disease complications and the magnitude of the
problem in developing countries, where conventional treatment with safe blood
and iron chelation therapy is often unavailable [10], as are effective programs for
prenatal screening.
This article discusses the approach for recognition, diagnosis, and management
of the thalassemias, and reviews new prospects of therapy, focusing mostly on the
b-thalassemias, which are the more severe and clinically important type.

Hemoglobin production and pathophysiology

Normal hemoglobin production requires the formation of fully balanced
hemoglobin tetramers consisting of two types of globin chains and a heme moiety.
Different hemoglobins are synthesized in the embryo, fetus, and adult that are
classified as a-like or b-like globin chains. The a-like chains (zeta [z] and alpha
[a]) are controlled by genes on the short arm of chromosome 16, and the b-like
chains (epsilon [e], gamma [g], delta [d], and beta [b]) are controlled by genes on
the short arm of chromosome 11. A sequential expression of the different
hemoglobin genes results in different pairs of an a-like with a b-like globin
chain: z2e2 during embryonic life and a2g2 (fetal hemoglobin) during fetal life,
which declines after birth. Ultimately, the adult types a2b2 (hemoglobin A) and
a2d2 (hemoglobin A2) are expressed. The mechanisms that control the hemo-
globin switch from fetal to adult hemoglobin at approximately 38 weeks of
gestation are not fully understood [7,11].
Thalassemia is caused by defective or absent synthesis of either of the two
chains, a or b, of the adult hemoglobin tetramer, as a result of a gene deletion or
mutation. At the cellular level this results in a reduced amount of normal functional
hemoglobin and an imbalance between the two globin types as the unaffected chain
is continuously produced, whereas the affected chain production is decreased or
absent. The precipitation of the remaining globin chains alters red cell cellular and
membrane properties, leading to early destruction of the red cell in the intramedul-
lary spaces, known as ineffective erythropoiesis, essentially an intramedullary
apoptosis. The mature red cells that make their way out from the marrow have a
shortened survival because of increased hemolysis, resulting in severe anemia [12].
Ineffective erythropoiesis is a feature of b thalassemia as the relative excess
unstable a chains precipitate and disintegrate causing oxidative damage to the red
cell membrane. Conversely, the excess of b chains (named Hb H) in a thalassemia
is a more stable denaturated globin chain aggregate, resulting in less intra-
medullary membrane damage, which accounts for the clinical differences in
disease symptoms and severity.

Definitions
Thalassemias are classified according to the particular globin chain that is
ineffectively produced, a or b thalassemia being the more common and most
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important types. Less common types, not discussed in this article, include db
thalassemia and gdb thalassemia (Tables 1 and 2). Other hemoglobinopathies
frequently found in the same population as the thalassemias involve genes for
structural hemoglobin variants, such as hemoglobins S, C, and E. Frequently a
gene for thalassemia is inherited from one parent together with one of these
structural variants from another parent. The important diseases of this type are
hemoglobin E-b thalassemia and sickle-cell thalassemia; the latter is discussed
elsewhere as its clinical manifestations are those of sickle-cell disease.

Molecular aspects

b Thalassemia
The mutations can be classified as resulting in complete absence of b-globin
production: b zero thalassemia (b-0), or a reduction in synthesis, b plus
thalassemia (b+). More than 200 different mutations have been described and
the majority are nucleotide substitutions [13]. They generally involve one of
four mechanisms:

 DNA transcriptional mutations at the promotor site, usually resulting in a

b+ thalassemia
 mRNA modification at the splicing or cleavage steps resulting in b-0 or b+,
depending on the splice site impairment
 RNA mutations causing abnormal translation of the gene to a globin chain
product, resulting in b-0 thalassemia (mostly caused by premature
termination codon)
 Mutations causing unstable globins (usually located in exon 3). These can
cause a dominantly inherited thalassemia, as heterozygotes can have an
unstable hemoglobin and anemia.

Beyond the underlying b mutation that affects the level of b globin chain
synthesis, other globin chain factors are involved in altering the phenotype.
Several mechanisms reduce the degree of globin chain imbalance, a key factor in
the determination of b thalassemia severity. These mechanisms include: (1) the
ability to synthesize larger amounts of g chains, which combine with the excess a
chains to form Hb F (a2g2). Generally a higher Hb F level results in a milder
phenotype. The mechanisms involved in persistent Hb F synthesis are not
fully understood; some include the g globin genes, whereas others are outside
the b globin gene cluster [14]; (2) the coexistence of one or two a thalassemia
genes results in more balanced globin chain synthesis. In addition, interactions
with structural hemoglobin variants affect disease manifestations. The most
common examples include hemoglobin S and hemoglobin E, the first resulting
in a different severity of sickle-cell disease, the second in a serious and
common type of thalassemia discussed later in this article. The diversity of the

Table 1
a thalassemia
Definition
1 gene deletion - silent carrier
2 gene deletion - a thalassemia trait – ,a/ – ,a or – , – /a,a Newborn: Bart’s 3% – 10%
3 gene deletion - Hb H
Hb H + Constant Spring
2 gene deletion and
Constant Spring mutation
4 gene deletion - Hydrops Fetalis
Nondeletional mutation
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Genotype Hb electrophoresis Hematologic expression Clinical expression
– ,a/aa Newborn: Bart’s 1% – 2% Normal Normal
Microcytosis, hypochromia Normal to mild anemia
– , – / – ,a Newborn: Bart’s 20 – 30% Marked microcytosis, Moderate anemia, splenomegaly,
Older child: Hb H 10% – 15% hypochromia occasional transfusions
Hb F 10%
– , – /a,a cs 2% – 3% CS Hb H 20% – 40% Hypochromia and Moderate-severe anemia,
moderate microcytosis splenomegaly, occasional transfusions
–,–/–,– Newborn: Bart’s 80% – 100% Abnormal morphology, Severe anemia, edema,
hypochromia, anisopoikilocytosis hepatosplenomegaly
variant
a,a/a,a 2% variant Hb Variable microcytosis Normal or variable anemia;
depending on the a chain stability
Table 2
b thalassemia (Selected types)
Definition
b thalassemia trait
(heterozygote carrier state)
b thalassemia major
(Cooley anemia)
b thalassemia intermedia
(db)0 thalassemia heterozygote
Hb Lepore trait
Hb Lepore homozygote
Hereditary persistent fetal Hb
(HPFH) deletional, homozygous
Hereditary persistent fetal Hb
(HPFH) non-deletional, heterozygote
L. Lo, S.T. Singer / Pediatr Clin N Am 49 (2002) 1165–1191
Genotype Hb electrophoresis Hematologic expression Clinical expression
b/b+ or b/b0 Elevated Hb A2 3.5% – 7.0% Microcytosis, hypochromia, Normal
Variable elevation of Hb F, mild or no anemia
but <5%, the rest Hb A
b0/b0 or b0/b+ or b+/b+ Hb F 30% – 98%, Hb A2 Microcytosis, hypochromia, Transfusion-dependent
or structural Hb variant with 2%, no Hb A elevated nucleated RBC,
a b mutation: HbE/b0 target cells
b0/b0 or b0/b+ or b+/b+ or Hb F 70% – 95%, Hb A2 Microcytosis, hypochromia, Pallor, hepatosplenomegaly
structural Hb variant with 2%, trace Hb A elevated nucleated RBC, transfusion-dependent or
a b mutation: HbE/b0 ; HbE/b+ target cells intermedia phenotype
(db)0/A Hb F 5% – 20%, the rest Hb A Hypochromia Mild anemia
bLepore/A Hb lepore 5% – 15%, Hb F Microcytosis Mild anemia
<5%, normal Hb A2
bLepore/bLepore Hb F 80%, Hb Lepore 5% – 15% Microcytosis, hypochromia, Moderate/severe anemia
HbA/A Hb F 100% Microcytosis Mild anemia
HbA/A Hb F 15% – 40% Normal Normal
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b thalassemias likely relates to complex genetic interactions, many not yet

defined, that underline these conditions, together with nongenetic, environmental
modulators [15,16].

a Thalassemia
Normal individuals inherit a total of four a globin genes, two from each parent,
resulting in a a,a/a,a genotype. Most mutations are gene deletions; one or both a
genes may be affected per haploid genome [17,18]. Phenotypic expression of a
thalassemia therefore depends on the number of available a genes. Four clinical
syndromes emerge:

 Homozygous state, deletion of four a globin genes (– /– ), results in hydrops

fetalis, a severe, usually fatal disease in utero or shortly after birth [19]. In the
fetus, the excess gamma chains form tetramers named hemoglobin Barts (a
useless type of hemoglobin, as it cannot deliver oxygen) which can be
detected on hemoglobin electrophoresis in the newborn. The few cases that
survive the perinatal period are transfusion-dependent and have a high pre-
valence of malformations.
 Hemoglobin H disease, a deletion of three a globin genes, is a combination of
a cis deletion and a single a globin gene deletion (a / ), resulting in a
moderately severe anemia. The remaining unpaired b globin chains form
tetramers named hemoglobin H.

Hydrops fetalis and Hemoglobin H disease are usually limited to Southeast

Asia because both require cis a gene deletion, known as ( – – SEA), which is
endemic to that area. Rare double deletional mutations have been described in the
Mediterranean population.

 a thalassemia trait and silent carrier are mild variants. a thalassemia trait
expresses two a gene deletions (trans deletion, a– /a– ) or cis deletion
(a,a/ ), causing mild microcytic chromic anemia. Silent carriers have
one gene deletion and three intact a globin genes (a,a/a– ) and are
clinically and hematologically undetectable (Table 1).

Diagnosis and screening

Carrier detection and prenatal diagnosis

Though family history of thalassemia is important, a significant number of
patients do not have previously affected family members. A complete blood count
should be obtained in all women in their reproductive years. If the red cell indices
are suggestive of thalassemia trait MCH < 27 pg, MCV < 82 fl, especially in
women of high-risk ethnic groups, further screening with hemoglobin electro-
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phoresis and quantitative HbA2 should be performed (Fig. 1) [20,21]. Severe iron
deficiency can mask a diagnosis of thalassemia and therefore must be excluded
before a hemoglobin electrophoresis. If b thalassemia is unlikely (low indices with
a normal Hb A2) and a thalassemia is suspected, referral to centers that can
identify the different forms by DNA testing is recommended [22]. Screening of the
partner may not be necessary if the results are normal [23,24].
Once a couple has been identified as being at risk for having a child with
thalassemia, genetic counseling and education regarding prenatal testing should be
pursued [25,26]. First trimester testing is a more acceptable choice to those groups

Fig. 1. Assessment of MCV is accompanied by other complete blood count measurements: Increased
RDW suggests iron deficiency anemia; high reticulocyte may suggest hemolytic anemia and not iron
deficiency. RBC count is usually elevated in thalassemia syndromes, low or normal RBC count is
atypical for thalassemia. Normal ranges of MCV by age: See Nathan DG, Orkin SH. Hematology of
infancy and childhood. 5th edition. Philadelphia; Saunders: 1998; appendix 11.
1172 L. Lo, S.T. Singer / Pediatr Clin N Am 49 (2002) 1165–1191

with convictions against prenatal testing [27]. Prenatal testing is accomplished by

fetal DNA polymerase chain reaction (PCR) methods or later by direct fetal
hemoglobin testing [28,29].
Although difficult to foresee with certainty, the relationship between genotype
and phenotype has important clinical implication, as it enables us to predict the
likely prognosis for a particular genotype a child will inherit or has the potential to
inherit [30,31].
Some couples who already experienced giving birth to an affected child may
opt for preimplantation diagnosis, avoiding issues of pregnancy termination. This
method (of limited availability) uses in vitro fertilization, DNA testing of a single
blastomere for the suspected mutations, and uterine implantation of nonaf-
fected blastomeres.

Postnatal diagnosis
A large percentage of patients who are not detected in prenatal screening are
detected during newborn screening in those countries and in areas of the United
States where newborn screening is implemented. Hb Barts (tetramer of g globin
chains) in a thalassemia patients or an elevated Hb A2 or Hb F in b thalas-
semia patients suggests these diagnoses. DNA-PCR analysis and parental
testing can specify further the type and severity of disease. b hemoglobin
variants, such as Hb E or an a hemoglobin variant named Hb Constant Spring,
also may be detected by newborn screening, the latter frequently requiring DNA
diagnosis [32].
In older children, suspicion of thalassemia arises with a microcytic, hypochro-
mic anemia and an abnormal hemoglobin electrophoresis. Other causes for
microcytic anemia need to be looked at also (Table 3).

Clinical presentation and heterogeneity

a Thalassemia
The most important clinical form is hemoglobin H disease, a three-a gene
deletion, common in people from Asian descent and causing a chronic moderately
severe hemolytic anemia. Patients may develop splenomegaly, cholelithiasis, and
may require transfusions during episodes of oxidative stress induced by infections,
fever, or certain medications [33]. A more severe clinical form named hemoglobin
H-Constant Spring results from coinheritance of a nondeletional a gene variant,
hemoglobin Constant Spring, with two a gene deletions. Patients with this
disorder have more severe hemolytic anemia and hypersplenism requiring more
frequent transfusions. Conversely, concomitant hemoglobin H disease and
b thalassemia trait reduces severity of the a thalassemia. Monitoring of spleen
size and hemoglobin level, especially during febrile episodes, and supplementa-
tion with daily folic acid, are the main treatment measures. In addition, avoiding
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Table 3
Diagnosis and intervention for a thalassemia trait and b thalassemia trait after the newborn period
Serum
Diagnosis Hb RBC MCV Hb A2 Hb F RDW FEP Fe/TIBC Intervention
b thalassemia trait Normal or Normal or <75 fL Elevated Slightly Normal Normal Normal
Screen partner, siblings
slightly low slightly elevated 3.5% – 7% increased No need for iron supplementation
Educate about the risk of an affected
child with thalassemia major
a thalassemia trait Normal Normal <75 fL <3% Normal Normal Normal Normal Screen partner, siblings
No need for iron supplementation
Educate about the risk of an affected
child with thalassemia major (if Asian)
Iron deficiency Low Low <83 fL <3% Normal Elevated Elevated Reduced/ Iron therapy
anemia elevated May look again for thalassemia after therapy,
as can be masked by low iron

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medications or substances likely to cause oxidative stress and increased hemolysis

is important. A partial list includes sulfa, antimalarial agents, aspirin, and
naphthelin. Though an almost universally fatal disease, hydrops fetalis patients
who are long-term survivors have been described; some underwent bone marrow
transplantation [34,35].

b Thalassemia
The important forms of b thalassemia result from homozygosity or compound
heterozygosity and are classified based solely on their clinical severity into
thalassemia major and thalassemia intermedia. Even within these categories,
however, there is a remarkable variability from a mild anemia to complete
transfusion dependency for survival.
Patients with thalassemia major usually develop anemia within the first 6 months
of life, because the decreasing levels of fetal hemoglobin cannot be replaced by
normal adult hemoglobin. Hemoglobin in the range of 3 – 4 g/dL is not uncommon.
If regular transfusion therapy is not initiated, a clinical picture of severe untreated
b thalassemia develops, characterized by profound anemia, splenomegaly, and
progressive bone changes caused by marrow expansion of blood-forming skeleton
areas. Typical bone changes result in characteristic thalassemic face: prominent
maxillary bones, flat nose bridge, and frontal bossing, and in thinning of long bones
and joint deformities. Occasionally masses of extramedullary hematopoiesis,
mostly in the paraspinal area, develop, occasionally resulting in spinal cord
compression and neurologic symptoms. These manifestations are uncommon in
developed countries where transfusion therapy is initiated early in life, ‘‘turning
off’’ the marrow and evading the continuous marrow expansion.
Patients are categorized as having b thalassemia intermedia when presenting
later in life, usually during the second year, and when they do not require early
intervention with blood transfusions. These children with a moderate but well
compensated anemia usually grow and develop well. Not infrequently, however,
symptoms of progressive anemia, heart failure, pulmonary hypertension, hyper-
splenism, and bone expansion evolve during the second and third decades of life.
These clinical developments essentially categorize the patient as having thalasse-
mia major, frequently necessitating initiation of regular transfusion therapy.
b thalassemia trait, the heterozygote or carrier state, is generally asymptomatic
and carries mainly a screening and diagnostic significance for genetic counseling.
In clinical practice, however, occasionally it needs to be distinguished from iron
deficiency anemia (Table 3).

b Thalassemia: transfusion therapy and considerations for splenectomy

Transfusions
Once a child is diagnosed with b thalassemia major, the decision to start regular
transfusions is usually a life-long commitment and entails its own risks for infec-
tions and iron overload [36]. These serious side effects together with the emotional
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impact make the decision a difficult one. Initiation of transfusions is based mostly
on clinical assessment and on the level of hemoglobin. Monitoring for signs of
anemia, heart failure, poor growth, splenomegaly, and marrow expansion deter-
mines the need to start transfusions. Occasionally the need for a single transfusion
may represent a nutritional deficiency, such as folic acid or iron, or an infectious
complication. Therefore, patients should be reevaluated once these issues are
corrected to avoid unnecessary premature initiation of transfusion therapy.
Chronic transfusions eliminate the primary complications of severe thalassemia
by ameliorating anemia and suppressing erythropoiesis. Current goals of chronic
transfusion also include lessening iron intake as opposed to the earlier ‘‘hyper-
transfusions’’ approach in which an attempt was made to completely turn off the
marrow by maintaining a higher post-transfusion hemoglobin. A practical regimen
is to transfuse every 3– 4 weeks and maintain baseline pretransfusion hemoglobin
of 9.5 – 10.5 g/dL and post-transfusion hemoglobin of 13 – 13.5 g/dL. This
adequately eradicates the consequences of anemia and erythropoiesis, yet mini-
mizes iron contribution. The patient’s red cell phenotype for ABO, Rh, C, E, and
Kell is determined before initiation of transfusion, and, ideally, blood matched for
these antigens should be given. Infection prevention mandates hepatitis B (HBV)
vaccination, ideally before starting transfusions, and the use of current methods of
leukocyte-depleted RBCs.

Splenectomy
Extramedullary hematopoiesis leads to splenomegaly and hypersplenism. It was
generally believed that splenectomy may decrease the transfusion requirements by
increasing red cell survival and it has been recommended when the total yearly
RBC use exceeds 200 cc/Kg [37]. Splenectomy has short- and long-term down-
sides, however. Spleen removal does not always result in a sustained reduced blood
consumption or a substantial decrease of iron burden. In addition, pilot studies
suggest that pulmonary vascular disease and thrombosis may be a long-term
problem. It is possible that with current effective transfusion regimens, spleno-
megaly and hypersplenism occur less often. In young children, a known risk for
overwhelming sepsis exists. These factors must be weighed against the increased
iron accumulation inherent in augmented transfusion requirements from hyper-
splenism. In nontransfused and intermittently transfused patients, splenomegaly
and hypersplenism develop at a younger age and can be ameliorated by removal of
the spleen. The plan for splenectomy must be accompanied by thorough family
education concerning fever and the risk for life-threatening infection. Vaccination
with 23-valent or 7-valent pneumococcal, Haemophilus influenzae, and meningo-
coccal vaccines, ideally 3– 6 weeks before splenectomy, is required. Lifelong
penicillin prophylaxis against pneumococcus is initiated postsplenectomy. Con-
siderations for a low-dose antiplatelet agent should be made in older splenectom-
ized patients, especially those with high platelet counts. An alternative approach of
partial splenectomy has been explored only in a limited number of thalassemia
patients and needs further evaluation [38].
1176 L. Lo, S.T. Singer / Pediatr Clin N Am 49 (2002) 1165–1191

B Thalassemia major: disease manifestations

Given that patients are typically transfused from infancy, many of the classic
‘‘Cooley anemia’’ manifestations are not apparent, and the disease expression
turns into the consequences of chronic blood transfusions, namely those of iron
overload and blood transmitted infections [39,40]. Therefore, though a treatable
condition with regular transfusions and life-long iron chelation, it remains a
complex, multiorgan disease, as discussed later.

Iron overload
Iron overload is a major complication of b thalassemia and is the cause of organ
damage, morbidity, and mortality, unless adequately removed from parenchymal
tissues [41,42]. Moreover, the magnitude of the body iron load is the main
determinant of patients’ clinical outcomes [43]. A packed red blood cell unit of
250 cc delivers approximately 175 mg of iron. Because iron is highly conserved
and sparingly excreted by humans, iron introduced by transfusions accumulates
and exceeds 70 g by the beginning of the second decade in transfused patients
[44]. Methods for removal of the tissue iron with chelation therapy are a major
aspect of thalassemia management [45,46].
After approximately a year of regular transfusions, iron starts accumulating in
parenchymal tissues, where it can cause progressive toxic damage. As iron loading
persists, serum transferrin, the main iron-transporting protein, becomes saturated
so that nontransferrin-bound iron (NTBI) is present in plasma. This iron fraction is
able to catalyze reactions that generate free hydroxyl-radicals, which cause further
cell damage [47]. Most clinical manifestations of iron overload, which include
progressive dysfunction of the heart, liver, and endocrine organs, appear during
the second decade of life. There is evidence, however, that the harmful effects of
iron start earlier, as demonstrated by hepatic fibrosis seen in liver biopsies after
2 years of transfusion therapy [48,49].

Assessment of body iron burden

A single method for measuring body iron load does not exist. Plasma ferritin
levels, iron studies, 24-hour deferroxamine-induced urinary iron excretion, and
imaging studies of the liver or heart can be used as indirect assessments. Periodic
assessment of ferritin levels is used most commonly; however, it was shown to be
a poor indicator of iron load, as it is affected by other conditions like infection or
inflammation, liver disease, vitamin C deficiency, and hemolysis [50]. Relying on
ferritin levels only can result in inaccurate assessment of body iron and inadequate
chelation. Direct measurement is done by measuring hepatic iron concentration by
liver biopsy and is considered the most sensitive and specific method providing
quantitation of iron concentration and extent of liver damage. Magnetic suscep-
tometry using a superconducting quantum interference device (SQUID) is not
generally available but provides an excellent noninvasive correlation with liver
 L. Lo, S.T. Singer / Pediatr Clin N Am 49 (2002) 1165–1191 1177

biopsy-determined iron concentration [42]. If hepatic iron measurement is not

feasible, ferritin levels can be used, with the noted limitations, for assessment of
the trend of iron overload and for the risk for cardiac complications, using a
threshold level of approximately 2500 mg/L.

Clinical complications of iron overload

The heart
Mortality from cardiac disease (heart failure or fatal arrhythmia) remains the
main cause of death in transfusion-induced iron-overload patients [51,52].
Myocardial iron deposition causes cardiac hypertrophy and dilatation and degen-
eration of myocardial fibers. The unbound iron generates toxic oxygen metabolites
resulting in further injury to the myocytes. Patients therefore develop conductive
disturbances and progressive heart failure [53]. In addition, a higher susceptibility
for myocarditis and the occasional development of pulmonary hypertension can
further accelerate the cardiac disease [54].
Currently, patients who started chelation therapy with desefrioxamine in early
childhood lived long enough to show that early and effective chelation can prevent
death from cardiac disease [45]. Quantitation of cardiac iron is difficult as cardiac
muscle biopsy is not regularly feasible and none of the imaging studies has been
shown to be optimal. Magnetic resonance imaging (MRI) can estimate cardiac
iron, but no good correlation with cardiac iron obtained by biopsy has been shown.
Recently a T2* MRI technique showed good correlation with cardiac iron stores
[55]. Methods for detecting early iron-induced cardiac dysfunction in asympto-
matic patients include low-dose dobutamine stimulation, exercise cardiac radio-
nucleotide angiography, and stress echocardiogram [54]. Their prognostic
significance for the development of symptomatic cardiac disease is debatable.
Regular monitoring for cardiac function and arrhythmias with annual echocardio-
gram, EKG, and 24-hour Holter monitoring is extremely important, though not
sufficiently sensitive for early detection of disease. In clinical practice, measure-
ments of liver iron has been shown to best correlate with the total body iron
burden and to predict the threshold for risk for cardiac disease and early death
(levels of 15 mg/g dry weight or greater) [42]. Persistent ferritin levels greater than
2500 mg/L and assessment of annual blood requirement can assist in predicting
development of cardiac disease.
Once diagnosed, every effort for aggressive chelation should be made, as
cardiac dysfunction still can be reversed and improved [36,56]. Treatment with
angiotensin-converting enzyme (ACE) inhibitors may prevent or delay congestive
heart failure in asymptomatic patients with left ventricular dysfunction. Digitalis
therapy, diuretics, and low sodium diet benefit those patients with established
congestive heart failure, in addition to intensive chelation therapy [54]. Those
patients refractory to pharmacologic therapy are candidates for cardiac transplant
assessment [57].
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The liver and infectious hepatitis

Iron-induced hepatic disease is a common cause of morbidity and early death,
and is frequently worsened by coexistence of hepatitis C (HCV) infection, often
seen in transfused adult patients. As the primary uptake and storage site for
excessive amounts of iron, the liver undergoes progressive damage [58,59].
Hepatic fibrosis is notable on liver biopsies within a few years of initiation of
transfusions. This may progress to cirrhosis and liver failure in heavily iron-
overloaded, poorly chelated patients. A liver iron level exceeding 7 mg/g of liver
dry weight is associated with hepatic fibrosis [60].
The prevalence of HCV varies globally among b-thalassemia major patients
[61]. With current nucleic acid testing (NAT) blood screening methods in North
America, HCV infection is present in less than 1/250,000 transfused blood units.
Because of less optimal screening measures in developing countries, however, the
prevalence of new infections is still high in other parts of the world [62]. Most
patients with HCV infection develop chronic hepatitis. In some, cirrhosis, liver
failure, or hepatocellular carcinoma may develop [63]. Coinfection with HBV also
may accelerate the disease course; therefore, annual HBV screening and early
immunization is advisable.
Regular monitoring of liver function tests, annual screen for antibody for
HCV, and periodic measurement of hepatic iron levels and histology are
essential. Once HCV is suspected in the setting of elevated transaminases and
positive antibody screen, liver biopsy and HCV RNA polymerase chain reaction
(PCR) should be obtained. For patients with chronic HCV, annual assessments
of liver histology and of viral load by PCR are recommended. Periodic imaging
studies are needed to rule out development of hepatocellular carcinoma [64].
Early treatment of HCV with a interferon can result in sustained response of
liver disease consisting of clearance of HCV virus RNA and improved liver
histology. Treatment with a interferon and pilot data on combination treatment
using a interferon and ribavirin resulted in improved response in adults, a
major side effect being hemolysis and therefore increased transfusion require-
ment [65].

Endocrine glands
As the life expectancy of well chelated thalassemia patients has improved,
endocrinopathies have emerged as important complications. Iron deposition in the
anterior pituitary gland, thyroid and parathyroid glands, pancreatic cells, and
adrenal cells, results in significant morbidity [66]. Delayed puberty, short stature,
and hypogonadism are major problems from childhood to adulthood, found in
more than half of the patients [67,68]. Yet again, appropriate iron chelation can
prevent or improve many of these complications.
Growth delay, short stature, and particularly a disproportional short trunk are
common findings; the causes are multifactorial and vary in different age groups
[69]. Chronic anemia and marrow expansion result in growth delay in non-
 L. Lo, S.T. Singer / Pediatr Clin N Am 49 (2002) 1165–1191 1179

transfused young patients. Well transfused patients, however, also experience

growth problems: iron toxicity to the hypothalamus and anterior pituitary,
abnormalities in growth hormone (GH) release, GH resistance, and reduced liver
synthesis of insulin-like growth factor (IGF-1) all have been described [70].
Desferoxamine, particularly when used in early childhood in high dose levels or in
the presence of low-iron burden, can cause reduced height because of its effect on
long bone growth and vertebral body flattening [71]. Adolescents represent a
particularly vulnerable group. A combination of abnormal gonadotropin release
during puberty, poor compliance with chelation (found in up to 40% – 50% in this
age group), and inadequate diet are all contributing factors. Liver disease and
nutritional factors, zinc deficiency in particular, also add to the growth impair-
ment. Administration of exogenous GH as daily subcutaneous shots, or more
recently as a long-acting monthly treatment, sex steroid replacement, and
optimizing transfusion and chelation therapy, can improve linear growth in many
but not all cases [72,73].
Delayed puberty and hypogonadism are reported in 30% – 50% of b-thalasse-
mia major patients, observed even in well chelated patients [74,75]. As with other
organs, the iron deposition and oxidative damage induced by free radicals affects
the anterior pituitary, ovarian follicles, and testes. Secondary hypogonadism, after
puberty was completed, is also commonly seen. Women present with amenorrhea,
early loss of bone mass, and other symptoms of menopause, whereas men present
with reduced energy, declining libido, and sexual dysfunction. Hormone-replace-
ment therapy, testosterone for men and estrogen for women, with endocrinologist
consultation, is required. As patients now more often survive into adulthood, the
attention to reproductive potential has increased together with the patients’ desire
to have a family. Reports have shown that a successful pregnancy is possible in
women who are well chelated, with or without ovulation induction therapy and
more than 100 successful pregnancies have been reported [76,77]. In men with
fertility problems, aggressive chelation and spermatogenesis induction with
gonadotropins is occasionally needed.
Impaired glucose tolerance and progression into diabetes mellitus is another
serious complication that usually emerges in late adolescence. Diabetes mellitus
arises from impaired insulin secretion caused by iron-induced pancreatic dys-
function, and insulin resistance caused by impaired clearance by the liver [78].
Routine testing with fasting serum glucose levels, oral glucose tolerance test
(OGTT), and insulin and fructosamine levels, may detect early preclinical disease.
Aggressive chelation therapy and exercise can reverse the abnormalities and
prevent advancement to clinical diabetes. Once insulin-dependent diabetes melli-
tus develops, it is usually not associated with ketoacidosis and lacks typical
findings of HLA haplotypes and anti-islet antibodies seen in the typical cases of
type I diabetes [79].
Hypoparathyroidism and vitamin D deficiency are common causes of calcium
and phosphorus metabolism disturbance in thalassemia patients, and are an
important contribution to the osteopenia and osteoporosis so often diagnosed.
Acute symptoms for parathyroid disease are uncommon. Annual screening for
1180 L. Lo, S.T. Singer / Pediatr Clin N Am 49 (2002) 1165–1191

parathyroid and calcium abnormalities, calcium and vitamin D supplementation,

and nutritional counseling should be initiated early.
Subclinical primary hypothyroidism, detected only by mildly elevated thyroid
stimulating hormone (TSH) levels, is a frequent finding in transfused patients.
Annual screening for T3, free T4, and TSH is recommended. Occasionally,
clinically evident disease develops [80].

Iron chelation therapy

Iron chelation therapy has a major impact on quality of life and life
expectancy. Optimal body iron corresponds to a hepatic iron range of approx-
imately 3 – 7 mg iron per gram liver dry weight, as derived from data on
hereditary hemochromatosis. Higher levels indicate increased risk for iron-
induced complications, whereas lower levels may increase the risk for deferox-
amine toxicity [42].
Ideally, iron-chelating therapy should minimize the iron-overload induced com-
plications and have minimal adverse effects of the chelating agent itself. Subcuta-
neous desferioxamine (desfrioxamine) administration is the best means of iron
chelation at this time. Because of its poor gastrointestinal absorption and toxicity, it
requires continuous parenteral infusion given mostly subcutaneously with a por-
table pump. Although an effective chelator, patient compliance remains poor in
approximately 50% of patients because of its cumbersome, uncomfortable, and
expensive mode of administration. This gives rise to an intense need for a better
system of chelation.
Several potential side effects of deferoxamine generally can be avoided with
periodic monitoring. These include high frequency hearing loss, ocular abnor-
malities, and renal function impairment. Acute pulmonary toxicity also has been
reported. The effect on cartilaginous dysplasia, mostly in the spine, is more likely
in high doses used since early childhood.
Chelation is usually initiated at the age of 3 years, an emotionally difficult
process for the patient and family. If liver iron is available, start chelation when
ferritin level is greater than 1000 mg/dL in 2– 3 consequent measurements.
Ideally, the first liver biopsy should be performed after 1 year of transfusions.
A low subcutaneous desferioxamine dosage of 25 mg/kg/3 – 5 days a week is
used before the age of 5 years to avoid undesirable growth disturbances,
followed by higher dose adjustments up to 30 –50 mg/kg/5 –6 days a week later
in life. Dosages greater than 50 mg/kg/day are reserved for those patients
requiring rescue from life-threatening iron-induced organ damage. Ascorbic acid
(vitamin C) supplementation, given with the desferioxamine chelation, opti-
mizes the mobilization of iron from the reticuloendothelial system [42,81].
Several alternative approaches aimed at decreasing the frequency and duration
of administration are under investigation, including a long-acting hydroxyethyl
starch desferioxamine.
Extensive research for developing an effective oral iron chelator has been
proceeding for more than 20 years, and if successful, may have tremendous
 L. Lo, S.T. Singer / Pediatr Clin N Am 49 (2002) 1165–1191 1181

usefulness around the world. Several agents reached clinical trials; the most
extensively evaluated is deferiprone; L1 [82]. Data have shown its short-term
efficacy, but controversy over its toxicity and effectiveness, together with a lack
of controlled studies, has limited its widespread use. Recent studies have
suggested synergistic and additive effect of using desferioxamine with defer-
iprone, a ‘‘shuttle’’ mechanism in which the oral agent mobilizes tissue iron,
then exchanges with the parenteral agent, has been proposed. Although a
promising approach, more studies are needed for assessment of the effectiveness
and toxicity [83].

Other disease complications

Bone disease
Bone complications affect most adult patients and seem to occur despite ade-
quate transfusion or chelation status. Osteopenia and osteoporosis are the most
prevalent complications, occurring in more than 90% of patients with thalassemia
major [84]. Common clinical presentations include persistent backache, scoliosis,
fractures, cord compression, and spinal deformities. Those patients with diabetes,
pubertal delay, or male gender seem to be most frequently and severely affected by
osteoporosis. Testosterone stimulates osteoblastic activity, whereas estrogen and
progesterone can limit bone resorption. Therefore, gonadal failure, prevalent in
thalassemia major, largely contributes to bone disease. Bony abnormalities also
are associated with inadequate calcium and vitamin D levels, lack of physical
activity, iron deposition in the bone matrix, and long-term desferioxamine
chelation [85,86]. Other factors outside the thalassemia setting also can affect
bone mass; however, the significance for these patients has not been clearly
defined. These include genetic factors controlling the vitamin D receptor, estrogen
receptor, and type I collagen genes. Low bone mass is also common among
nontransfused adult thalassemia intermedia patients, likely caused by a different
mechanism of marrow expansion.
Early diagnosis and treatment intervention are extremely important. Dual x-
ray absorptiometry (DEXA), a low-irradiation, safe technique, is the preferred
method for bone density assessment. It can measure total body bone density, or
more commonly, only lumbar spine and the femoral neck. Based on the World
Health Organization (WHO) definitions, a T score of bone mineral density
value of less than – 2.5 defines osteoporosis. A value of – 1 to –2.5 signifies
osteopenia. Yearly screening for osteoporosis starting in the second decade is
recommended, as inadequate bone density may be detected in children as
young as 10 –12 years of age. Evaluation with plain radiographs is inadequate.
Easy preventative measures include calcium supplementation (1200 mg/day in
adolescents), maintenance of normal levels of vitamin D, and nutritional
counseling. Early initiation of hormone replacement therapy for hypogonadism
is critical for achieving a normal peak bone mass and preventing accelerated
bone resorption [87]. Biphosphonates, inhibitors of osteoclasts and bone
resorption, may improve established disease, as demonstrated in elderly
1182 L. Lo, S.T. Singer / Pediatr Clin N Am 49 (2002) 1165–1191

osteoporotic women. Several studies reported improved T scores with the use
of a biphosphonate administered intravenously, or less commonly, orally. A
study looking at the causative factors and treatment intervention is under
way [88].

Immune function and infectious complications

Increased susceptibility to infectious diseases is observed in chronically trans-
fused, iron overloaded, and frequently, splenectomized thalassemia patients.
Studies suggest absolute lymphocytosis, chronic lymphocyte activation, and ab-
normal lymphocyte subsets [89,90]. A pathogen seen particularly in iron overload
patients is the Yersinia family of bacteria. Pediatricians need to be alert to the
possibility of Yersinia infection in a patient presenting with gastrointestinal
symptoms and fever, and must obtain stool and blood cultures and start empiric
antibiotic treatment. Deferoxamine chelation needs to be stopped for the length of
the active infection.

Hypercoagulable state
A less well recognized complication in b thalassemia major and thalassemia
intermedia is the hypercoagulable state. Pulmonary embolism, mostly asympto-
matic, cerebral ischemia, and deep vein thrombosis all have been described. A
multifactorial mechanism that involves abnormal platelet function, elevated
endothelial adhesion protein levels, and activation of the coagulation cascade
by the damaged RBC has been described [91].

Alloimmunization and RBC autoimmunization

Transfused patients might develop anti-RBC antibodies of two kinds:
alloantibodies or autoantibodies; some are not harmful but others may cause
hemolytic transfusion reactions and may limit the availability of further safe
transfusion. The rate of alloimmunization ranges from 5% –20% in different
reports and can be prevented if donor RBCs are matched for all major antigens
[92]. Though adopted by many thalassemia medical centers, this approach is
somewhat controversial because of its cost and the notion that not all
alloantibodies are hemolytic. Those patients with autoantibodies have an
autoimmune hemolytic anemia, and may therefore have a higher transfusion
rate and require splenectomy, immunosuppressive drugs, or even termination of
transfusions [93].

Psychologic impact
The chronic nature of thalassemia and its intensive and demanding treatment
result in a significant psychologic burden on the patients and their families.
Social isolation, reduced self-esteem, lower academic achievements, and stig-
 L. Lo, S.T. Singer / Pediatr Clin N Am 49 (2002) 1165–1191 1183

matization all have been described. In addition, depression and fear of early
death are common findings. As increasing numbers of patients now reach
adulthood, marry, and work, the psychologic burden is changing. Rising
concerns include accomplishing future expectations, physical appearance, sexual
development, education, establishing relationships, and the ability to have a
family. In adolescents and young adults, low compliance with chelation treat-
ment, denial, anxiety, and a ‘‘living for today’’ approach are observed. Psycho-
logic support is therefore particularly important and is a vital part of the
comprehensive medical treatment. Support strategies need to be developed in
ways appropriate to each culture. Medical providers need to inform patients on
therapeutic developments and future directions and encourage psychologic
support [94,95].

Thalassemia intermedia
Thalassemia intermedia, a clinical definition, applies to those patients who
are more mildly affected than thalassemia major patients and therefore do not
have severe anemia, growth failure, or evidence of marrow expansion in the
first years of life and may not require chronic transfusion therapy. Thalas-
semia intermedia patients frequently do not get the careful clinical care they
deserve, and can develop complications that may be prevented, as they do not
represent a well defined group of patients who receive regular treatment and
followup [96].
It is an extremely heterogeneous disorder on a molecular and clinical level. The
molecular basis of b thalassemia intermedia arises from a multitude of factors.
Mild or silent b thalassemia mutations, coinheritance of a thalassemia, and
enhanced gamma chain production all improve clinical outcome. Double hetero-
zygosity for b thalassemia and triplicated a genes also may lead to thalassemia
intermedia. Coinheritance of unstable hemoglobin variants, such as Hb Knossos,
Hb Lepore, or Hb E, may alter clinical severity of b-thalassemia. Although
identifying the molecular defect allows a retrospective analysis of a patient’s
disease, the b-genotype alone cannot fully predict the phenotype [97]. Among the
a-thalassemias, patients with hemoglobin H disease (a 3 a gene deletion) have a
mild thalassemia intermedia phenotype; however, the coinheritance of hemo-
globin H disease with the Constant Spring termination codon mutation is a more
severe form of thalassemia intermedia, occasionally requiring intermittent trans-
fusion therapy [98].
Although thalassemia intermedia patients avoid the complications associated
with chronic transfusion therapy, they have progressive clinical manifestations of
chronic hemolytic anemia and ineffective erythropoiesis. They may experience
cardiac complications, pulmonary hypertension, skeletal deformities with chronic
bone and joint pain, and bone deformities and fractures [99]. Significant extra-
medullary marrow expansion may develop, with occasional paraspinal hemato-
poietic pseudotumors causing neurologic symptoms. Leg ulcers, hypersplenism,
and gallstones are other common complications. The endocrine system is
1184 L. Lo, S.T. Singer / Pediatr Clin N Am 49 (2002) 1165–1191

generally spared. Despite the avoidance of chronic transfusions, iron overload is

still a problem, because of increased gastrointestinal iron absorption and occa-
sional transfusions [52,97].
Treatment intervention is controversial and depends on the severity of the
disease and extent of complications. In early childhood many thalassemia
intermedia patients undergo splenectomy with a usual resulting increase in
hemoglobin, though this is currently a somewhat debatable procedure. Trans-
fusions are indicated during periods of stress, such as infection and surgery;
however, adolescences and young adults frequently progress to a chronic
transfusion regimen. Patients are advised to maintain a low-iron diet and may
go on to require iron chelation therapy. Thalassemia intermedia is an ideal model
for fetal hemoglobin augmentation treatment, as even a modest increase in their
hemoglobin can significantly affect their clinical well being. Studies using oral
agents like 5-azacytidine, hydroxyurea, butyric acid derivates, and erythropoietin
have shown promising results in subgroups of patients [100].

Hemoglobin E/b thalassemia

The coinheritance of b globin and hemoglobin E mutations deserves special
attention, as it is one of the most common types of thalassemia prevalent mostly
in Southeast Asia, but increasingly in Western countries. Hemoglobin E, the most
common hemoglobin variant worldwide, differs from hemoglobin A by the
replacement of lysine for glutamic acid at position 26 of the b-globin chain. The
DNA mutation also results in an altered splicing site, and therefore decreased
production of b-globin mRNA and b-globin chain. Three main syndromes can
emerge: hemoglobin E trait (AE) and homozygous hemoglobin E (EE). Both
types are clinically asymptomatic, with a low-normal hemoglobin level and
microcytosis, more pronounced in the latter. The third type, a double hetero-
zygote for a b thalassemia and E mutation, results in a clinically severe
thalassemia. It has a large clinical variability ranging from severe transfusion-
dependent thalassemia major phenotype to a mild anemia [101,102]. Most
patients have a thalassemia intermedia phenotype and a hemoglobin range of
6 – 7 g/dL. The reasons for this extreme variability are not fully understood.
Studies on the natural history of this type of thalassemia and the best treatment
approach are currently underway. Obstetricians, who now care for increasing
numbers of Asian women in their practice, should be aware of this syndrome and
screen for hemoglobin E and b mutations in the pregnant woman and her partner
if indicated. Confusion can occur in newborn hemoglobin electrophoresis
between the mild form of EE and the severe form of E/b thalassemia, as both
have no hemoglobin A present, high hemoglobin E, and low hemoglobin
F. Parental testing is occasionally required [103]. If an infant is diagnosed with
E/b thalassemia, it is important to observe the child closely, and to not start
transfusion therapy until the clinical course and prognosis are clear, as this form
of thalassemia is so variable, and some patients may grow and develop without
transfusion therapy.
 L. Lo, S.T. Singer / Pediatr Clin N Am 49 (2002) 1165–1191 1185

Alternative treatments for thalassemia

Bone marrow transplantation

Bone marrow transplantation (BMT) from an HLA-identical donor is the only
available cure for thalassemia at this time. More than 1000 HLA-identical
successful transplants have been performed [104,105]. Only a small percentage
of patients (estimated at 30%) who have a matched donor and low risk factors,
however, can undergo the procedure. BMT for thalassemia is somewhat debatable
because of the procedure’s inherent risks. Early studies showed that transplant
outcome depends on risk categories based on adequacy of chelation, degree of
hepatomegaly, and hepatic portal fibrosis. Class 1 patients, with no risk factors,
have excellent outcomes (event-free survival [EFS] of 90%) and class 3 patients,
with all three risk factors, have guarded outcomes (EFS 54%). Those patients in
class 2 have intermediate outcomes (EFS 83%) [8]. Overall, younger patients and
those lacking the complication of the disease or its treatment, in particular chronic
hepatitis, have the best outcome [106]. BMT from alternative donors, HLA-
phenotypically matched unrelated donors, and HLA-nonidentical relatives have
shown high graft failure and graft-versus-host disease (GVHD) rates. Pretrans-
plant conditioning regimen at this time is myeloablative and carries the usual toxic
and infectious risks. Other investigational approaches include nonmyeloablative,
chimer-inducing regimens to reduce the transplant-related toxicity, and the use
of umbilical cord blood (UCB) stem cells, which may yield improved results
[107 –109]. In addition to the standard post-BMT management, patients with
thalassemia need to continue their efforts to remove preexisting iron-load using
chelation and phlebotomy, and must treat endocrinopathies that were not fully
reversible [110].

Gene therapy and gene manipulation

Though research is in progress for developing a system of stable, long-term
expressions of genes transferred into stem cells, it is not an available treatment
modality in the near future. Development of high-level stable gene expression,
safe vectors, and gene regulation are among the remaining problems [111]. Recent
achievements in gene expression and continuous active research may make gene
therapy feasible sooner than expected [112]. Other approaches include repairing
defective genes or suppressing selective genes, for instance, suppressing the a
gene production in b thalassemia.

Pharmacologic agents for fetal hemoglobin augmentation

A widely explored experimental strategy in the management of thalassemia is
to decrease transfusional dependence through the induction or reactivation of
g-globin synthesis, which binds a chains to produce fetal hemoglobin. A higher
fetal hemoglobin may improve overall hemoglobin production and reduce
ineffective erythropoiesis. This has improved the clinical course of many sickle
cell patients and has benefited thalassemia patients also. Results with the most
1186 L. Lo, S.T. Singer / Pediatr Clin N Am 49 (2002) 1165–1191

frequently used compounds, hydroxyurea and butyrate, were remarkable in

subgroups of patients with specific mutations, and showed a milder response in
many others. Other studies have used high-dose erythropoietin as a single agent or
in combination with hydroxyurea. Several reviews summarized many of the
clinical studies [100,113,114]. This is a cost-effective treatment and an ideal
option for million of patients who are unable to receive safe transfusion and
chelating therapy in developing countries. More research looking at other
pharmacologic compounds, combination therapy, and patient candidates is
required, however.

Future perspectives and challenges

Thalassemia is a widespread, highly prevalent disease, despite improved
prenatal diagnosis and genetic counseling. Worldwide, improved medical and
health care has resulted in increased life expectancy for affected infants and young
adults. Globally, this translates into increasing public health problems, particularly
in countries with limited resources like Southeast Asia and India. It is expected
and warranted that more attention be given to the screening and management of
thalassemia in these parts of the world.
Current research may have a significant beneficial impact for Western and
Asian countries. More effective screening technology using advanced DNA
thalassemia mutation analysis can significantly affect prenatal programs.
Improvements in standard treatment approach for the management of thalassemia
continue. The search for effective and cheap oral chelating agents is in progress,
and several new agents are expected to be available in the near future. Improving
donor blood screening for infectious agents, mostly HCV and HIV, is proceeding
also. Other major therapeutic advances are expected in the next decade. Treatment
of HCV with the improved agent, pegylated interferon, in conjunction with
ribavirin, may offer a cure to many patients suffering from HCV. Further advances
are expected in the field of iron overload, as is better screening of affected organs,
for instance, accurate assessment of cardiac iron loading, improved understanding
of iron and chelation kinetics, and development of new chelators.
Increasing understanding of the pathophysiology of thalassemia and that of
genotype-phenotype relation could provide further tools for therapy. For instance,
manipulation of the b- and g-globin genes for augmented globin chain synthesis,
or conversely, silencing the a-globin gene for reduced synthesis and globin-chain
imbalance. These research advances are expected to translate into better care and
treatment modalities of thalassemia in the future.
Progress in methods for the cure of thalassemia continues; improved BMT
methods like nonmyeloablative regimens could decrease the toxicity of transplant
and improve outcome. The use of related UCB stem cells has shown to
successfully reconstitute patients’ myeloablated marrow with less GVHD. The
use of mismatched or unrelated donor or UCB also may become a treatment option
for patients with severe disease without an HLA-matched sibling. A continuous
but slower progress in the field of gene therapy is also expected.
 L. Lo, S.T. Singer / Pediatr Clin N Am 49 (2002) 1165–1191 1187

The pediatrician’s role

Though it is a complex hematologic disease, pediatricians have an active role in
recognizing and treating thalassemia. Suspicion of a thalassemia syndrome in
asymptomatic patients with microcytosis, and looking for a hemoglobinopathy,
especially in immigrants from affected areas, can reduce unnecessary treatment
with iron and may prevent future births with more serious thalassemia conditions.
Patients with established diagnosis of thalassemia major or severe thalassemia
intermedia, like other chronic genetic diseases, need extensive long-term support.
Mutual hematologic and pediatric care can assist in providing support for difficult
issues like organ damage and compliance with chelation therapy.

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