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Pathophysiology and Clinical Manifestations

of the b-Thalassemias

Arthur W. Nienhuis1 and David G. Nathan2

1
Department of Hematology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105
2
Department of Pediatric Oncology, Dana-Farber Cancer Institute, and the Division of Hematology and
Oncology, Childrens Hospital, Boston, Massachusetts 02215
Correspondence: [email protected]

The b-thalassemia syndromes reflect deficient or absent b-globin synthesis usually ow-
ing to a mutation in the b-globin locus. The relative excess of a-globin results in the formation
of insoluble aggregates leading to ineffective erythropoiesis and shortened red cell survival.
A relatively high capacity for fetal hemoglobin synthesis is a major genetic modifier of
disease severity, with polymorphisms in other genes also having a significant role. Iron
overload secondary to enhanced absorption and red cell transfusions causes an increase
in liver iron and in various other tissues, leading to endocrine and cardiac dysfunction.
Modern chelation regimens are effective in removing iron and preserving or restoring
organ function.
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he b-thalassemias are genetic disorders the disturbance is only in b-globin synthesis, but
T of hemoglobin synthesis characterized by
deficient (bþ) or absent (b0) synthesis of the b-
rare deletional mutations may remove one or
more of the other genes on chromosome 11,
globin subunit of hemoglobin molecule (Weath- resulting in forms of the disease characterized
erall and Clegg 2001). The vast majority of indi- as db-, gdb-, or 1gdb-thalassemia.
viduals with thalassemia inherit their disorder
as a Mendelian recessive. Heterozygous individ-
HETEROZYGOUS b-THALASSEMIA
uals have mild anemia and microcytosis and are
categorized as having thalassemia minor or trait, The hematological features of thalassemia trait
and homozygous individuals have severe ane- are microcytosis, hypochromia, and usually an
mia of varying degrees and are characterized as increase in the percentage of HbA2. The hemo-
having homozygous b-thalassemia or thalasse- globin composition is 92% – 95% HbA, .3.8%
mia major or intermedia, as discussed in detail HbA2, and variable amounts of HbF amounting
below. Much rarer is a dominantly inherited b- to 0.5% – 4%. In addition to microcytosis and
thalassemia in which disease occurs in heterozy- hypochromia, there is marked variation in size
gous individuals because of synthesis of a highly and shape of red blood cells with the red cells
unstable b-globin variant (Thein 1999). Usually of b0-thalassemia trait having a lower mean

Editors: David Weatherall, Alan N. Schechter, and David G. Nathan

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A.W. Nienhuis and D.G. Nathan

corpuscular volume than those of bþ-thalasse- termedia syndrome are rather ill defined and are
mia trait (Cao and Galanello 2010). Historical- largely based on the hemoglobin level without
ly, the mild anemia with microcytic, hypochro- transfusion. Generally, a cutoff of 7 g/dL is used
mic red cells characteristic of thalassemia trait to distinguish between the two forms, but this
has been thought to lack clinical consequences criterion is confounded by the fact that the se-
other than its association with the anemia of verity of the anemia and associated spleno-
pregnancy (White et al. 1985). However, a re- megaly and defective development may vary in
cently controlled trial performed in Sri Lanka individual patients at different times, and the use
suggested that individuals with thalassemia trait of transfusion is partly based on socioeconomic
may experience symptoms of anemia including issues as well as access to an adequate blood sup-
headache, lethargy, fatigue, dizziness, and exer- ply. As noted in a definitive review of this topic,
cise intolerance despite having hemoglobin lev- the remarkable phenotypical diversity of b-thal-
els that overlap the normal range (Premaward- assemias reflects the heterogeneity of mutations
hena et al. 2008). There was no difference in the of the b-globin locus, the action of many sec-
frequency of these symptoms between the two ondary and tertiary modifiers, and a wide range
groups that had either mild anemia or hemo- of environmental factors (Weatherall 2001).
globin levels in the normal range. There was also
a significant increase in frequency of infectious
HEMOGLOBIN E b-THALASSEMIA
episodes in individuals with b-thalassemia trait.
Men but not women with thalassemia trait have Hemoglobin E has a substitution of lysine for
a reduced frequency of advanced coronary ar- glutamic acid at position 26 of the b-globin
tery disease, and myocardial infarction occurs at chain. This hemoglobin variant is particularly
an older age in men with thalassemia trait (Tas- common in Southeast Asia (Weatherall and
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siopoulos et al. 2005). Clegg 2001). Both heterozygotes and homozy-

gotes for HbE have hypochromic and microcyt-
ic cells, and molecular studies have documented
HOMOZYGOUS b-THALASSEMIA
deficient accumulation of the bE mRNA. Mo-
The clinical spectrum of patients with homozy- lecular analysis indicates that the GAG change
gous b-thalassemia is highly variable (Weather- to AAG at codon 26, which is responsible for the
all and Clegg 2001; Cao and Galanello 2010). amino acid substitution, also creates a cryptic
Many individuals present with severe anemia splice donor site that slows splicing of intron 1
early in life and remain transfusion dependent and results in abnormally spliced mRNA species
for their entire lives. Such individuals carry the (Orkin et al. 1982). Double heterozygosity for a
diagnosis of thalassemia major. Others with ho- b-thalassemia mutation and the bE mutation
mozygous b-thalassemia present with milder account for almost 50% of the patients with
anemia and never require transfusion, and severe b-thalassemia worldwide. This genotype
some have variable degrees of anemia and may is particularly common in certain countries in
require transfusion intermittently. Such indi- Southeast Asia (Olivieri et al. 2010a). Because of
viduals are designated as having thalassemia in- the Asian migration to the United States, this
termedia. The degree of anemia in those with genotype is common where Asians have set-
thalassemia intermedia is from nearly normal tled (e.g., California). The phenotype of HbE
levels to sufficiently severe anemia to require oc- b-thalassemia is highly variable, with many pa-
casional blood transfusions. Erythroid hyper- tients remaining largely free of transfusion
plasia leads to medullary expansion with facial throughout their lifetime, whereas others are
deformity and osteoporosis, which may be quite started on transfusion at an early age (Olivieri
severe. Extramedullary hematopoiesis results in et al. 2010a). For those for whom transfusions
enlargement of the liver and spleen and para- were initiated early in life for unclear reasons,
spinal and pulmonary masses of erythroid cells. discontinuation of transfusion support may be
Diagnostic criteria for the major versus the in- possible later in life (Olivieri et al. 2010b). Recent

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Pathophysiology of b-Thalassemia Syndromes

reviews of the clinical features of HbE b-thalas- Once the capacity of AHSP is exceeded, a-
semia summarize the clinical heterogeneity and globin forms molecular aggregates, which pre-
the approach to management of these patients cipitate, forming inclusions that damage the cell
(Olivieri et al. 2008, 2010b). This condition is membrane and the membranes of intracellular
discussed in more detail by Fucharoen and organelles (Fig. 1). Aggregated a-chains also
Weatherall (2012). trigger the formation of reactive oxygen species,
which further damage the protein and lipid
constituents of cell membranes. As well as
PATHOPHYSIOLOGY
heme and iron, one of the most toxic products
Erythropoiesis in individuals with b-thalasse- of unpaired a-chains is hemichromes, which
mia reflectsthe consequences of excess, unpaired bind to the membrane and promote clustering
a-globin (Nathan and Gunn 1966; Nathan et al. of band 3, one of its major constituents (Rund
1969; Cao and Galanello 2010; Sankaran and and Rachmilewitz 2005). The formation of a-
Nathan 2010). Indeed, the degree of imbalance chain inclusions occurs early during erythro-
in the a-globin versus b þ g-globin biosyn- poiesis and peaks in the polychromatophilic
thetic ratio is the major determinate of disease erythroblasts, leading to cellular apoptosis (Ma-
severity rather than the underproduction of thias et al. 2000). Thus, anemia in the severe b-
hemoglobin (Weatherall et al. 1965; Bank and thalassemias reflects both ineffective erythro-
Marks 1966; Nathan and Gunn 1966; Nathan poiesis as well as shortened red cell survival
et al. 1969; Weatherall 2001; Rund and Rachmi- as a consequence of a-globin inclusions (Na-
lewitz 2005). In b-thalassemiatrait there is atwo- than and Gunn 1966; Nathan et al. 1969). The
fold excess in the synthesis of a-globin, which is pathophysiology of b-thalassemia has been
consistent with fairly normal hematopoiesis compared with other disorders such as Parkin-
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with only mild microcytosis and hypochromia son’s disease and Huntington’s disease, which
of the red cells. The a to non-a biosynthetic ratio are caused by accumulations of unstable, aggrega-
in individuals with thalassemia intermedia is tion-prone proteins (Khandros and Weiss 2010;
typically 3– 4/1 because residual capacity for Khandros et al. 2011). Almost all cells have some
b-globin synthesis along with usually modest capacity to detoxify and remove damaging pro-
but variable g-globin synthesis mitigates the teins via multiple biochemical pathways termed
consequences of excess a-globin production. In- protein quality control (PQC). The ubiquitin –
dividuals with b0-thalassemia mutations have proteasome system (UPS) and the lysosome-
marked chain biosynthetic imbalance as the un- autophagy pathways that function in PQC are
derlying basis for their severe phenotype. thought to participate in the degradation of a-
Following synthesis, a-globin interacts with globin, but the capacities of these pathways are
its molecular chaperone, a-hemoglobin stabi- exceeded in the erythroid cells of individuals
lizing protein (AHSP), to form a protein com- with the severe forms of b-thalassemia.
plex before it is released to interact with b-glo-
bin in forming the hemoglobin tetramer (Yu
GENETIC MODIFIERS
et al. 2007; Weiss and dos Santos 2009). AHSP
facilitates folding of a-globin and prevents the The thalassemias are heterogeneous at the mo-
formation of misfolded aggregates. a-Globin lecular level, with more than 200 disease-causing
mutations that impair interaction with AHSP mutations having been identified (Weatherall
are associated with microcytosis and anemia 2001; Rund and Rachmilewitz 2005; Cao and
in humans (Yu et al. 2009). Loss of AHSP has Galanello 2010; Thein 2013). Alleles character-
also been shown to impair erythropoiesis in a ized by a mild phenotype typically include pro-
mouse model of b-thalassemia (Kong et al 2004). moter mutations, although splicing and frame-
Evidence suggests that AHSP levels may influ- shift mutations have also been discovered in
ence the phenotype of b-thalassemia (Lai et al. individuals homozygous for b-thalassemia but
2006). having a mild phenotype. Coinheritance of an a-

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A.W. Nienhuis and D.G. Nathan

Excess free Formation of heme

α-globin chains and hemochromes
Denaturation
Degradation

Iron-mediated toxicity

Membrane
Ineffective
Hemolysis binding of
erythropoiesis
IgG and C3 Removal of
damaged red cells

Increased
erythropoietin Reduced tissue Anemia Splenomegaly
synthesis oxygenation

Skeletal Erythroid
Increased Iron
deformities, marrow
iron absorption overload
osteopenia expansion
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Figure 1. Pathophysiology of b-thalassemia. Because of the imbalance in chain synthesis, an excess of freed a-
globin chains accumulates within erythroid cells. Aggregation, denaturation, and degradation of these chains
leads to the formation of insoluble precipitates as well as hemichromes, which damage cell membranes. Mem-
brane damage leads to ineffective erythropoiesis within the bone marrow, hemolysis of red cells within the
circulation, and binding of immunoglobulin and complement components to red cell membranes, triggering
loss of red cells in the spleen. The resulting anemia leads to diminished tissue oxygenation, an increase in
erythropoietin levels, and further stimulation of the bone marrow. Bone marrow expansion causes skeletal
deformities and osteopenia. Substances released from degenerating red cells increase iron absorption, which
contributes to iron overload.

thalassemia gene is another mechanism that globin gene arrangement (Premawardhena et al.
mitigates the phenotype of homozygous b-thal- 2005).
assemia (Kan and Nathan 1970; Wainscoat et al. Fetal hemoglobin is a much more common
1983; Cao et al. 1994). Individuals doubly het- and major modifier of disease severity in indi-
erozygous for a- and b-thalassemia have micro- viduals with b-thalassemia. In normal individ-
cytosis but essentially normal circulating hemo- uals, HbF synthesis occurs in a minority of ery-
globin concentrations. Individuals homozygous throid cells. Only 5% – 8% of red cells, called
for b-thalassemia who inherit a chromosome F cells, contain HbF, amounting to 5% – 20% of
having a single a-globin gene deletion may the total hemoglobin in those cells (Boyer et al.
have a milder phenotype, whereas deletion of 1975). In the context of a severe deficiency of b-
both a-globin genes on one chromosome is typ- globin synthesis, even the low levels of g-globin
ically associated with thalassemia intermedia. in F cells reduce the relative excess of a-globin
Another mechanism for thalassemia intermedia and provide a potent selective survival advantage
is heterozygous b-thalassemia inherited along for cells making HbF in the context of the inef-
with either triplicated a-globin gene arrange- fective erythropoiesis characteristic of the most
ment or with homozygosity for a triplicated severe forms of b-thalassemia. This selective

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Pathophysiology of b-Thalassemia Syndromes

survival is thought to account for the elevated thalassemia phenotype and, when absent, allows
levels of fetal hemoglobin percentage in a signif- higher levels of HbF expression and the HPFH
icant majority of patients who are homozygous phenotype (Sankaran et al. 2011). This region
for b-thalassemia (Gabuzda et al. 1962; Weath- includes sites for binding of the transcription
erall 2001). Certain b-globin promoter muta- factor BCL11A. Alternatively, augmentation of
tions are associated with increased g-chain syn- HbF production may reflect a single nucleotide
thesis from the same chromosome (Cao and polymorphism (SNP) in one of the g-globin
Galanella 2010). The number of F cells in nor- gene promoters or elsewhere in the globin locus,
mal individuals, and presumably those with b- which leads to overexpression of the cognate
thalassemia, is under genetic control and varies gene. Among the most common is an SNP at
among individuals (Galarneau et al. 2010). Pre- 2158 bp of the Gg gene promoter that creates
sumably having F-cell numbers at the higher an XMNI site polymorphism. Detailed linkage
range of normal is associated with a milder clin- analysis has shown that this SNP is not the actual
ical phenotype. Study of a large pedigree has causal mechanism of HPFH, but, rather, aug-
shown that coinheritance of an HPFH gene is mentation of Gg gene expression occurs as a con-
associated with higher mean corpuscular hemo- sequence of an SNP in linkage disequilibrium
globin, mean corpuscular volume, and HbA2 with the aforementioned Xmn-1 site located
levels (Garner et al. 2003). A recent study in un- midway between Ag- and d-globin genes, which
transfused patients with thalassemia intermedia may affect BCL11A binding (Galarneau et al.
has documented an inverse correlation between 2010). Fetal hemoglobin is normal in normal
HbF levels and the frequencies of morbidities re- subjects and in b-thalassemia heterozygotes
flecting disease severity (Musallam et al. 2012). with this polymorphism, but the variant leads
Hydroxyurea has been reported to increase HbF to increased production during hematopoietic
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in some untransfused patients with severe b-thal- stress such as occurs in homozygous b-thalasse-
assemia and to reduce the transfusion require- mia (Labie et al. 1985). Another HPFH SNP, a
ment in a minority of patients on regular transfu- substitution at 296 bp of the Ag promoter, has
sions (Karimi et al. 2011). A favorable response to been found linked to a nonsense mutation in the
hydroxyurea may be more frequent in thalassemic b-globin gene in individuals with Sardinian b-
individuals with certain haplotypes (Italia et al. thalassemia (Pirastu and Kan 1984). Homozy-
2009). gotes for this combination of mutations are clin-
Hereditary persistence of HbF (HPFH) was ically normal other than having predominantly
initiallyobserved morethan50 years ago(Weath- HbF in their red cells.
erall and Clegg 2001). Recent molecular stud- In addition to SNPs within the b-globin lo-
ies have shown that HPFH may result from de- cus, genome-wide association studies (GWAS)
letion mutations or point mutations within the have identified additional loci that can contrib-
b-globin gene cluster. Deletion mutations in- ute significantly to the variation in HbF levels
volving the d- and b-globin genes may cause (Garner et al. 2000; Uda et al. 2008; Galarneau
the phenotype of db-thalassemia, characterized et al. 2010). An SNP in the BCL11A gene has
by microcytosis and heterocellular distribution been shown to contribute to the level of HbF
of HbF, or be associated with increased produc- expression. As discussed by Sankaran and Or-
tion of HbF in a pancellular distribution with kin (2013), functional studies have shown that
morphologically normal red cells, the pheno- BCL11A is a significant component of the silenc-
type of HPFH. Recent characterization of several ing mechanism that turns off the g-globin genes
deletional mutations in individuals with either (Sankaran et al. 2009). Suppression of BCL11A
the HPFH phenotype or the phenotype of db- levels in cultured thalassemic erythroid cells
thalassemia has identified a functional element markedly increases HbF production (Wilber
within a 3.5-kb region between the Ag- and d- et al. 2011a). Experimental evidence shows cor-
globin genes that, when present, results in rela- rection of sickle cell disease in a mouse model by
tive silencing of the g-globin genes and the gb- suppression of Bcllla (Xu et al. 2011). BCL11A

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A.W. Nienhuis and D.G. Nathan

binds several points in the region between the endocrine tissues, and, more slowly, in the myo-
A
g- and d-globin genes including within the cardium.
critical region that differentiates HPFH from In normal humans, iron homeostasis is
db-thalassemia deletions (Sankaran et al. 2011). achieved by controlling absorption (see Ganz
The other locus that has been implicated in mod- and Nemeth 2012). Only 1 mg is lost from
ulating HbF levels is MYB (Galarneau et al. the body each day, largely through shedding of
2010). An SNP in what is thought to be a regu- the epithelial cells from the intestine, urinary
latory region near the gene is associated with tract, skin, and other mucosal organs. Each mil-
differences in the level of MYB expression. Indi- liliter of transfused blood contains 1 mg of
viduals with lower levels of MYB have higher iron, thus receipt of a unit of packed red cells
HbF levels than individuals with higher MYB typically results in the deposition of 200 mg of
levels. In another study, a 3-bp deletion in an iron ultimately in the tissues following red
intragenic region near the MYB gene with en- cell senescence. Lacking excretory mechanisms,
hancer-like activity was associated with higher individuals with thalassemia who receive blood
HbF levels (Farrell et al. 2011). Variants in both transfusion inevitably experience significant iron
the BCL11A and MYB loci have been shown to overload.
modify disease severity in individuals homozy- In individuals with thalassemia intermedia,
gous for Sardinian b0-thalassemia (Galanello increased tissue iron occurs as a consequence of
et al. 2009). Other transcription factors, includ- occasional transfusions but mainly reflects in-
ing KLF1, have been implicated in regulation of creased iron absorption (Ginzburg et al. 2011).
HbF levels (for review, see Wilber et al. 2011b). This paradoxical increase in iron absorption
KLF1 may mediate its effects on HbF through a despite systemic iron overload probably reflects
dual mechanism acting both on the b-globin release of erythroid factors during the cellular
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and BCL11A promoters. apoptosis associated with ineffective erythro-

Individuals with thalassemia have hyperbi- poiesis that inhibit hepcidin production by the
lirubinemia secondary to ongoing hemolysis liver. Hepcidin is a 25-amino-acid peptide hor-
and ineffective erythropoiesis. Iron loading oc- mone that negatively regulates iron flow into the
curs because of increased iron absorption as well plasma by inhibiting the absorption of dietary
as the administration of blood transfusions. Os- iron, the release of iron from macrophages, and
teoporosis is common, potentially secondary to the release of stored iron from hepatocytes (Ganz
hypogonadism and other endocrine abnormal- and Nemeth 2011). Ferric iron exits from cells
ities as well as expansion of marrow cavities. via the iron exporter ferroportin, a multipass
Increased susceptibility to infection is also char- transmembrane protein. Ferroportin is abun-
acteristic of the severe forms of b-thalassemia. dant in duodenal enterocytes, in splenic and he-
Genetic polymorphisms in various genes in- patic macrophages, and in hepatocytes, all cells
volved with these clinical features have been de- known to export iron (Ganz and Nemeth 2011).
scribed as acting as tertiary modifiers of the phe- Hepcidin inhibits iron efflux by binding ferro-
notype of thalassemia (Weatherall 2001). portin and triggering endocytosis of both mol-
ecules with subsequent lysosomal degradation
(Nemeth et al. 2004). Factors released from ap-
IRON OVERLOAD
optotic erythroblasts include growth differenti-
Patients with the more severe forms of b-thal- ation factor 15 (GDF15), a member of the trans-
assemia, both intermedia and major, have in- forming growth factor-b superfamily (Tanno
creased tissue deposition of iron. Senescence of et al. 2007). Serum from thalassemia patients
transfused red cells in patients with transfusion- suppressed the production of hepcidin by pri-
dependent b-thalassemia results in iron depo- mary human hepatocytes, and depletion of
sition within the reticuloendothelial system. As GDF15 prevented the hepcidin suppression. A
iron overload progresses, deposited iron also second molecule, named twisted gastrulation
appears within the hepatic parenchyma, various (TWSGI), was also shown to be highly expressed

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Pathophysiology of b-Thalassemia Syndromes

in erythroblasts and also able to inhibit hepcidin various forms including in complex with citrate
expression in mouse and human erythroid cells and proteins (Evans et al. 2008). Strategies have
(Tanno et al. 2009). The roles of GDF15 and been devised to detect labile plasma iron (LPI),
TWSGI remain to be fully defined. The end result a fraction of the NTBI pool that is metabolically
of suppression of hepcidin expression is to en- active in interacting with membrane constitu-
hance iron absorption from the intestine and to ents, leading to membrane damage via the for-
allow iron release from macrophages. The normal mation of reactive oxygen species (ROS) (Poo-
and pathological regulation of hepcidin synthesis trakul et al. 2004; Hershko 2010). Rather than
has recently been reviewed (Nemeth 2010). Syn- using the transferrin receptor, NTBI enters cells
thetic mini-hepcidins with a longer half-life have by various cellular channels in forms that have
been shown to reduce iron absorption in mice the potential to damage cells (Oudit et al. 2003;
after oral administration and have been proposed Liuzzi et al. 2006). The liver and myocardium
as potential therapeutic agents in individuals clear NTBI at a rate 200-fold that of transferrin-
with severe b-thalassemia (Preza et al. 2011). bound iron (Oudit et al. 2003, 2006). A portion
Iron released from cells is bound to transfer- of the NTBI is accessible to iron chelators di-
rin and transported to the bone marrow and rectly (Breuer et al. 2001), whereas additional
other tissues, where iron is taken up by the trans- iron may be chelated in the presence of iron-
ferrin receptors. Less than 1% of the total body mobilizing agents (Esposito et al. 2003). Chela-
iron is found in blood at any one time, although tors administered to patients with thalassemia
up to 25 mg may circulate as transferrin-bound have the potential to reduce NTBI (Porter et al.
iron throughout the 24-h cycle. The expanded 1996). Intravenous administration is more ef-
erythropoiesis in individuals with b-thalasse- fective at reducing NTBI than subcutaneous ad-
mia results in a dramatic increase in plasma ministration. The reduction and reemergence of
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iron turnover of 10-fold to 15-fold over normal NTBI have rather complex kinetics (Porter et al.
(Hershko et al. 2005). Normally, the transferrin 1996), although these studies support the use of
saturation is maintained in a relatively low range continuous rather than intermittent chelation
of 10% – 50%. Iron is stored in tissue in the in high-risk patients. As discussed in detail be-
form of ferritin, a multicomponent protein shell low, cardiac myocytes are a critical target for
that internalizes iron, thereby protecting cellular iron-induced ROS. Using an in vitro model of
constituents from potential oxidative damage. neonatal rat cardiomyocytes, the oral chelators
Intracellular ferritin iron is in equilibrium with deferasirox and deferiprone were able to effec-
the cytosolic soluble iron pool. Hemosiderin tively access and reduce the intracellular labile
is an insoluble aggregate of iron that forms iron compartments, whereas desferrioxamine
in lysosomes when ferritin is degraded (Wu removed iron mainly by eliminating the LPI in
et al. 2010; Kim et al. 2011). Both ferritin and plasma (Glickstein et al. 2006). These in vitro
hemosiderin accumulate in the cells of individ- studies suggested that the rapid accessibility of
uals with severe b-thalassemia. Accumulation of oral chelators to intracellular labile iron com-
iron in reticuloendothelial cells is relatively partments may render them potentially effica-
harmless, whereas accumulation of iron in pa- cious for protection and reversal of cardiac
renchymal tissues may damage critical cells in damage induced by iron overload (Glickstein
the heart, endocrine glands, and liver (Hershko et al. 2006).
et al. 2005).
As a consequence of iron overload in pa-
tients with thalassemia either from blood trans- CLINICAL MANIFESTATIONS
fusion or excessive absorption or a combination
Anemia
of the two, transferrin saturation increases to
75% – 100% and non-transferrin-bound iron Classically, individuals with severe b-thalasse-
(NTBI) is found in the blood (Hershko et al. mia have presented with variable but often very
1978). NTBI is very heterogeneous and exists in severe degrees of anemia, expansion of the bone

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A.W. Nienhuis and D.G. Nathan

marrow spaces secondary to erythroid hyper- sive combination therapy, may reverse the com-
plasia, hepatosplenomegaly, and extramedul- plications of iron overload (Farmaki et al. 2010).
lary hematopoiesis in the chest and abdomen.
The external appearance is characterized by
Noninvasive Measurement of Tissue Iron
pallor and slight jaundice, frontal bossing and
other abnormalities of the facies secondary to Hepatic biopsy and measurement of liver iron
marrow expansion, and abdominal enlarge- concentration long remained the gold standard
ment due to hepatosplenomegaly. Usually, these for estimating the degree of iron overload in pa-
manifestations are absent or minimally present tients with severe b-thalassemia. Magnetic sus-
in patients with thalassemia major if transfu- ceptibility imaging was the first noninvasive
sion therapy is initiated early during the first quantitative technique, which established a
year of life provided that the hemoglobin levels correlation between liver iron concentration by
are maintained at 9 – 10 g/dL. Where transfu- biopsy and this noninvasive measurement (Brit-
sion is readily available, the classical physical tenham et al. 1982). The instrumentation re-
findings of thalassemia are now more common- quired for this technique is available in only a
ly found in patients with thalassemia interme- few institutions, and therefore this method has
dia, particularly those who are at the severe end not been widely applied. Only when liver iron
of the phenotypical spectrum. In such patients, concentration could be reliably estimated by
the physical manifestations can be suppressed in magnetic resonance imaging (MRI) with clini-
part with subsequent transfusion. Transfusion cally available devices that could be standardized
practices for thalassemia intermedia vary con- from institution to institution, did noninvasive
siderably. Individuals with thalassemia inter- measurement of liver iron supplant hepatic bi-
media in developed countries are likely to be opsy as the gold standard (Gandon et al. 2004; St
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transfused, whereas transfusion is used more Pierre et al. 2005).

sparingly in countries where resources are lim- MRI has also been applied to estimate cardiac
ited (Rachmilewitz and Giardina 2011; Taher iron. The T2 parameter and its reciprocal 1/R2
et al. 2011). The natural history of thalassemia have been shown to correlate with the degree of
intermedia is highly variable, although the com- iron overload in the liver and, by extrapolation, to
plications of severe anemia are common (Bor- the concentration of iron in the myocardium
gna-Pignatti et al. 2010). Splenectomy may be (Wood 2011). Limited autopsy studies support
required because of very large spleen size, with a direct correlation between chemically deter-
increasing anemia or increasing transfusion re- mined myocardial iron and MRI measurements
quirement with or without a decrease in neutro- (Carpenter et al. 2011). MRI has also been ap-
phil or platelet count. plied to the evaluation of iron deposition in
the pituitary gland and the pancreas. Availability
of these noninvasive techniques has been useful
Iron Overload
in determining the relative rate of mobilization
The clinical manifestations of iron overload have of iron from various tissues during chelation
come to dominate the clinical phenotype of therapy. Iron is mobilized more readily from
individuals with severe b-thalassemia. Cardiac the liver and much more slowly from the heart
dysfunction is the main clinical problem that and endocrine tissues (Wood 2011).
may lead to early death. Endocrine abnormali-
ties, particularly hypogonadism, low growth
Cardiac Manifestations
hormone, hypothyroidism, and diabetes melli-
tus, are also significant problems. Iron deposi- The institution of regular transfusions for pa-
tion of the liver may be substantial, although tients with thalassemia major prevents the overt
functional abnormalities are usually mild unless consequences of anemia. However, iron accu-
iron overload is very severe. Fortunately chela- mulation progresses with iron deposition in
tion therapy prevents and, when given in inten- the myocardium and toxic NTBI in the plasma,

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Pathophysiology of b-Thalassemia Syndromes

becoming problematic during the late teenage the major risk factors that have been identified.
years or early twenties. Cardiac abnormalities Among the pathophysiological factors are red
include arrhythmias, both atrial and ventricular, cell membrane pathology, coagulation abnor-
and/or congestive heart failure (Engle 1964). malities, platelet activation, oxidative stress,
Sudden death often occurred, whereas other pa- and chronic hemolysis with release of thrombo-
tients died of progressive congestive heart fail- genic vesicles (Morris and Vichinsky 2010).
ure. Death by the mid twenties was the norm. Although the incidence of pulmonary hyper-
This dismal clinical course was modified tension is more common in patients with
with the introduction of regular chelation with thalassemia intermedia, a recent cross-sectional
desferrioxamine, particularly when it was given study showed that pulmonary hypertension
by continuous subcutaneous infusion over a sig- may occur in both children and adults with
nificant portion of each 24-h period (Propper age, splenectomy, hepatitis C infection, and
et al. 1976, 1977; Pippard et al. 1978; Wolfe et al. smoking as significant univariate risk factors
1985; Olivieri et al. 1994; Brittenham et al. (Morris et al. 2011). When present, pulmonary
1993). Not unexpectedly, compliance with the hypertension may contribute to the severity of
cumbersome subcutaneous administration via cardiovascular symptomatology and compli-
a small infusion pump varied widely among cate heart failure due to left ventricular dysfunc-
participants, providing an unintended oppor- tion.
tunity to compare well-chelated versus poorly
chelated individuals (Brittenham et al. 1994;
Endocrine Abnormalities
Olivieri et al. 1994). The dramatic reduction
in cardiac mortality in well-chelated groups Growth retardation secondary in part to growth
was among the first unequivocal evidence that hormone deficiency and hypogonadism are typ-
www.perspectivesinmedicine.org

chelation therapy could modify the clinical phe- ically the initial manifestations of iron over-
notype with respect to the cardiac manifesta- load in b-thalassemic patients (Chatterjee and
tions of iron overload. Subsequent large studies Bajoria 2010). In unchelated patients, failure
have strongly supported the use of chronic che- to develop secondary sex characteristics during
lation to prevent cardiac death (Borgna-Pignatti the teenage years was very common. Regular
et al. 2006; Wood 2011). chelation therapy has reduced the incidence of
Improvement in established cardiac disease hypogonadism, although hormone replace-
was first achieved with continuous interfusion ment is often required (Wood 2011). Well-che-
of desferrioxamine (Anderson et al. 2004). Iron lated young men with thalassemia are fertile,
was mobilized more readily from the liver than although potentially requiring hormonal ad-
the heart as established by MRI T2 measure- ministration, and women with severe b-thalas-
ments. Some evidence suggests that mobiliza- semia may achieve motherhood either with
tion of iron from the myocardium is more effi- or without obstetrical intervention. Other endo-
cient with the low-molecular-weight chelator crine complications include impaired glucose
deferiprone (Brittenham et al. 2003), and that tolerance and diabetes (Noetzli et al. 2011), hy-
desferrioxamine and deferiprone administra- pothyroidism, hypoparathyroidism, and growth
tion together are more effective than desferriox- hormone deficiency (Borgna-Pignatti et al.
amine alone in reversing cardiac dysfunction 2004a).
as shown in a randomized trial (Tanner et al.
2007). Deferasirox has also been shown to re-
Hepatic Manifestations
duce and prevent cardiac iron overload (Pennell
et al. 2010, 2011). Progressive iron deposition is characteristic in
Pulmonary hypertension is an increasingly patients with severe b-thalassemia. Invasive
recognized complication in patients with severe liver biopsies and now non-invasive methodol-
b-thalassemia (Morris and Vichinsky 2010). ogies (see below) have established the corre-
Advancing age and history of splenectomy are lation between liver iron concentration and

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A.W. Nienhuis and D.G. Nathan

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Pathophysiology and Clinical Manifestations of the β-Thalassemias

Arthur W. Nienhuis and David G. Nathan

Cold Spring Harb Perspect Med 2012; doi: 10.1101/cshperspect.a011726

Subject Collection Hemoglobin and Its Diseases

The Natural History of Sickle Cell Disease Transcriptional Mechanisms Underlying

Graham R. Serjeant Hemoglobin Synthesis
Koichi R. Katsumura, Andrew W. DeVilbiss,
Nathaniel J. Pope, et al.
Current Management of Sickle Cell Anemia Iron Deficiency Anemia: A Common and Curable
Patrick T. McGann, Alecia C. Nero and Russell E. Disease
Ware Jeffery L. Miller
Cell-Free Hemoglobin and Its Scavenger Proteins: Management of the Thalassemias
New Disease Models Leading the Way to Targeted Nancy F. Olivieri and Gary M. Brittenham
Therapies
Dominik J. Schaer and Paul W. Buehler
Clinical Manifestations of α-Thalassemia The Molecular Basis of β-Thalassemia
Elliott P. Vichinsky Swee Lay Thein
Erythroid Heme Biosynthesis and Its Disorders Erythropoiesis: Development and Differentiation
Harry A. Dailey and Peter N. Meissner Elaine Dzierzak and Sjaak Philipsen
Hemoglobin Variants: Biochemical Properties and Erythropoietin
Clinical Correlates H. Franklin Bunn
Christopher S. Thom, Claire F. Dickson, David A.
Gell, et al.
The Prevention of Thalassemia Classification of the Disorders of Hemoglobin
Antonio Cao and Yuet Wai Kan Bernard G. Forget and H. Franklin Bunn
The Switch from Fetal to Adult Hemoglobin The Molecular Basis of α-Thalassemia
Vijay G. Sankaran and Stuart H. Orkin Douglas R. Higgs

For additional articles in this collection, see http://perspectivesinmedicine.cshlp.org/cgi/collection/

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