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Molecular basis ofiron metabolism 183
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now rare. It is a late- onset disorder, inherited in an autosomal recessive pattern and characterized by iron deposition
in parenchymal cells of the liver, pancreas, and heart.
Macrophages of the reticuloendothelial system are irondepleted or at least relatively spared. This disorder results
from a small but chronic increase in intestinal iron absorption, averaging about twofold to threefold above the normal
level. Over time, the presence of iron causes damage by promoting the formation of toxic oxygen radicals, which attack
cellular structures and thereby cause reactive fibrosis. The
earliest manifestation of HFE- related hemochromatosis is
increased transferrin saturation, often approaching 100%
before tissue iron deposition is noted. The treatment for
hemochromatosis is phlebotomy, and this has been used
effectively for more than half a century. Initially, blood is
removed frequently to rapidly decrease stored iron. Later,
iron balance is maintained by periodic phlebotomy, titrated
to meet the needs of the individual patient. This treatment
apparently produces no significant morbidity and has been
shown to normalize the life expectancy of affected patients.
Hemochromatosis has been recognized as an inborn error
of iron metabolism since the 1930s. In 1976, a French physician, Marcel Simon, made the important observation that
the genetic predisposition to hemochromatosis was linked to
the human major histocompatibility complex on chromosome 6p, and was most frequently associated with an HLAA3 haplotype. This insight laid the groundwork for the
discovery of causative mutations in the HFE gene 20 years
later. It is now known that most patients with classical hemochromatosis are homozygous for a unique mutation (cysteine
282 to tyrosine, or C282Y) in HFE, perhaps originating in a
northern European ancestor.
HFE is an atypical HLA class I molecule, similar to its
chromosomal neighbors. Although most members of this
family are involved in immune regulation, HFE has no
known function in the immune system. It interacts with
TFR1 on the cell surface, where its binding site overlaps with
that of transferrin. Recent studies indicate that the binding of
transferrin to TFR1 displaces HFE, making it active as a
stimulus for hepcidin synthesis. HFE is thought to induce
hepcidin by activating the BMP-
SMAD signaling cascade,
possibly by interacting with proteins in the BMP receptor
complex (Figure13.5).
The C282Y mutation is highly prevalent. In typical populations of northern European descent, the carrier frequency
has been estimated to be between about 1in 8 and 1in 10.
This indicates that about 1in 200individuals are homozygous, and at risk of iron loading. However, not all C282Y
homozygotes will develop clinical hemochromatosis. There
is a wide range of iron loading and its complications. Some
individuals will have severe manifestations by the third decade of life, whereas others may never have signs or symptoms
of hemochromatosis. This variability is probably explained
by gender (iron loss through menstruation), other genetic
factors (modifying genes), and environmental factors (e.g.
alcohol intake, dietary iron consumption). Although several
modifying genes have been proposed, their identification
and characterization are still incomplete.
In addition to C282Y, other mutations and polymorphisms have been identified in the HFE gene. The most common of these is a histidine-
to- aspartic acid substitution at
amino acid 63 of the protein (H63D). This polymorphism is
found in about one- fifth of the world’s population. Although
it may occasionally be associated with iron overload, particularly when it is found in individuals heterozygous for the
C282Y mutation, its clinical significance is probably minor,
though clinical laboratories test for it. Most other HFE mutations are quite rare and are not identified by routine screening tests.
In the past, the proportion of at- risk C282Y homozygous
individuals who develop clinical hemochromatosis was estimated to be about 20–40%. However, Beutler and colleagues
published the results of a large questionnaire- based study of
patients seen by a health maintenance organization, in which
they concluded that fewer than 1% of C282Y homozygotes
would have severe disease. There is no consensus yet on
laboratory parameters that identify C282Y homozygotes at
riskfor clinically significant organ damage, but recent data
indicate that few if any patients with serum ferritin levels
below 1000 ng/mL develop cirrhosis, the main complication
of hemochromatosis.
Non- HFE- related hemochromatosis
Non- HFE- related hemochromatosis is similar to HFE-
related hemochromatosis, but very rare, and characterized
by earlier onset of iron loading and its complications. The
target organs are the same as those affected in HFE- related
hemochromatosis, but in some forms that were previously
termed juvenile or type 2 hemochromatosis, cardiac and
endocrine dysfunction are more severe, liver cirrhosis and
failure are uncommon, and untreated patients typically die
from cardiomyopathy by age 30
years. There are several possible explanations for this pattern. Firstly, experience with
patients who develop siderosis from chronic transfusion
therapy suggests that rapid iron loading is especially toxic
for the heart and endocrine tissues. Secondly, pathological
iron deposition in the adolescent years may be particularly
bad for young hearts which are growing to meet the demands
of a larger body mass; this is analogous to the problems
noted with doxorubicin cardiotoxicity in this age group.
Furthermore, endocrine problems are probably more apparent in adolescents because they fail to go through normal
pubertal development. Similar to HFE- related hemochromatosis, non- HFE- related hemochromatosis can be effec-
tively treated by phlebotomy.
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184 Molecular Hematology
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Studies of families with juvenile hemochromatosis have
shown that there are at least two genetic loci responsible.
Some individuals are homozygous for ablative mutations in
the hepcidin gene on human chromosome 19q. However,
most families have homozygous or compound heterozygous mutations in HJV (also called HFE2, or repulsive
guidance molecule RGMC) on chromosome 1q. HJV is a
GPI- linked membrane protein that functions as a BMP coreceptor to induce the production of hepcidin (Figure13.5).
Disruption of both copies of HJV has been shown to cause
profound hepcidin deficiency. It thus appears that the
greater severity of the juvenile form of the disease is due to
the lower levels of hepcidin compared with HFE- related
hemochromatosis.
A third form of non- HFE hemochromatosis, previously
called type 3 hemochromatosis, is caused by mutations in the
TFR2 gene on chromosome 7q. TFR2- related hemochroma-
tosis is clinically similar to HFE- related hemochromatosis,
but the age of onset is earlier and the affected patients have
no mutations in the HFE gene. TFR2 is a protein that is
highly homologous to the transferrin receptor (also known
as TFR1), and highly expressed by hepatocytes and hematopoietic cells. TFR2 binds transferrin and transports it into
the cell, but it does so much less efficiently than TFR1. TFR2
is stabilized by interaction with iron- transferrin and is also
able to bind HFE. Patients and mice with homozygous TFR2
mutations have low hepcidin expression, implicating this
protein in the regulation of hepcidin synthesis, possibly as a
sensor of transferrin saturation. Like HFE, TFR2 is thought
to induce hepcidin by activating the BMP- SMAD signaling
cascade (Figure13.5). Two siblings with combined HFE and
TFR2 mutations were reported to have a severe juvenile form
of the disease, suggesting that HFE and TFR2have additive
effects on hepcidin expression.
A final form of non- HFE hemochromatosis, previously
termed type 4B, is an autosomal dominant disorder due to
ferroportin (SLC40A1) mutations that confer resistance to
hepcidin-
induced internalization (gain of function). Such a
lesion would be expected to act dominantly and mimic hepcidin deficiency. Its most severe form involves serine or
tyrosine substitutions in C326in the hepcidin- binding site of
ferroportin. Affected patients presented with early onset of
liver disease and arthritis.
Other forms ofhemochromatosis
Two additional classifications of hemochromatosis include
(1) Digenic, patients with mutations in two different hemochromatosis genes or (2) Molecularly undefined, patients
without mutations in the five known hemochromatosis
genes (HFE, TFR2, HJV, hepcidin, or ferroportin). The
genetic characterization of the molecularly undefined
patients may help to expand the range of genetic defects that
cause hemochromatosis. For example, recent studies have
reported molecularly undefined patients with relatively mild
hemochromatosis who were found to have heterozygous
mutations in the BMP6 propeptide, which may interfere
with BMP6 secretion.
Ferroportin disease
Ferroportin disease, formerly (formerly type 4A hemochromatosis), has a distinct clinical picture dominated by siderosis (iron- loading of macrophages). Patients with this disorder
may have iron- deficiency anemia early in life, but later present with (sometimes massively) increased serum ferritin
concentration and macrophage iron accumulation. Some
may eventually develop parenchymal iron deposition in
addition to macrophage iron loading, probably because their
specific mutations may also cause resistance to hepcidin.
This disorder has a very interesting pathogenesis. It is due
to missense mutations in ferroportin, the cellular iron
exporter. This seems paradoxical at first because the mutations alter ferroportin function, and ferroportin acts as the
basolateral enterocyte transporter involved in intestinal iron
absorption (see Figure13.1). However, it is important to consider that ferroportin also plays a major role in macrophage
iron release. The lack of nonsense mutations in this disorder,
and evidence from cellular and animal models of this disease,
suggest that the mutated ferroportin exerts a dominant negative effect on the normal version of the molecule. The resulting loss of functional ferroportin is severe enough to impair
macrophage iron release, resulting in accumulation of iron in
macrophages and decrease in the amount of plasma iron
available to developing erythroid precursors. Iron- restricted
erythropoiesis probably signals for a compensatory increase
in intestinal iron absorption, overcoming the genetic deficiency of ferroportin in the enterocytes. It appears that iron
loading of macrophages has few if any clinical consequences.
African siderosis
The pathology of African siderosis is strikingly similar to that
of ferroportin disease, although the genetic basis of African
siderosis has not been described. Once called Bantu siderosis
because of the population affected, this disorder was originally attributed to excessive dietary iron intake. It is common
in sub- Saharan Africans, many of whom drink a traditional
alcoholic beverage brewed in non- galvanized steel drums.
The iron content of the brew is substantial, resulting in massive iron ingestion. However, the observations that not all
drinkers develop iron overload and that some individuals
develop similar iron overload without drinking the beverage
support the notion that there is a genetic component to this
disorder. The ferroportin mutation Q248H is relatively common (2–13%) in southern Africa and may cause mild resistance to hepcidin and tendency to iron overload. It is not yet
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Molecular basis ofiron metabolism 185
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known whether European and American individuals of
African descent are also more susceptible to iron overload as
a result of the same iron- loading gene.
Abnormal iron distribution
Atransferrinemia and aceruloplasminemia are two wellcharacterized (but very rare) disorders due to mutations in
plasma proteins important in iron metabolism. These mutations do not directly affect intestinal iron absorption. Rather,
they perturb tissue iron distribution.
Atransferrinemia
Atransferrinemia is a severe deficiency of the plasma ironbinding protein transferrin, due to mutations that truncate or
alter the coding sequence of the transferrin gene. As a result,
erythroid precursors are iron- starved and severe anemia
results. Paradoxically, all non- hematopoietic tissues are ironloaded, probably because intestinal iron absorption is enhanced
by mechanisms that compensate for the iron deprivation of
erythroid precursors and because NTBI is avidly taken up by
many parenchymal cell types. Mice and humans with this disorder have low hepcidin, indicating that iron- transferrin is an
important regulator of hepcidin synthesis. This disorder can be
treated by transfusion of packed red blood cells or, more appropriately, by infusion of human transferrin.
Aceruloplasminemia
hormone hepcidin, its receptor/iron channel ferroportin,
or their interaction. Iron overload is underdiagnosed
becauseit produces signs and symptoms that are common
inadult populations. However, iron overload disorders are
usually easy to treat and clinicians should be vigilant in
considering them.
Further reading
General
Coffey, R. and Ganz, T. (2017). Iron homeostasis: an anthropocentric
perspective. J. Biol. Chem. 292: 12727–12734.
Fisher, A.L. and Babitt, J.L. (2022). Coordination of iron homeostasis by
bone morphogenetic proteins: current understanding and unanswered questions. Dev. Dyn. 251: 26–46.
Regulation ofiron homeostasis
Canali, S., Zumbrennen- Bullough, K.B., Core, A.B. et al. (2017).
Endothelial cells produce bone morphogenetic protein 6 required for
iron homeostasis in mice. Blood 129: 405–414.
Nemeth, E., Tuttle, M.S., Powelson, J. etal. (2004). Hepcidin regulates
cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306: 2090–2093.
Nicolas, G., Chauvet, C., Viatte, L. etal. (2002). The gene encoding the
iron regulatory peptide hepcidin is regulated by anemia, hypoxia,
and inflammation. J. Clin. Invest. 100: 1037–1044.
Aceruloplasminemia is deficiency or absence of plasma
ceruloplasmin. Ceruloplasmin was once thought to be a
plasma copper carrier, but it is now clear that its primary role
is as a ferroxidase, aiding in the release of iron from macrophages, hepatocytes, and cells of the central nervous system. Patients with this disorder are generally well early in
life, but gradually develop tissue iron deposition in the liver,
pancreas, and brain. They typically present in middle age
with retinal degeneration, dementia, hepatic iron deposition,
and diabetes. Treatment with deferoxamine is ineffectual;
treatment with normal plasma may provide some benefit.
Conclusions
Iron disorders are among the most common of human
afflictions. They invariably result from abnormalities of iron
balance, most often due to defects in the iron regulatory
Iron overload disorders
Corradini, E., Buzzetti, E., and Pietrangelo, A. (2020). Genetic iron
overload disorders. Mol. Aspects Med. 75: 100896.
Girelli, D., Busti, F., Brissot, P. etal. (2022). Hemochromatosis classifi-
cation: update and recommendations by the BIOIRON Society.
Blood 139: 3018–3029.
Olynyk, J.K. and Ramm, G.A. (2022). Hemochromatosis. N. Engl. J.
Med. 387: 2159–2170.
Abnormal iron distribution
Bartnikas, T.B. (2012). Known and potential roles of transferrin in iron
biology. Biometals 25: 677–686.
Marchi, G., Busti, F., Lira Zidanes, A. etal. (2019). Aceruloplasminemia:
a severe neurodegenerative disorder deserving an early diagnosis.
Front. Neurosci. 13: 325.
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Chapter14
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Perspectives ingenomics
andsickle cell disease therapeutics
Ambroise Wonkam
Department of Genetic Medicine, McKusick- Nathans Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Introduction, 187
Epidemiology of sickle cell disease, 191
Pathophysiology, 192
Mortality and life expectancy of SCD, 192
Management of SCD, 193
Exploring the missing heritability of fetal hemoglobin in
Africa to uncover therapeutic targets, 196
Introduction
Sickle- cell disease (SCD) is the most common monogenic,
recessive disease in humans, both a life- threatening disease
in children, and a chronic debilitating disease in adults, with
nearly 300 000newborns affected annually, worldwide, 80%
of which are born in Africa. Without intervention, an excess
of 30–90% of affected children die before their fifth birthday
in many African countries. Fortunately, like in high- income
countries, there are increasing initiatives for newborn
screening (NBS) and comprehensive care including penicillin prophylaxis, contributing to the reduction in morbidity
and mortality in Africa and worldwide. As mortality declines,
quality of life and increased life expectancy become the
major targets for interventions in all parts of the world.
Hydroxyurea (HU) and hematopoietic stem cell transplantation (HSCT) therapies have already proven effective in
resource- rich settings, but are, however, either not widely
accessible or expensive for most settings where SCD is prevalent. Genomics research can accelerate the development of
new curative therapies for SCD in three main ways. First, this
research should explore the missing heritability of fetal
hemoglobin (HbF), which is the strongest known modifier
of SCD clinical expression, among highly genetically heterogeneous and understudied African populations to provide
novel therapeutics targets for HbF induction. Second, SCD
research should invest in RNA therapies, either via microRNA to target the production of HbF proteins by binding to
the transcription machinery in a cell, or to directly mediate
HbF or adult hemoglobin production through injection of
Investigating the prospect of RNA therapy for SCD, 197
Developing genetic risk models for SCD complications, 198
Conclusion and perspectives, 199
Further reading, 200
messenger RNA. Third, investigators should aim to identify
novel genetic risk factors for SCD cardiovascular complications, in addition to wellated with kidney disease, which will address mortality,
particularly in adults. In this chapter, we describe the epidemiology, pathophysiology, clinical and biological profile,
current treatment, and advocate for a global research program to uncover genomic keys to new SCD therapeutics.
SCD is a group of blood disorders characterized by sickle
hemoglobin (HbS), caused by a single nucleotide substitution (HBB: Glu6Val) in the beta- globin gene (Figure14.1),
that encodes a component of hemoglobin (Hb), the protein
complex that constitutes 70% of red blood cells (RBCs) and
is responsible for transportation of oxygen to the body’s
organs. Sickle- cell anemia (SCA), the most severe form, and
the commonest in Africa, results from the inheritance of two
alleles of HbS (HbSS). Mutations that lead to the termination
of production of β- globin chains (β
inherited with one HbS allele (HbS/β0- thalassemia), also
cause SCA. The co- inheritance of the HbS allele with other
HBB variants (e.g. HbC leading to HbSC) results in other
forms of SCD. It is now known that the sickle- cell mutation
(βS) originated in Africa. As a result of the protection that
carriers of one copy of the HbS allele (HbAS) have against
severe Plasmodium falciparum malaria, the mutation has
persisted at high frequencies in Africa, where P. falciparum
malaria is endemic (Figure14.2).
It is estimated that over 75% of the estimated 300 000
SCA live births occur annually in Africa. In SCD, the
abnormal, sickled Hb (HbS) tends to polymerize in RBCs
known variants in APOL1 associ-
0
- thalassemia), when co-
Molecular Hematology, Fifth Edition. Edited by Drew Provan and Hillard M. Lazarus.
© 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.
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187
188 Molecular Hematology
(A)
Citrulline
heterogeneity
https://t.me/med1917
HbS polymer
β6
Triplet
codon
T
hbS
solution
Oxygenated
HbS cell
β6 GluGAG
hbS
polymer
Deoxygenated
Cell
Valine
residue
(C)
Hemolysis
NO
NO
–
3
(B)
ArginineArginase
Ornithine
Vasoocclusion
NO synthase
NO
Figure14.1 Sickle- cell anemia pathophysiology. (A) Hemoglobin polymerization triggered by sickle mutation at position 20 of codon six on the
beta- globin gene. (B) Sickling those results causes substantial change in red blood cell (RBC) rheology and blockage of blood vessels (vasoocclusion). (C) Rigid sickled red cells breakdown (hemolysis), releasing hemoglobin and its breakdown product (heme), as well as enzymes
including arginase. Heme depletes nitric oxide (NO), the regulator of endothelial cell (EC) function. Arginase breaks down l- arginine, the precursor
for NO synthesis. The cascade of reactions leads to endothelial cell dysfunction and vascular occlusion leading to ischemia (ISC).
under specific conditions, such as dehydration, infection,
or lack of oxygen. That process causes the RBCs to become
deformed and rigid and to take on a sickle or banana- like
shape. Sickled RBCs are most often destroyed in a process
called hemolysis, as they live an average of 20 days instead
of 120 days, leading to anemia. In addition, sickled RBCs
tend to obstruct small blood vessels in all organs, leading to
painful episodes, resulting in a lack of oxygen in critical
organs that causes multiple organ damage. As a result, people living with SCD can suffer recurrent silent or overt
stroke and acute or chronic heart and kidney dysfunctions,
leading to early mortality (Figure14.2). Despite this, as a
result of insufficient public health interventions in most
African countries, such as NBS for SCD followed by comprehensive preventive care (Figure14.3), it is estimated that
about 50–90% of affected children in sub- Saharan Africa
(SSA) die before their fifth birthday.
The first clinical case of SCD was described in 1911, but
controversially, progress in drug development has been very
slow, with only four FDA- approved medications: hydroxycarbamide or HU, - glutamine, crizanlizumab, and voxelotor.
HU and voxelotor are EMA- approved drug in Europe;
however, HU is the only medication available in selected
African settings. However, the impetus for developing novel
therapies for SCD is supported by limited clinical acceptance
of HU in certain areas of the world, including in the United
States due to negative and uninformed perceptions of HU,
and its potential side effects including higher infections rates,
and effects on fertility and reproduction such as quantitative
and qualitative semen and spermatogenesis abnormalities,
with conflicting evidence. To date, the only widely curative
approach to SCD has been hematopoietic HSCT. Allogeneic
stem cells lacking the genetic mutation will yield healthy
erythrocytes in the recipient. However, significant expertise is
needed to deliver peri- transplant care for SCD patients,
including blood transfusion support that might require
extensive RBC antigen matching. In general, pediatric SCD
patients have better outcomes, while adults who have acquired
significant organ damage due to chronic inflammation and
transplant- related toxicity have potentially prolonged recovery. Moreover, delayed immune reconstitution with infectious complications remains significant problems, and SCD
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(A)
(B)
I
)
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Perspectives ingenomics andsickle cell disease therapeutics 189
S
β
LCR
5′
HBE1
HBG2 HBG1 HBBP1 HBDHBB
3′
Al
CAR
BEN
CAM
SEN
Atypical
HincII
(rs3834466)
+
–
–
–
–
Xmnl
(rs7482144)
+
–
–
–
+
HindIII
(rs2070972)
+
–
+
+
+
HindIII
(rs28440105)
–
–
–
+
–
HincII
(rs10128556)
+
–
–
–
–
HincII
(rs968857)
+
+
–
+
+
Avall
(rs10768683)
+
+
+
+
+
HinfI
(rs10837631)
–
+
+
+
+
BamH
(No rs
–
+
+
–
+
Figure14.2 Epidemiology of sickle mutation (HbS): (A) β- like globin gene cluster haplotypes defined by presence (+) or absence (−) of specific restriction sites that are associated with
the HbS mutation. (B) Global distribution of HBB haplotypes: CAR=Central African Republic, BEN=Benin, CAM=Cameroon, SEN=Senegal.
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190 Molecular Hematology
SCD treatment center
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No. centres
(A)
Figure14.3 Important infrastructure relevant to SCD management in Africa. (A) SCD treatment centers in SSA (NB: those captured on the website of the GSCDN, https://www.
globalsicklecelldisease.com/treatalthough the services may be available in the countries).
111
centre- maps). (B) SSA countries that have initiated NBS. (C) Countries with HSCT. NA=not available (no record was found on public databases
(B)
Sierra Leone
NBS pilot
NA Yes Planned
(C)
Nigeria
HSCT centre
Yes NA Planned
Tanzania
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Perspectives ingenomics andsickle cell disease therapeutics 191
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patients are at risk of rejection, and death due to immunological
responses. Ultimately, only a small proportion of SCD patients
have matched- sibling donors, which is currently the only
standard curative option. The urgency to discover novel SCD
therapeutics is beginning to be addressed by over 30 ongoing
treatment intervention trials. As genetic factors influence
many pathophysiological aspects of SCD, I propose three
main strategies to accelerate the development of novel curative therapies for SCD through genomics research.
Epidemiology ofsickle cell disease
It is now more than 112 years since the first description of
SCD in a 20- year- old African American by the American
physician, James B. Herrick in Chicago, USA. Based on
large- scale genomic analyses, of HBB haplotype
(Figure14.2A) the single African origin of βS has been confirmed, although a recent review indicates that the correct
age of the mutation and precise location of its origin still
remain to be determined. When in 1954, the South African
scientist, AC Allison and his colleagues showed that carrying
a single allele of HbS (HbAS, called the sickle- cell trait–
SCT) protects individuals against severe P. falciparum
malaria, they confirmed the evolutionary link between Hb
variants and malaria– the “malaria hypothesis”– that was
postulated in 1949 by the British- Indian scientist, JBS
Haldane, based on β- thalassemia data. Studies have since
shown that human genetic factors are responsible for up to
25% of the inter- individual differences of severe malaria
clinical expression, and that the SCT contributes the largest
proportion due to a single gene (up to 2%). Indeed, it has
been observed that the SCT affords up to 90% protection
against severe P. falciparum malaria. As a result, the HbS
allele is highly prevalent in regions with historical malaria
endemicity (Figure14.2B), with up to 20% in some regions.
Outside of Africa, the HbS allele is most frequent in individuals of African descent reflecting the effect of migrations
to the spread of pathogenic mutations. For instance, in the
Mediterranean region including in Padova and Monza of
Italy, and in the Americas where it is absent in the indigenous population, or in regions where malaria is endemic or
was historically endemic such as in the Indian subthe Middle East, and the Mediterranean (Figure14.2B). The
HbC, the second most common cause of SCD in Africa, is
almost entirely restricted to West Africa with an epicenter
around Burkina Faso, although changing population dynamics is seeing wider distribution of the variant, for instance in
the population surrounding Karachi in Pakistan. The
homozygosity of the HbS allele (HbSS or SCA) is the most
common cause of SCD in Africa (65–70%), the compound
heterozygote form HbSC is the second most common
(~30%), while the HbS/β
0
- thalassemia accounts for the rest
of SCD cases in Africa.
continent,
The prevalence of SCD in SSA is largely driven by the
prevalence of SCT, HbC, and β
0
- thalassemia. The best
measure of the impact of SCD in a population would be the
total number of affected births per 1000live births (birth
prevalence). Such estimates have been possible to obtain in
developed countries where universal NBS has been implemented. Only recently has it been possible to make such estimates in specific African settings where NBS has been
piloted as an SCD management strategy. Generally, most
national SCD prevalence rates do not exceed 2% (Table14.1).
However, high birth prevalence rates greater than 3% have
been reported such as in Shirati of Tanzania (3.9%), suggesting that there might be more such cases in specific geographic regions in Africa, especially in rural areas where
awareness is typically low. In Nigeria, where up to 20 children are born with SCD per 1000 live births annually, a
recent National Demographic and Health Survey showed
that 10% of children aged six months to five years who were
found to have severe anemia also had SCA. This stresses the
need for countries to invest in epidemiological surveys of the
prevalence of the important HBB variants in SSA; HbS, HbC,
Table14.1 Birth andpopulation prevalence ofsickle- cell anemia,
andtrait inAfrica
Birth
prevalence
Country, Region
Liberia 1.19 – 10.31
Burkina Faso,
Ouagadougou
Benin – 0.2–4 22.3
Nigeria, Abuja 1–1.4 – 21
Nigeria, northern 1.72 – 22.36
Nigeria, national – 2.69–5 –
Cameroon, Yaounde 1.79 18.2
Democratic Republic
of Congo (DRC),
Kisangani
DRC, national 1.4 – 16.9
Angola, Luanda 1.51 – 21
Angola, national 1.55 – 21
Uganda, national 0.7 – >18
Uganda, East Central
and Mid- Northern
districts
Uganda, Eastern – 1.5 19.8
Tanzania 0.8 – 12.6
Tanzania, Shirati 3.9 – 31.6
Kenya, Kilifi – 0.8 7.8
Burundi 0.16 – 4.40
Rwanda 0.09 – 2.54
Sudan, Darfur 3.5 – 11.3
(%)
1.75 – 7.3
– 0.96 23.3
– >1 >18
Population
prevalence
(%)
SCT
prevalence
(%)
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192 Molecular Hematology
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and β- thalassemia. Increased investment in epidemiological
surveys of all the variants will enable the identification and
prioritization of regions with the highest need for critical
interventions. For examples demographic projections show
that SCD prevalence will increase by ~100 000newborns by
2050 and that Nigeria and DRC will be the most in need of
interventions. Therefore, the rollout of intervention strategies such as universal, or at least large- scale NBS is particularly imperative in these countries now. Indeed, a survey of
school children in Bahrain showed that health education,
carrier screening, and premarital genetic counseling are the
best ways to reduce the prevalence of inherited blood disorders including SCD.
Pathophysiology
Hemoglobin polymerization is the trigger to the downstream complications of SCD, while vascular occlusion and
hemolysis are the two most important pathophysiological
events (Figure14.1). Hemoglobin polymerization mediated
by high RBC HbS concentration and low oxygen tension in
RBCs causes RBC sickling and premature breakdown. This
releases Hb which causes the consumption of nitric oxide
(NO), leading to vasoconstriction and increased expression
of endothelial cell adhesion molecules, as well as increased
platelet inactivation. In addition, arginase is released as a
result of RBC destruction leading to the consumption of
- arginine (the substrate of NO synthesis). These events
lead to repeated tissue ischemia (ischemia–reperfusion)
and hypoxia that causes oxidative stress. Increased platelet
and white blood cells count (neutrophils and monocytes)
incites inflammatory responses. The major factors that
influence Hb polymerization include intracellular concentration of HbS relative other hemoglobins (particularly
HbF– high levels of HbF reduce Hb polymerization), duration of low oxygen tension, and pH. Vaso- occlusion and
hemolysis that follow Hb polymerization are the two most
important pathophysiological events – the hallmarks of
SCD. Physiological processes that are notably affected by
these events include inflammatory pathways (increase in
inflammatory activities), endothelial cell adhesion
promolecule expression (increase P- and E- selectins), nitric
oxide bioavailability (reduced), as well as changes in leucocyte counts (increased neutrophil, monocytes, and platelet
counts). The understanding and targeting of these major
pathophysiological pathways has led to the unraveling of
several therapeutic targets. For instance, the drug
Crizanlizumab (Adakveo®), an anti- P- selectin molecule,
has recently been approved by the USA Food and Drug
Administration (FDA) to help reduce vaso- occlusive pain
crisis (VOC) in SCD patients ≥16 years old. The drug was
shown to be safe and effective in the United States, Brazil,
and Jamaica, and it has now been planned for clinical trials
in Ghana and Kenya by the drug manufacturing company
Novartis. - glutamine, an agent that reduces the redox
potential and oxidative stress in sickle RBCs, was also
recently approved by the FDA for reduction of VOC, acute
chest syndrome, and hospitalization in SCD patients. Prior
to these treatments, HU, an anti- sickling agent, was the
only FDA- approved therapy for SCD treatment due to its
ability to mediate the prevention of Hb polymerization (its
exact mechanism of action, however, remains unknown).
Several other strategies targeting various pathophysiological pathways are currently under clinical trial, including
HSCT and agents targeting inflammatory and Hb polymerization pathways. Continued research is therefore important to delineate more pathophysiological pathways that
might uncover novel therapeutic targets.
Mortality and life expectancy of SCD
It has been estimated that the HbS allele has a recessive
lethality of 80% in malaria- endemic regions, meaning that
80% of all children born with SCA (HbSS) will die if the
disease is not diagnosed and immediately managed. In
resource- rich countries such as in the United States and
Europe, universal NBS and prophylactic penicillin, as well as
pneumococcal vaccination, have dramatically reduced
SCD childhood mortality. As SCD becomes more a chronic
disease of adults in these settings, other interventions including, HU therapy (HUT), blood transfusion, HSCT, and transcranial doppler screening to detect risk of stroke, among
others, have considerably increased the life expectancy of
SCD patients into their fifth decades (although their life
expectancy is still about 20 years lower than that of normal
individuals). In most countries in Africa, where early detection of SCD and initiation of prophylactic penicillin and
pneumococcal vaccination, among other interventions, have
been lacking, and where the high burden of infectious diseases such as malaria, and respiratory diseases contributes to
childhood mortality, it is estimated that about 30–90% of
children with SCD will die before their fifth birthday,
accounting for between 150
deaths in Africa annually. Given that these are mostly statistical estimates, it is imperative that studies be conducted
across Africa to determine the exact SCD mortality rates. For
instance, an overall U5mortality of 16% was reported in the
Republic of Benin, and that was reduced by 10- folds after an
NBS and follow- up programs were piloted in the country.
The implication of this high childhood mortality rate due to
SCD in some African countries is that most affected newborns are at high risk of death in settings where awareness
about the disease is low and access to healthcare is limited or
non- existent.
000 and 300 000 under- five (U5)
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