Invest Clin 66(4): 378- 389, 2025 https://doi.org/10.54817/IC.v66n4a03
Corresponding author: Gilberto Vizcaíno. Department of Public Health Sciences, Medical University of South Ca-
rolina, 135 Cannon Street, Suite 300, Charleston, SC 29425. Email: gilvizcaino@gmail.com
The burden of iron overload in sickle cell
disease: insights from South Carolina, USA.
Gilberto Vizcaíno1,2, Christina M. Abrams3, Caroline B. Foster1, Hermes Flórez1,
Natalia Dávila4 and Sabrina C. Rainey5
1Department of Public Health Sciences, Medical University of South Carolina,
Charleston, SC, USA.
2Instituto de Investigaciones Clínicas “Dr. Américo Negrette”, Facultad de Medicina,
Universidad del Zulia, Maracaibo, Venezuela.
3Department of Pediatrics, Division of Hematology/Oncology, Medical University
of South Carolina, Charleston, SC, USA.
4College of Nursing, Medical University of South Carolina, Charleston, SC, USA.
5University of Louisville, Pediatric Hematology Oncology, Louisville, KY, USA.
Keywords: Anemia; Sickle Cell; Iron Overload; Liver Iron Concentration; Ferritin;
Liver Function Tests; Chelation Therapy.
Abstract. Red blood cell transfusions can lead to iron overload (IO) in
sickle cell disease (SCD). We aimed to determine the relationship between SCD
patients with IO and SCD comorbidities. Iron chelation regimen for IO in SCD
patients was also studied. A cohort of 245 SCD adult patients receiving care at
the Medical University of South Carolina (MUSC) was studied. Information was
obtained from medical records. Statistical analysis was performed to examine
correlations and odds ratios with 95% confidence intervals. We identified 85
(34.7%) participants who met IO criteria. The results showed a significant as-
sociation of IO with stroke (OR= 14.67, p= 0.0001), pulmonary hypertension
(OR= 4.75, p= 0.0006), acute chest syndrome (OR= 2.46, p= 0.003), and
deep vein thrombosis (OR= 1.84, p= 0.04). There was a strong correlation bet-
ween liver iron concentration (LIC) and ferritin levels (r= 0.5148, p<0.0001).
Liver enzymes correlated well with LIC and ferritin levels. Eighty-six percent of
participants (74/85) were on chelation therapy, but only 19% of them achieved
a good response to the treatment. One-third of SCD individuals developed IO,
associated with several comorbidities. Comprehensive measures must include
periodic determinations of LIC and ferritin, followed by appropriate chelation
therapy to prevent organ damage.
Iron overload in sickle cell disease 379
Vol. 66(4): 378 - 389, 2025
La sobrecarga de hierro en la anemia falciforme: perspectivas
desde Carolina del Sur, EEUU.
Invest Clin 2025; 66 (4): 378 – 389
Palabras clave: Anemia de Células Falciformes; Sobrecarga de Hierro; Concentración
Hepática de Hierro; Ferritina; Pruebas de Función Hepática; Terapia
por Quelación.
Resumen. Las transfusiones de glóbulos rojos pueden provocar sobrecarga
de hierro (SH) en la enfermedad de células falciformes (ECF). Nuestro objetivo
fue determinar la relación entre pacientes con ECF con SH y comorbilidades
asociadas a la ECF. También se estudió el régimen de quelación de hierro para
la SH en pacientes con ECF. Se estudió una cohorte de 245 pacientes adultos
con ECF atendidos en la Medical University of South Carolina (MUSC). La in-
formación se obtuvo de las historias clínicas. Se realizó un análisis estadístico
para analizar las correlaciones y las razones de probabilidades (odds ratios) con
intervalos de confianza del 95%. Se encontraron 85 (34,7%) participantes con
criterios de SH. Los resultados mostraron una asociación significativa de la SH
con el ictus (OR = 14,67, p = 0,0001), la hipertensión pulmonar (OR = 4,75,
p = 0,0006), el síndrome torácico agudo (OR = 2,46, p = 0,003) y la trombosis
venosa profunda (OR = 1,84, p = 0,04). Se observó una fuerte correlación entre
la concentración hepática de hierro (CHH) y el nivel de ferritina (r = 0,5148,
p<0,0001). Las enzimas hepáticas se correlacionaron adecuadamente con la
CHH y los niveles de ferritina. El 86% de los participantes (74/85) recibía tera-
pia de quelación, pero solo el 19% obtuvo una buena respuesta al tratamiento.
Un tercio de los pacientes con enfermedad de células falciformes desarrolló so-
brecarga de hierro asociada a diversas comorbilidades. Las medidas integrales
deben incluir determinaciones periódicas de la CHH y la ferritina, seguidas de
un tratamiento de quelación adecuado para prevenir el daño orgánico.
Received: 27-07-2025 Accepted: 07-10-2025
INTRODUCTION
Sickle cell disease is a common he-
moglobinopathy, and approximately 4,000
people in South Carolina, USA, live with this
disease (SCD) 1. In the management of SCD,
chronic transfusion therapy is used to pre-
vent and treat complications 2. Each unit of
transfused packed red blood cells (pRBCs)
provides 200-250 mg of iron, and repeated
blood transfusions will lead to iron overload
(IO) in SCD patients. Previous studies have
shown that the IO resulting from transfu-
sional therapy in other patient populations
is associated with significant morbidity and
mortality 3. Iron overload has been consid-
ered a major cause of end-organ damage in
multitransfused patients with hemoglobin-
opathies 4, and the source of excessive iron
burden in SCD is primarily blood transfu-
sions and intravascular hemolysis.
To assess the degree of IO, liver iron
concentration (LIC) can be measured in-
vasively via liver biopsy or noninvasively by
380 Vizcaíno et al.
Investigación Clínica 66(4): 2025
magnetic resonance imaging (MRI). There
is a very close correlation between the two
methods; thus, MRI has largely eliminated
the need for liver biopsies 5. Ferritin should
be used as a measure of IO in SCD patients,
but its values should be interpreted with
caution for therapeutic decision-making 6.
Iron accumulation depends on the age at
which blood transfusions are started, the
rate of transfusions, and the nature of the
transfusion regimen7. Compared with thalas-
semia, iron deposition in cardiac, renal, or
endocrine organs is lower in SCD because in-
travascular hemolysis promotes biliary and
urinary elimination of iron as hemosiderin,
heme, and hemoglobin, and the chronic
inflammatory state reduces toxic accumu-
lation of iron in macrophages 7–9. Addition-
ally, there is a difference between multiple
simple transfused SCD patients and patients
receiving blood with exchange transfusions
because there is less liver accumulation of
transfused iron in the latter 8,9.
It is complicated to establish if organ
damage is caused by iron from transfusion
as a treatment for some SCD comorbidities
or if damage is a consequence of the compli-
cations themselves 5,6. The non-transferrin-
bound iron free in plasma is toxic because
it produces radicals with oxidation products
that are responsible for a significant part of
iron accumulation and cell injury associated
with regular multiple transfusions. Addition-
ally, inflammation, as a pathophysiologic
mechanism in SCD, leads to increased hepci-
din synthesis and decreased iron absorption,
with increased iron retention in the reticulo-
endothelial system 9.
IO is known to increase morbidity and
mortality in SCD, although the exact mech-
anism is unclear 10-12. This risk of increased
mortality could be associated with a high rate
of comorbidities 13. Except for the comorbidi-
ties of stroke or the presence of an abnormal
transcranial doppler (TCD), whose preven-
tive treatment is based on chronic transfu-
sions 14, it is difficult to determine whether
IO induces the presence of comorbidities or
whether these comorbidities are indepen-
dent of IO. It has been shown that in groups
of SCD patients with IO, there was a higher
mortality rate than those without IO. Those
deaths were attributable to sudden death or
pneumonia associated with acute chest syn-
drome 13. The rate of admission for vasooclu-
sive crisis related to the prevalence of organ
damage and SCD complications only found
a meaningful relationship with IO and acute
chest syndrome (ACS) 15. Ferroptosis has also
been recognized as a novel mechanism in
SCD and an additional avenue for organ dam-
age in SCD patients. In ferroptosis, elevated
iron levels trigger cell death by increasing re-
active oxygen species (ROS) and lipid perox-
ides, leading to organ impairment 16.
Iron chelation is the primary treatment
for IO in SCD, and it can be initiated if more
than 18 transfusions have been received
(or >120 cc/kg of PRBC) within a defined
period. Additionally, a serum ferritin level
>1000 ng/mL on two separate measure-
ments, or hepatic MRI-quantified iron>3
mg/g of dry weight, indicates IO treatment.
Because SCD causes a degree of chronic in-
flammation, ferritin, an acute-phase reac-
tant, is less reliable as a diagnostic tool than
in other anemias.
There are three iron chelators currently
approved for clinical use: (1) deferoxamine
(DFO), (2) deferiprone (DFP), and (3) defera-
sirox (DFX). DFO is the oldest drug and is ad-
ministered intravenously or subcutaneously,
while DFP and DFX are taken orally 14,15.
The primary aim of this study was to
determine the relationship between iron
overload and comorbidities in SCD patients.
The secondary aims included evaluating the
association between liver iron concentration
(LIC), serum ferritin levels, liver enzymes,
and the characteristics of the iron chelation
regimen in chronically transfused SCD pa-
tients.
Iron overload in sickle cell disease 381
Vol. 66(4): 378 - 389, 2025
MATERIAL AND METHODS
We conducted a retrospective chart review
of the electronic medical records (EMRs) of
245 adults with SCD who receive care at MUSC
in Charleston, South Carolina, and are enrolled
in the Sickle Cell Disease Implementation Con-
sortium (SCDIC) 17. The study participants had
a diagnosis of SCD, were English-speaking, and
aged 15-50. From that population, we identi-
fied 85 subjects with both SCD and iron over-
load (34.7%). EMR data were collected over
seven years (2017-2024). The inclusion crite-
ria for this study were a diagnosis of SCD, en-
rollment in the MUSC-SCDIC-II Registry and
REAL Answers projects, and a diagnosis of IO
using the previously mentioned parameters.
Age, sex, genotype, blood ABO group, comor-
bidities, ferritin, LIC, liver enzymes, and iron
chelation treatment were obtained from the
EMR. Patients with iron overload who received
a hematopoietic stem cell transplant were ex-
cluded from this study.
Institutional review board (IRB) approv-
al was obtained from each of the eight study
sites and a central IRB (CIRBI/Advarra) pri-
or to data collection, and a written informed
consent was obtained from each participant.
Statistical Analysis
Statistical analysis was performed using
GraphPad InStat3 (GraphPad Software, Bos-
ton, MA 02110) to analyze frequency distribu-
tions for categorical variables and to perform
linear regression and Pearson correlation for
continuous variables. A 2 x 2 contingency ta-
ble was used to calculate odds ratios with 95%
confidence intervals by Fisher’s exact test and
to calculate sensitivity and specificity param-
eters. The reference group for the odds ratio
(OR) was adult SCD patients (160/245) with-
out iron overload. A p<0.05 was considered
statistically significant.
RESULTS
Table 1 describes the demographic char-
acteristics of the 85 (34.7%) subjects with SCD
and IO who met inclusion criteria. Seventy-
three IO patients (85.9%) were between 18-
45 years old with a median age of 32.5 years
(range 16-55), 61.2% were female, 95.3% had
SS genotype, and 56.5% had blood group O.
From 67.0% with IO criteria receiving transfu-
sions (57/85), 51% (29/57) were treated un-
der manual blood exchange regimen, and the
rest of them by erythrocytapheresis regimen.
The prevalence of several comorbidities
with SCD is described in Table 2. Patients with
IO were noted to have a higher rate of four
comorbidities: acute chest syndrome (OR=
2.46, p= 0.003), deep vein thrombosis (DVT,
OR= 1.84, p= 0.04), stroke (OR= 14.67, p=
0.0001) and pulmonary hypertension (PH,
OR= 4.75, p= 0.0006), seen in Table 2 and
Fig. 1. Pulmonary hypertension (PH) was de-
fined as a mean pulmonary arterial pressure
of at least 25 mm Hg, and a TRV >2.5m/s.
MRI studies, liver biopsy, LIC, and ferritin
Seventy-four percent of subjects with IO
initially had MRI/LIC records available (63/85)
and 26% had also liver biopsy data available
(22/85). Twenty-four percent (20/85) of them
did not have a subsequent record of LIC, as
measured by liver MRI or liver biopsy, and were
followed only with ferritin determination. Car-
diac MRI data were available for 25% (21/85)
of subjects, and only one patient showed myo-
cardial iron deposition.
The average values at the start and end
of the study for LIC were 11.71±8.46 mg/g
dry weight (n=59) and 12.88±7.86 mg/g
dry weight (n=44), respectively; the average
values for ferritin were 3779.5±2852 ng/mL
(n=85) and 5055.1±5567.4 ng/mL (n=85),
respectively; p=0.06 for both.
There was a strong correlation between
LIC (mg/g dry weight) and ferritin level
(ng/mL) (r=0.5148, p=0.0001), as seen in
Fig. 2. We also observed a strong correlation
between serum ferritin and LIC in individu-
als with serum ferritin levels > 2500 ng/mL
(r=0.5220, p=0.0026, n= 31). There was
no correlation in patients with serum ferri-
tin levels below 2500 ng/mL (r=0.3133, p=
0.3213; n=12).
382 Vizcaíno et al.
Investigación Clínica 66(4): 2025
Table 1. Demographic characteristics of Iron overload in Sickle Cell Disease.
Characteristics Iron Overload (N=85) No Iron Overload
(N=160)
Total
(N=245)
Age group (years)
<18 4 (4.7%) 10 (6.3%) 14 (5.7%)
18-24 20 (23.5%) 22 (13.7%) 42 (17.2%)
25-34 24 (28.2%) 65 (40.6%) 89 (36.3%)
35-45 29(34.2%) 43 (26.9%) 72 (29.4%)
>45 8(9.4%) 20 (12.5%) 28 (11.4%)
Median 32.5 31.0 32.0
Gender
Male 34 (40.0%) 62 (38.8%) 96 (39.2%)
Female 51 (60.0%) 98 (61.2%) 149 (60.8%)
Age (N)
Male 31.36±10.4 (34) 34.36±11.0 (62) 33.33±10.8(96)
Female 33.43±9.4 (51) 32.51±11.1 (98) 32.75±10.7(149)
Mean±SD 32.61±9.8 (85) 33.26±11.2 (160) 33.05±10.7 (245)
SCD Genotype
SS 81 (95.3%) 98 (61.3%) 179 (73.1%)
SC 1 (1.2%) 40 (25.0%) 41 (16.7%)
SThal 3 (3.5%) 19 (11.9%) 22 (9.0%)
Other 0 (0%) 3 (1.8%) 3 (1.2%)
Blood Group (ABO)
Group O 48 (56.5%)
Group A 20 (23.5%)
Group B 10 (11.8%)
Group AB 7 (8.2%)
Table 2. Sickle Cell Disease Iron overload and comorbidities relationships.
Comorbidity IO
(N=85)
No IO
(160)
Total
(N=245)
OR
(CI95%)
OR
p-value
ACS 65 (26.5%) 91 (37.1%) 156(63.7%) 2.46 (1.37-4.45) 0.0032
DVT 33 (12.2%) 41 (18.0%) 74(30.2%) 1.84 (1.05-3.23) 0.0406
Retinopathy 13 (5.3%) 42 (17.1%) 55 (22.4%) 0.50 (0.26-1.01) 0.0548
Stroke* 46(18.8%) 13 (5.3%) 59(24.1%) 13.34 (6.56-27.12) 0.0001
CKD 20 (7.8%) 25 (10.2%) 45 (17.9%) 1.66 (0.86-3.21) 0.1650
Anxiety/Depression 39 (16.7%) 61 (23.3%) 100(40.0%) 1.38 (0.80-2.34) 0.2752
AVN 42 (17.1%) 62(25.3%) 104 (42.4%) 1.54 (0.91-2.63) 0.1351
Pulmonary Htn 17 (7.8%) 8(2.9%) 25 (10.7%) 4.75 (1.96-11.54) 0.0006
ACS: Acute Chest Syndrome; DVT: Deep Vein Thrombosis; CKD: Chronic Kidney Disease; AVN: Avascular Necrosis;
Htn: Hypertension. *Include overt stroke and abnormal transcranial doppler (TCD).
Iron overload in sickle cell disease 383
Vol. 66(4): 378 - 389, 2025
An increasing number of comorbidi-
ties was associated with rising LIC and se-
rum ferritin (Table 3). The median number
of co-morbidities per patient was 3 (mean
3.12 ± 1.5).
Accuracy estimation of ferritin as
a marker of iron overload in SCD
participants
Among 69 IO subjects with paired LIC
and ferritin levels, 36 had a LIC≥ 10 mg/g
dw and 23 had a LIC < 10 mg/g dw. Using
a ROC curve and a serum ferritin cut-off of
≥2500 ng/mL, we obtained 78% sensitivity,
74% specificity, 86% positive predictive val-
ue, and 61% negative predictive value. In our
patient sample, 46 subjects were correctly
diagnosed with IO based on their serum fer-
ritin levels (TP), and 13 patients were in-
correctly identified as not having IO (FN).
The accuracy of the serum ferritin level to
diagnose IO was 76% and the area under
the curve (AUC) was 76% (Table 4), (Garcia-
Casal et al. 18).
Iron overload and liver enzymes
In SCD individuals with IO, liver en-
zymes showed a good correlation with LIC
and ferritin levels (Supplemental Table 5),
except for alkaline phosphatase and LIC.
The mean serum values ± SD were AST:
47.8±26.32 U/L, ALT: 33.86±27.36 U/L,
and AP: 113.66±55.12 U/L.
Iron chelation treatment
Transfused patients with IO received
an average of 22 pRBCs per year with a
median of 12 transfusions. Eighty-six
percent (74/85) were prescribed chela-
tion therapy with deferasirox (DFX), and
two patients were prescribed deferiprone
(DFP) chelation therapy. Of those on che-
Fig. 1. Odds Ratio for Comorbidities in Sickle Cell patients with IO.
Fig. 2. Linear regression with 95%CI between LIC (mg/g dry weight) and Ferritin (ng/mL) in SCD partici-
pants (n=59) diagnosed as Iron overload, r= 0.5148, p<0.0001.
384 Vizcaíno et al.
Investigación Clínica 66(4): 2025
lation therapy with deferasirox, only 19%
(14/74) obtained a good response with se-
rum ferritin <1000 ng/mL. Providers fol-
lowed 54% of these patients with periodic
LIC determinations and serum ferritin
(40/74), and the remaining patients were
followed with serum ferritin alone. Infor-
mation about the side effects of DFX treat-
ment was scarce and difficult to collect
from the data records. Fifty-four percent
(40/74) of the subjects were on disease-
modifying treatment.
DISCUSSION
These findings show a significant asso-
ciation of IO with several comorbidities in a
cohort of SCD patients. Most of the patients
were SS genotype young adults receiving fre-
quent blood transfusions. Parameters such
as LIC, measured by MRI and/or liver biopsy,
were used to diagnose IO in many of these
patients, and serum ferritin levels were used
as a marker of IO. There was a strong corre-
lation between LIC and serum ferritin when
the serum ferritin levels were above 2500
ng/mL. Liver enzymes showed a good corre-
lation with LIC and serum ferritin levels, and
chelation therapy with DFX was unsuccessful
in most cases.
Previous research has demonstrated
that SCD patients with IO have an increased
risk of mortality 11,12, and this risk could be
associated with a high rate of comorbidi-
ties13. Moreover, liver injury is associated
with mortality in SCD, with increased ferri-
tin and direct bilirubin as predictors of mor-
Table 3. Values of LIC and ferritin associated with the number of comorbidities
in subjects with Iron overload.
No comorbidities LIC (N=43) Ferritin (N=85) p
1 11.58±5.2 (7) 5538.28±7793.6 (9) 0.0661
2 14.82±7.6 (17) 5748.89±5336.7 (29) 0.0001
3 12.83±9.6 (6) 7026.32±7608.4 (15) 0.0031
4 7.74±4.37 (5) 2588.65±2552.1 (14) 0.0023
>5 11.58±8.17 (8) 3936.66±3800.9 (18) 0.0004
LIC: liver iron concentration (mg/g dry weight), ferritin (ng/mL).
Table 4. Sensitivity and specificity of ferritin
as a marker in Sickle Cell Disease to assess
iron overload (N=69).
Variable Value 95% Confidence
Interval
Sensitivity 0.7750 0.6159 to 0.8917
Specificity 0.7368 0.4879 to 0.9085
Positive Predictive Value 0.8611 0.7052 to 0.9533
Negative Predictive Value 0.6087 0.3856 to 0.8027
Likelihood Ratio 2.945
DOR 9.65
DOR: diagnostic odds ratio, calculated as the effectiveness
as an index of iron overload 18. DOR= (sens x spec) / (1-
sens) x (1-spec) = (sens x spec) / (FNs) x (FPs).
Table 5. Correlations between LIC
and ferritin versus liver enzymes.
Variable (N) rp
LIC vs AST (43) 0.5551 0.0001
LIC vs ALT (43) 0.5248 0.0003
LIC vs AP (43) 0.1393 0.3730
Ferritin vs AST (85) 0.5794 0.0001
Ferritin vs ALT (85) 0.6015 0.0001
Ferritin vs AP (85) 0.3644 0.0006
LIC: liver iron concentration; AST: aspartate trans-
ferase; ALT: alanine aminotransferase; AP: alkaline
phosphatase. The values of liver enzymes were expres-
sed in U/L, LIC in mg/g dry weight, and ferritin in ng/
mL. The reference ranges for liver enzymes were AST
(5-34 U/L), ALT (5-45 U/L) and AP (35-150 U/L).
Iron overload in sickle cell disease 385
Vol. 66(4): 378 - 389, 2025
tality. All patients with advanced liver fibro-
sis had IO, but not all patients with IO had
fibrosis 19. We have seen an increased num-
ber of comorbidities in our study patients
with IO, and so this condition may be a pre-
disposing factor for increased morbidity and
mortality in SCD patients. In our study, five
(2.0%) patients with SCD died, and three of
those had IO.
As demonstrated previously 20, our
findings showed a stroke or at-risk-of-
stroke prevalence of 24% (59/245) in SCD
patients. Of the patients with stroke or at
risk of stroke, 78% of them had IO (70%
stroke, 30% abnormal TCD), making stroke
the most common comorbidity that we ob-
served with IO. This high rate of IO could
be explained by the use of frequent blood
transfusion as primary or secondary preven-
tion in SCD individuals with abnormal TCD
or cerebrovascular event14. In our study
population, none of these patients had re-
current strokes after the initial event.
Sixty-four percent of our study popu-
lation had ACS, and 41.6% of patients with
ACS also had IO. In this population, patients
with IO were at a significantly higher risk of
ACS. This relationship, at least in part, may
be related to the use of simple blood trans-
fusions to improve oxygen-carrying capacity
in persons with symptomatic ACS, and to
the urgent exchange transfusion performed
when there is rapid progression of ACS 21,22.
The prevalence of DVT was 30.2%
(74/245) in individuals with SCD, with a
predominance in the female sex (66.2%), as
has also been described in one other study23.
A significant relationship between IO and
DVT could be explained by the occurrence of
a hypercoagulable state in individuals with
SCD24, driven by inflammation, in part due to
oxidative stress and iron deposition-induced
ferroptosis, leading to thrombogenesis and
activation of the coagulation cascade in SCD
individuals 25.
Epidemiological studies reveal that PH
development is associated with iron overload
and other comorbidities 26. Chronic anemia
in sickle cell disease results in cardiac cham-
ber dilation and a compensatory increase in
left ventricular mass. Elevated TRV as well
as ferritin and the number of red blood cell
units transfused, were also found to be as-
sociated with a higher risk of death 27. In the
current study, we found that the prevalence
of IO associated with PH, as diagnosed by
echocardiography, was 7.8%. Additionally,
patients with IO were statistically more like-
ly to have PH, with 68% of patients with PH
also having IO.
In this study, there was no significant
association between IO and other comor-
bidities such as anxiety and depression.
However, we found a 40% prevalence of these
mental health issues in the entire cohort
of SCD patients. Depression is prevalent in
adult patients with SCD and is associated
with worse health-related quality of life, so
an assessment of anxiety and depression in
persons living with SCD is vitally important,
given the prevalence of this comorbidity in
the general SCD population 12,28.
The relationship between IO and acute
kidney injury (AKI) and chronic kidney dis-
ease (CKD), although it was not significant
in our study, may be a subject of further
studies due to the risk of toxicity by iron
chelation treatment with an elevated risk of
mortality in SCD individuals 29. Recently, fer-
roptosis has been implicated in the develop-
ment of AKI/CKD, as renal cells are particu-
larly vulnerable to IO 30.
Usually, follow-up of patients with SCD
and IO is based on periodic MRI measure-
ments of LIC and serum ferritin levels. The
current study has demonstrated a strong
correlation between LIC and ferritin lev-
els above 2500 ng/mL, with a sensitivity of
78% and a specificity of 74%. This correla-
tion is compatible with other studies 6. Ad-
ditionally, this threshold could indicate the
need for chelation treatment if LIC cannot
be performed 31. However, when the serum
ferritin level is less than 2500 ng/mL, it is
less reliable as a marker of LIC. This may
be related to serum ferritin levels being af-
386 Vizcaíno et al.
Investigación Clínica 66(4): 2025
fected by chronic inflammation in SCD. Es-
pecially during an acute exacerbation of a
comorbidity or a vasoocclusive event, serum
ferritin may be less reliable for estimating
LIC 32. Additionally, it is important to note
that only one-third of the subjects in our
study with SCD and elevated serum ferritin
levels underwent MRI for LIC measurement,
reflecting a lack of appropriate follow-up for
screening, diagnosis, and treatment of IO.
This observation is in agreement with other
studies 31.
Liver enzymes, as a measure of liver func-
tion, correlated well with serum ferritin and
LIC levels in the SCD cohort with IO. Alkaline
phosphatase has been associated with mortal-
ity 19, and some studies have reported a correla-
tion between serum ferritin and AST as an esti-
mator of LIC. A serum ferritin/AST ratio >17
µg/U has been highly predictive of IO 33. Never-
theless, in the population, routine screening of
liver enzymes has poor sensitivity and specific-
ity for detecting liver damage 34.
As shown in our study, IO is associat-
ed with a greater number of comorbidities.
Thus, treating IO intuitively makes sense to
reduce the risks associated with this condi-
tion. We found that DFX was the most com-
monly prescribed treatment for IO. Although
86% of IO patients in our study population
were prescribed DFX, only 19% achieved fer-
ritin levels <1000 ng/mL during the study
period. According to other references 8,15,35,
one factor contributing to a limited response
to this treatment is poor adherence. While
we did not assess compliance with chelation
treatment as a cause of poor response in our
study, treatment compliance is an important
factor and should be evaluated when treat-
ing a patient for IO.
This study has several limitations: its
observational, retrospective, and cross-sec-
tional design, along with the reliance on
medical record abstraction and the patient’s
self-report of symptoms, could introduce
bias and affect the statistical power of the
results. In some cases, the evolution of IO is
represented solely by serial determinations
of serum ferritin, without a matched LIC,
and by periodic MRIs. Additionally, it was
not distinguished whether the serum ferritin
values were reported during vasoocclusive
crisis or in the steady state of the patients,
thus there is a risk that the vasooclusive
event could confound elevated serum ferri-
tin levels. It is well known that ferritin levels
increase significantly during a vaso-occlusive
crisis 9. Information on toxicities related to
DFX treatment was scarce and difficult to
extract from the data records.
In conclusion, iron overload in SCD is a
life-threatening condition, often associated
with an increased number of comorbidities
leading to a declining clinical course with
an inadequate quality of life, hepatic com-
plications and premature death. Manage-
ment suggests that MRI screening for liver
iron concentration should be performed ev-
ery one to two years in patients with SCD
receiving chronic transfusion therapy. Se-
rum ferritin levels should be measured after
each transfusion; this inexpensive blood test
broadly correlates with total body iron bur-
den and, due to its ease of acquisition, is a
valuable tool for monitoring trends in iron
burden over time 31. A significant limitation
for using ferritin levels as indicator of IO in
SCD is that inflammation can raise ferritin
levels irrespective of iron burden 2. Providers
should monitor patients and assess adher-
ence with chelation therapy in the treatment
of IO. Iron overload in SCD requires preven-
tive care and close monitoring to avoid irre-
versible organ damage.
Funding
The Sickle Cell Disease Implementa-
tion Consortium (SCDIC) has been support-
ed by US Federal Government agreement
(167036) from the National Heart, Lung and
Blood Institute.
Conflict of interest statement
Authors declare no conflicts of interest.
Iron overload in sickle cell disease 387
Vol. 66(4): 378 - 389, 2025
Ethical approval and informed consent
Institutional review board (IRB) approv-
al was obtained from each of the eight study
sites and a central IRB (CIRBI/Advarra) pri-
or to data collection and written informed
consent was obtained from each participant.
Consent for publication
Informed consent included agreement
to have de-identified data published and dis-
seminated in accordance with publication
guidelines for the Sickle Cell Disease Imple-
mentation Consortium (SCDIC).
ORCID number of authors
• Gilberto Vizcaíno (GV):
0000-0003-2785-1879
• Christina Abrams (CA):
0000-0002-6296-3844
• Caroline Foster (CF):
0000-0002-3544-3261
• Hermes Flórez (HF):
0009-0003-3812-9926
• Natalia Dávila (ND):
0000-0004-2996-4919
• Sabrina Rainey (SR):
0000-0001-9717-7248
Authors contributions
GV drafted the manuscript and per-
formed the statistical analyses. CA, CF, HF,
ND and SR contributed to the concept and
design of the study and revised manuscript
drafts. All the authors critically reviewed and
approved the manuscript.
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