Correlation between Heart and Liver Iron Levels
and Serum Ferritin in Patients with Sickle Cell
Disease “A local Experience”
Zizi saad1* and Ragab H Donkol2
1 Department of cardiology, Zagazig University, Egypt
2Department of Radiology, Zagazig University, Egypt
Submission: March 28, 2019; Published: April 09, 2019
*Corresponding author: Zizi saad, Department of cardiology, Zagazig University, Egypt.
Ragab Hani Donkol, Department of Radiology, Zagazig University, Egypt
How to cite this article:Zizi saad, Ragab H D. Correlation between Heart and Liver Iron Levels and Serum Ferritin in Patients with Sickle Cell Disease “A local
Experience”. J Cardiol & Cardiovasc Ther. 2019; 13(4): 555867. DOI: 10.19080/JOCCT.2019.13.555867
Aim of the study: Is to evaluate cardiac and hepatic transfusional iron overload in a series of teenagers and young adults sicklers by using a relaxometric T2* technique. Material and Methods: The study was performed on 25 transfusion-dependent sickler patients (13 men and 12 women), with median age of 22 years. Relaxometric T2* cardiac and liver scans were performed on a 1.5 Tesla Magnetic Resonance Imaging (MRI) scanner.
Results: No patients manifested with cardiac siderosis. Cardiac T2* was not significantly correlated with Hemoglobin (Hb), Ferritin, and liver T2*. No significant correlation was found between liver T2* and Hb; while a significant moderate negative correlation (rs -0.45; p value 0.024) was noted between liver T2* and serum Ferritin. Liver Iron Content was low/normal (<7 mg Fe/g dw), moderately increased (7-14mg Fe/g dw), and severely increased in, respectively 12 (48%), 7 (28%) and 6 (24%) patients. A low serum ferritin level (<1500 ng/ml) indicated a low Liver iron concentration (LIC) (<7 mg Fe/g dw) in 7/8 (88%). An intermediate increase (1500-3000 ng/ml), and an increased level (>3000 ng/ml) of serum ferritin indicated a significantly increased LIC (>7 mg Fe/g dw) in receptively 7/10 (70%), and in 5/7 (71%) of patients.
Conclusion: Our series shows that the correlation between liver iron content and serum Ferritin level is only moderate; liver T2* scan should be considered to adjust chelation especially in patients with intermediate serum Ferritin Level.
Keywords: Sickle cell disease; Iron overload; Chronic transfusions; Magnetic resonance imaging
Abbrevations: MRI: Magnetic Resonance Imaging; SCD: Sickle Cell Disease; LIC: Liver Iron Concentration; ACH: Aseer Central Hospital; FOV: Field of View; ROI: Region of Interest; Hb: Hemoglobin; Interquartile Range; TM: Thalassemia Major
Patient with Sickle cell disease (SCD) have experienced a great amelioration in quality of life, appreciations goes to the introduction of modern transfusions of filtered red cells . However, blood transfusions cause iron accumulation over the years, and in the absence of physiologic ability to excrete excess iron , there is a progressive damage of major organs; such as the heart, the liver, and endocrine system . End organ damage results from lipid peroxidation thru formation of reactive oxygen species by non-transferring bound iron, especially the labile plasma iron subset . Therefore, chelation therapy is necessary to prevent iron accumulation and/or to remove excess iron .
Several techniques can be used to assess iron overload. Traditionally, liver iron concentration (LIC) by liver biopsy is considered the gold standard to predict iron overload, and a value
of 7mg/g liver has been used as a guide to start chelation in both pediatric and adult patients [5,6]. LIC <7mg/g is not associated with obvious hepatic pathology, while >14 mg/g is consistently associated with liver fibrosis . The use of biopsy-measured LIC as a marker of iron overload is limited by the small but finite risk of complications of liver biopsy, lack of reproducibility of quantitative assays, and sampling error . Noninvasive methods including blood tests (Ferritin and iron saturation) and imaging techniques (MRI-based techniques) have been evaluated as predictors of LIC. Ferritin has been shown to correlate with LIC in thalassemia major, but the correlation in SCD is less clear . Iron overload in SCD differs from thalassemia major, where regular transfusions start later. Inflammation related increased synthesis of hepcidin decreases iron absorption and enhances retention of iron within the reticulo-endothelial system , and there is less pronounced extrahepatic distribution with rare cardiac iron
overload or endocrinopathies . However, the profile of SCD iron
overload in SCD has changed in recent years; indeed, long-term
transfusion therapy has significantly increased in both children,
mainly because of the primary prevention of stroke, and adults,
due to increased life expectancy . Heavily iron overloaded SCD
have comparable risk of death as those with thalassemia major,
and cardiomyopathy is the cause of∿30% of deaths .
Chelation should be closely monitored to ensure optimal
treatment. Serum ferritin levels should be obtained at least
quarterly to follow trends in iron loading. Liver and cardiac MRI
scans generally are obtained annually. Optimally LIC should be
maintained to less than 2 and cardiac T2* more than 20 ms. In
general, when the cardiac T2* decreases to less than 20 ms, and
especially less than 10 ms, or when the LIC is higher than 7 mg/g
dw and not improving, better chelation is needed thru increasing
dose and improving adherence. The addition of a second chelator
can be taken into consideration, especially if iron burden is at very
concerning levels (LIC >15 mg/g dw or cardiac T2* <10 ms) or if
adverse effects prevent dose escalation .
The objective of this study was to examine the extent
of myocardial and hepatic Iron overload (siderosis) using
MRI Relaxometer T2* Technique, and to evaluate its clinical
associations in chronically transfused patients with SCD.
A prospective observational study was done for 25 patients
including 13 men and 12 women with a median age of 22 years
(range: 17 to 24). All patients were transfusion-dependent sickle
cell anemia patients recruited from Hematology Department
in Aseer Central Hospital (ACH), Abha, Saudi Arabia, most
having required blood transfusions from early childhood.
Clinical information regarding duration of transfusion, history
of splenectomy, chelation therapy, hemoglobin level, liver
function test, and ferritin levels were collected. Patients gave
their informed consent. The study was approved by the hospital
ethics committee. All patients underwent cardiac and hepatic
iron overload measurements by MRI T2* scanning between June
of 2017and August of 2018 in the Medical Imaging Department
of ACH using the imaging protocol previously elaborated in
Site qualification and initiation requires the site to scan
test object or “phantom” prior to conducting patient studies for
imaging facility qualification. The phantom used and software
for analysis was provided from BioMed Informatics, LLC 31225
La Baya Dr, Suite 200 Westlak Village, and CA. The precision and
accuracy of T2* MRI measurements were assessed by measuring
a series of MnCl2 solutions with different concentrations for
phantom calibration. Measurements of T2* for a series of ten
aqueous MnCl2 phantoms with a range of ionic concentrations
resulting in theoretical T2* values from 1 to 24 ms were made in
the scanners [14,15].
MRI acquisition instructions for phantom scanning are found
in Table 1.
Sedation was not required for this clinical study, as all patients
are adults and cooperative. Exam duration was approximately 45
to 60 minutes. Patients were examined in the supine, head first
position. Phased array torso and dedicated cardiac coil were used
during scanning. Cardiac gating was used to decreases cardiac
motions artifacts and respiratory bellows monitoring was used
assess cooperation with breath- holding.
Cardiac T2* and Liver T2* scans were performed during the
same exam on the same scanner by using a dedicated cardiac
coil for Cardiac MRI and phased torso coil for the liver scan. All
patients were scanned on a 1.5 Tesla MRI scanner (Intera, Philips
Medical Systems, Best, the Netherlands).
For cardiac iron evaluation, the double inversion recovery
“black blood” sequence were used as it has shown greater
reproducibility than the white blood” sequence; especially in
patients with higher T2* values (less iron) as the blood signal is
Using a multi-plane localizer ensured the heart is at the center
of the magnetic field. Using 2 and 4 chamber and short axis scouts
select a mid-ventricular imaging plane (usually mid papillary
muscle level) not encroaching on the outflow tract. Table 2
summarized the parameters for cardiac T2* imaging. To calculate
the T2* value of the myocardium, a region of interest was drawn in
the ventricular septum, avoiding blood pool and cardiac vessels.
Predicted myocardial iron concentration was converted from the
T2* value according to the study of Carpenter et al. , Values
of T2* less than 20 ms were regarded as abnormal cardiac iron
Imaging parameters for the liver T2* assessment are
summarized in Table 3. Liver acquisition will consist of using
the torso phased array coil. The acquisition will consist of 4-5
contiguous slices, collected in a single breath hold, centered in
the middle of the liver. Imaging voxels are large to improve signal
to noise ratio and to decrease minimum echo time. Voxels should
be 4-5 mm in-plane and 10 mm through plane (slice thickness).
Field of view (FOV) should be adjusted to body habitus, but not
decreased below 32 cm because small FOV may prolong echo’
times. Repetition time and flip angle should be 100 ms and 20
degrees, respectively. Echo’ times should be sampled between 12
and 14 ms.
Liver T2* was measured from 5 regions of the mid hepatic slice.
Region of interest (ROI) was drawn near the periphery of the liver,
excluding obvious hilar vessels or breathing artifacts. Then the
median liver T2* (ms) was calculated. The liver iron content (mg
Fe/g dw), which is the predicted hepatic iron concentration, was
converted from the T2* value according to validated calibrations
curves using software provided by BioMed Informatics, LLC
31225 La Baya Dr, Suite 200 Westlak Village, CA [17,18].
Statistical analysis was performed on the Vassar Stats Website
for Statistical Computation (http://vassarstats.net/index.html).
Quantitative data are expressed as medians with interquartile
ranges, while qualitative variables are presented as frequencies
and percent. Correlation between cardiac and liver T2*, and
their correlation with ferritin and hemoglobin (Hb) levels has
been evaluated by Spearman rank correlation test; results are
presented as rs (p value). Association of cardiac and liver T2* with
prior splenectomy and transfusion rate has been assessed by the
Mann-Whitney test; results are presents as p values. Two sides p
values ≤0.05 are considered as significant.
Table 4 presents the baseline demographics, hematologic and
iron overload results. Of the 25 patients, 13 men and 12 women,
median age of 22 years (interquartile range (IQR) 17-24 years),
15 (60%) were receiving regularly transfusions, 12 had a history
of splenectomy (48%), and 6 (24%) had elevated liver enzymes,
but no one had positive markers of hepatitis. All patients were
receiving hydroxyurea as chelator. The median Hb (g/dl) and
Ferritin (ng/ml) levels were respectively 7.8 (IQR, 7.4-8.6) and
1970 (IQR, 960-2966). The median liver T2* (ms), liver iron
content (mg Fe/g dw) and cardiac T2* (ms) were respectively
3.4 (IQR, 2.05-8.73), 9.7 (IQR, 4.14-15.26), and 31.4 (IQR, 28.8-
33.4). Considering thresholds of 20 ms for cardiac T2* no patients
manifested with cardiac siderosis. LIC was low/normal (<7 mg
Fe/g dw), moderately increased (7-14 mg Fe/g dw), and severely
increased in, respectively 12 (48%), 7 (28%) and 6 (24%) patients.
IN Table 5, Cardiac T2* was not significantly correlated with
Hb, Ferritin and liver T2* (rs respectively 0.02, -0.01 and 0.26;
p values respectively 0.921, 0.984 and 0.209). No significant
correlation was found between liver T2* and Hb (rs -0.12; p value
0.595), while a significant negative correlation was noted between
liver T2* with Ferritin (rs -0.45; p value 0.024).
No significant association has been found between cardiac T2*
with prior splenectomy and transfusion rate (p values respectively
0.938 and 0.317). Liver T2* association with prior splenectomy
was not significant (0.429), while the association with transfusion
rate was at the limit of significance (0.0526) Table 6.
Table 7 presents the association between serum ferritin and
LIC levels. The serum ferritin and LIC categories ranges have
been defined according to the data of Raghupathy & Adamkiewicz
[4,19]. A low serum ferritin level (<1500 ng/ml) indicated a low
LIC (<7 mg Fe/g dw) in 7/8 (88%). An intermediate increase
(1500-3000 ng/ml) and an increased level (>3000 ng/ml) of
serum ferritin indicated a significantly increased LIC (>7 mg Fe/g
dw) in receptively 7/10 (70%) and in 5/7 (71%) of patients.
The profile of SCD iron overload in SCD has changed in recent
years; long-term transfusion therapy has significantly increased
in both children, mainly because of the primary prevention of
stroke, and adults, due to increased life expectancy . Blood
transfusions cause iron accumulation over years, and in the
absence of physiologic mechanism to excrete excess iron .
There is a progressive damage of major organs, such as the heart,
the liver and endocrine system . End organ damage results
from lipid peroxidation thru formation of reactive oxygen species
by non-transferring bound iron, especially the labile plasma iron
subset . The chelation therapy goals are to reduce plasma and
cytosolic levels of reactive labile iron as quickly as possible to
protect tissue from iron toxicity .
In the current study we have used a relaxometric T2*
technique to asses liver and heart overload in a series of teenagers
and young adults. In iron-loading anemias, liver iron content
provides a reliable marker of total body iron to guide, monitor, and
titrate therapy . Relaxometric techniques have the advantage
to be non-invasive in comparison to the LIC quantification by
liver biopsy which considered the gold standard for this purpose.
An LIC <7 mg Fe/g dw is not associated with obvious hepatic
pathology, while values beyond of 7 mg Fe/g dw liver indicates
need for chelation (Raghupathy) in both pediatric and adult
patients [5,6]. An LIC >14 mg Fe/g dw is consistently associated
with liver fibrosis  and the addition of a second chelator can
be considered . Our choice for thresholds was based on these
evidences: moderate (7-14 mg Fe/g dw) and severe (>14 mg Fe/g
dw) hepatic iron overload were seen, respectively in 7(28%)
and 6 (24%) patients. Level of liver iron overload was less than
the series of Aubert, including 56 liver MRI performed in 30
chronically transfused children with SCD; LIC categorization was
slightly different from ours: mild or absent for LIC <5.6 mg/g,
moderate: ≥5.6 and <14 mg/g; severe:≥14 mg/g, with respective
frequencies 17 (30%), 18 SCA (32%), and 21 (37%). In contrast to
this, the median LIC in ours series, 9.7 mg Fe/g dw is similar to the
series of Hankins : 10.3 mg Fe/g dw (35 patients; median age
18 years) and Badawi : 8 mg Fe/g dw (32 patients; median
age 15 years).
In our series, none had evidence of myocardial siderosis on
cardiac MRI and all T2* values were in the normal range (>20 ms)
similar to most of previous reports [23,24]. The largest group of
SCD patients with myocardial iron overload (MIO) ever described
has been reported by . Of the 201 pediatric and young adult
chronically transfused, six patients (3%) have prospectively
developed cardiac iron with major risk factors severe chelator
noncompliance (less than 50%) and total body iron overload
(Range 22.4-53.5 mg/g dry weight). Five among these six patients
had mild/moderate reduction of T2* (between 14.7 and 20ms),
while only one had marked reduction (7.8 ms).
These findings indicate that besides total iron, other factors
control iron trafficking in these organs, and iron loading and
unloading occurs at different rates in different tissues . In
contrast, thalassemia major (TM) patients have more frequently
extrahepatic iron overload especially cardiac iron overload or
Serum markers, such as serum iron, transferrin, and ferritin,
provide the simplest and least expensive method to assess body
iron stores and despite of limited correlation with quantitative
LIC. They remain the primary means of diagnosis and are often
used to initiate and modify chelation therapy . Serum ferritin
level has been shown to correlate with LIC in Thalassemia Major
(TM), but the correlation in SCD is less clear . Ferritin levels
are increased, not only by iron overload, but are also significantly
increased by interleukin 6 in responses to inflammation. In our
series, a significant moderate correlation between serum ferritin
and LIC was noted. Besides assessment of this correlation, we
have focused on the reliability of serum ferritin to predict a
significant increase of LIC (>7mg Fe/g dw). Serum ferritin level
was categorized according to the results of stroke prevention
trials STOP and STOP 2 : low (<1500 ng/ml), intermediate
(1500-3000 ng/ml) and increased (>3000 ng/ml). A low serum
ferritin level indicated a low LIC (<7 mg Fe/g dw) in 7/8 (88%).
An intermediate increase (1500-3000 ng/ml) and an increased
level (>3000 ng/ml) of serum ferritin indicated a significantly
increased LIC (>7 mg Fe/g dw) in receptively 7/10 (70%) and in
5/7 (71%) of patients. Our results do not indicate clear difference
in the predictive value for significant LIC between the intermediate
and high serum ferritin levels. This is in opposite of the STOP/
STOP2 results, where a gradual increase of the serum transferring
the predictive value for significant increase of LIC has been noted:
63%, 78% and 88% for serum ferritin levels, respectively, 1500-
2250 ng/ml, 2250-3000 ng/ml, and >3000 ng/ml. This difference
is likely related to the smaller size of our series, in comparison
to the STOP/STOP2 trials where the predictive value of serum
ferritin level was based on 164 observations (77 patients).
In our series, the serum ferritin level was not correlated with
cardiac T2*, similarly to previous series [24,27]. In the series of
Aubart , all 5 measurements of moderate or severe cardiac
iron overload concerned patients with TM with ferritin levels
systematically below 1500 mg/L, arguing for systematic MRI
imaging, particularly in patients with TM. Besides spot serum
ferritin level, the value of serum ferritin trend for MRI tissue
T2* trend (liver and cardiac) has been investigated by Aubart
. For the liver, similar, opposite and inconclusive (one trend
is stable whereas the other shows either increase or decrease)
trends were seen in, respectively, 13, 3 and 11 SCD patients. For
the myocardium, similar, opposite and inconclusive trends were
observed in, respectively, 2, 5 and 6 patients. This was in contrast
to thalassemia major patients in whom conflicting trends were
never evidenced: 6 similar and 4 inconclusive for the liver, 3
similar and 3 inconclusive for the heart.
Our series shows that correlation between Liver Iron Content
and serum Ferritin level is only moderate; Liver T2* scan should
be considered to adjust chelation especially in patients with
intermediate serum Ferritin Level. On the other hand, cardiac
T2* was not significantly correlated with hemoglobin, ferritin and