Case Report
Acta Haematol 2006;115:106–108
DOI: 10.1159/000089475
Development of Thalassaemic Iron Overload
Cardiomyopathy despite Low Liver Iron Levels
and Meticulous Compliance to Desferrioxamine
Lisa J. Andersona Mark A. Westwooda Emma Prescottb J. Malcolm Walkerc
Dudley J. Pennella Beatrix Wonkeb
a
Cardiovascular MR Unit, Royal Brompton Hospital, b Whittington Hospital and c University College Hospital,
London, UK
Key Words
-Thalassaemia  Chelation  Iron overload
Abstract
It is believed that myocardial iron deposition and the re-
sultant cardiomyopathy only occur in the presence of se-
vere liver iron overload. Using cardiovascular magnetic
resonance, it is now possible to assess myocardial and
liver iron levels as well as cardiac function in the same
scan, allowing this supposition to be examined. We de-
scribe a patient with progressive myocardial iron deposi-
tion and the development of early iron overload cardio-
myopathy despite excellent compliance to standard
subcutaneous desferrioxamine, minimal liver iron and
well-controlled serum ferritin levels. These indirect mark-
ers remained far below the thresholds conventionally be-
lieved to be associated with increased cardiac risk.
Copyright © 2006 S. Karger AG, Basel
Heart failure secondary to myocardial iron overload
remains the commonest cause of death in thalassaemia
major [1]. Conventional teaching dictates that iron-in-
duced cardiomyopathy only occurs in the presence of se-
vere liver iron overload, and as a late phenomenon. It has
been suggested that myocardial iron overload is unlikely
to occur in patients with liver iron levels below 15 mg/g
© 2006 S. Karger AG, Basel
0001–5792/06/1152–0106$23.50/0
Fax +41 61 306 12 34
E-Mail karger@karger.ch Accessible online at:
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Received: March 24, 2005
Accepted after revision: May 10, 2005
(dry weight) [2], or in patients who comply well with iron
chelation therapy and consistently maintain their serum
ferritin levels below 2,500 g/l [3]. As a result, these in-
direct markers have been, and in some centres are still,
used to guide iron chelation therapy in thalassaemic pa-
tients. With the emergence of advanced cardiovascular
magnetic resonance (CMR) techniques, it is now possible
to assess myocardial and liver iron levels along with car-
diac function in the same scan [4], and this leads us to
question conventional teaching on the mechanism of car-
diac iron deposition.
Case Report and Methods
A young male patient with homozygous -thalassaemia was
born of Iraqi parents and moved with his parents to the UK aged
6. The diagnosis of thalassaemia major had been made at the age
of 6 months and regular blood transfusions were started at that
time. Iron chelation therapy in the form of 12-hour overnight infu-
sions of subcutaneous desferrioxamine was commenced at 6 years,
and the patient underwent splenectomy at 8 years. From 6 years of
age, compliance to iron chelation therapy has been assessed as ex-
cellent. Desferrioxamine was administered over 12 h on 5 nights
per week (2 g per day from age 14 years; 36 mg/kg/day) and the
patient received intravenous desferrioxamine at the time of trans-
fusions (2 units every 4 weeks to maintain a pretransfusion haemo-
globin concentration between 9 and 9.5 g/dl). From age 9 onwards,
no serum ferritin levels over 1,600 g/l had been recorded. Other
relevant medical history includes hypogonadotrophic hypogonad-
ism and documented osteoporosis.
Prof. D.J. Pennell
Cardiovascular Magnetic Resonance Unit, Royal Brompton Hospital
Sydney Street
London SW3 6NP (UK)
Tel. +44 207 351 8810, Fax +44 207 351 8816, E-Mail d.pennell@ic.ac.uk
 Table 1. CMR scan results and serum ferritin levels

Normal CMR scan

ranges
1 2 3 4 5

Age, years 15.8 16.4 16.8 17.4 18.6

Serum ferritin, g/l >15–300 1,460 1,353 1,260 1,044 1,576
Myocardial T2a, ms >20 16 14.2 12 12 9.7
Liver iron, mg/g liver dry weight <1.35 1.6 1.8 1.7 0.7 2.5
Left ventricular measurements
End-diastolic volume, ml/m2 >96–138a 135 129 163 177 206
End-systolic volume, ml/m2 >13–33a 34 35 51 68 73
Ejection fraction, % >56–78 75 73 69 62 65
a
Normalized for body surface area.

Regular cardiovascular appraisal with exercise testing and echo-

cardiography was normal between the ages of 12 and 15. The pa-
tient was 15 at the time of his first CMR scan and in addition to
regular clinical review and serum ferritin readings, a total of 5
CMR scans were performed over 3 years. The patient complied
well with subcutaneous desferrioxamine therapy throughout this
time. Each CMR scan included the assessment of liver and heart
iron using T2* as previously described [4], and the measurement of
ventricular volumes, mass and ejection fraction with standard tech-
niques [5, 6]. T2* is a magnetic resonance parameter which is in-
versely related to tissue iron concentration and the technique has a
high degree of reproducibility both in the liver (coefficient of varia-
tion 3.3%) and in the heart (coefficient of variation 5.0%). As liver
T2* has been calibrated against liver biopsy iron concentration, liv-
er T2* measurements were converted into milligrams per gram liv-
er dry weight. Myocardial T2* values measured in healthy volun-
teers are normally distributed with a lower 95% confidence level of
20 ms [4]. Myocardial T2* levels of 20 ms or less therefore denote
excess myocardial iron deposition, and levels below 10 ms are con-
sidered to represent severe myocardial iron deposition. There is no
calibration of T2* for myocardial iron concentration and therefore
absolute myocardial iron values are not quoted.
Fig. 1. The primary vertical axis denotes myocardial T2* (ms) and
liver iron (mg/g liver dry weight), and the secondary vertical axis
denotes left ventricular ejection fraction (LVEF) percentage. There
Results is a progressive fall in ejection fraction associated with increasing
myocardial iron deposition (falling myocardial T2*) over time. Liv-
er iron remains well below the level of 15 mg/g dry weight believed
At the time of the first scan, the patient was found to to be associated with iron-induced cardiomyopathy (dashed line).
have mild myocardial iron loading with left ventricular
function and left ventricular volumes within the normal
range. Liver iron deposition was also minimal. As shown
in table 1 and figure 1, a progressive increase in myocar- ular dimensions were significantly dilated in both systole
dial iron was documented over time which was associ- and diastole, and left ventricular mass was raised. During
ated with a progressive increase in left ventricular end the entire review period, liver iron deposition was mini-
systolic and end diastolic volumes and left ventricular mal and serum ferritin remained stable, as would be ex-
mass, and a progressive fall in left ventricular ejection pected from the excellent compliance to desferrioxamine
fraction. By the time of the most recent scan left ventric- therapy.

Development of Cardiac Iron Overload Acta Haematol 2006;115:106–108 107

despite Low Liver Iron Level
 An intravenous port has been inserted for the admin-
istration of continuous intravenous desferrioxamine and
the patient remains under close cardiological and clinical
review.
Discussion
In transfusional iron overload, cardiac iron deposition
is believed to occur late, and only in the presence of severe
spleen and liver iron overload [7, 8]. On the basis of this
supposition, liver iron has been considered the gold stan-
dard indicator for body iron stores [9] and as serum fer-
ritin correlates with liver iron in normal individuals [10,
11], it is widely used as an indirect marker for tissue iron
levels in thalassaemia. CMR facilitates the simultaneous
assessment of heart and liver iron levels, and employing
this technique it has already been demonstrated that the
correlations between myocardial iron and liver iron or
serum ferritin are poor [4], and that iron clears at differ-
ing rates from the liver and the heart [12]. Frequent CMR
in this patient revealed progressive myocardial iron de-
position and the development of early iron overload car-
diomyopathy in the presence of minimal liver iron and
well-controlled serum ferritin levels. These indirect mark-
ers were well below the conventionally accepted levels of
liver iron (115 mg/g dry weight) or serum ferritin (consis-
tently 12,500 g/l) believed to be associated with in-
creased cardiac risk.
The mechanisms by which iron chelators modify the
distribution of body iron are not yet fully established and
require further investigation and research. Identical treat-
ment regimes appear to be successful in some patients but
fail in others and the explanations for this are required to
improve our understanding and to facilitate improved
therapy for individual patients. This case demonstrates
that even excellent compliance to standard subcutaneous
desferrioxamine treatment with favourable liver iron and
serum ferritin levels does not guarantee the prevention of
iron overload cardiomyopathy in thalassaemia major.
The case also emphasizes the importance of individual
patient assessment in thalassaemia major and the direct
assessment of myocardial iron in order to reduce the ex-
cessive and preventable cardiac mortality.

References

1 Borgna-Pignatti C, Rugolotto S, De Stefano P,
Piga A, Di Gregorio F, Gamberini MR, Sabato
V, Melevendi C, Cappellini MD, Verlato G:
Survival and disease complications in thalas-
semia major. Ann NY Acad Sci 1998;850:227–
231.
2 Brittenham GM, Griffith PM, Nienhuis AW,
McLaren CE, Young NS, Tucker EE, Allen CJ,
Farell DE, Harris JW: Efficacy of desferriox-
amine in preventing complication of iron over-
load in patients with thalassaemia major. N
Engl J Med 1994;331:567.
3 Olivieri NF, Nathan DG, MacMillan JH,
Wayne AS, Liu PP, McGee A, Martin M, Ko-
ren G, Cohen AR: Survival in medically treat-
ed patients with homozygous beta-thalassae-
mia. N Engl J Med 1994;331:574–578.
4 Anderson LJ, Holden S, Davis B, Prescott E,
Charrier CC, Bunce NH, Firmin DN, Wonke
B, Porter J, Walker JM, Pennell DJ: Cardio-
vascular T2* magnetic resonance for the early
diagnosis of myocardial iron overload. Eur
Heart J 2001;22:2171–2179.
5 Bellenger NG, Burgess M, Ray SG, Coats A,
Lahiri A, Cleland JGF, Pennell DJ: Compari-
son of left ventricular ejection fraction and vol-
umes in heart failure by two-dimensional echo-
cardiography, radionuclide ventriculography
and cardiovascular magnetic resonance: are
they interchangeable? Eur Heart J 2000; 21:
1387–1396.
6 Grothues F, Smith GC, Moon JCC, Bellenger
NG, Collins P, Klein HU, Pennell DJ: Com-
parison of interstudy reproducibility of cardio-
vascular magnetic resonance with two-dimen-
sional echocardiography in normal subjects
and in patients with heart failure or left ven-
tricular hypertrophy. Am J Cardiol 2002; 90:
29–34.
7 Buja LM, Roberts WL: Iron in the heart. Etiol-
ogy and clinical significance. Am J Med 1971;
51:209–221.
8 Johnston DL, Rice L, Vick GW, Hedrick TO,
Rokey R: Assessment of tissue iron overload
by nuclear magnetic resonance imaging. Am J
Med 1989;87:40–47.
9 Pippard MJ: Measurement of iron status. Prog
Clin Biol Res 1989;309:85.
10 Addison GM, Beamish M, Hales CN, Hodg-
kins M, Jacobs A, Llewellyn P: An immunora-
diometric assay for ferritin in the serum of nor-
mal subjects and patients with iron deficiency
and iron overload. J Clin Pathol 1972;25:326–
329.
11 Cazzola M, Borgna-Pignatti C, deStefano P,
Bergamaschi G, Bongo IG, Dezza L, Arato F:
Internal distribution of excess iron and sources
of serum ferritin in patients with thalassaemia.
Scand J Haematol 1983;30:289–296.
12 Anderson LJ, Westwood MA, Holden S, Davis
B, Prescott E, Wonke B, Porter JB, Malcolm
Walker J, Pennell DJ: Myocardial iron clear-
ance during reversal of siderotic cardiomyopa-
thy with intravenous desferrioxamine: a pro-
spective study using T2* cardiovascular
magnetic resonance. Br J Haematol 2004;127:
348–355.

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