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Successful management of cardiogenic shock in beta
thalassemia major by iron chelator
Righab Hamdan M.D. MSc. April, 2016
Introduction:
Heart failure mediated by cardiac iron overload has accounted for considerable early
mortality in β-thalassemia major [1]. Although early cardiomyopathy from iron overload
is becoming less common in Thalassemia Major(TM) patients, the terminal event for
older patients is often iron mediated cardiac disease. There is a lack of controlled data
regarding the management of cardiomyopathy mainly comparing different chelation
regimens in the management of heart failure beside the indication for heart
transplantation or left ventricular assist device (LVAD) for advanced heart failure. We
report the case of severe end stage heart failure in a 34 years old TM patient presenting
with cardiogenic shock and successfully managed medically.
Case report:
We report the case of a 34 years old female patient, weighing 85 kilograms for a height of
160 cm. She is known to have thalassemia major since childhood with regular recurrent
blood transfusions. She was on oral iron chelators at an appropriate dose adjusted to body
weight (Deferiprone: 500mg, 4 tablets, three times daily). She was referred to our center
for management of new onset heart failure. We note in her medical history, splenectomy
at the age of 5, a well-treated secondary hypothyroidism as well as secondary diabetes.
Cardiac ultrasound was performed regularly and the left ventricular function was normal
up to 3 months prior to her admission to our center. The patient started to complain from
dyspnea at mild exertion with progressive worsening, 2 months prior to her admission. A
new cardiac ultrasound was performed one month later showing a slightly dilated left
ventricle (LV) with moderate to severe LV dysfunction (LVEF30%). She was
hospitalized and started on inotropes one week prior to her transfer to our center; she was
then referred to us for further management and for failure to wean from inotropes.
Upon her admission she was hypotensive (mean arterial pressure: 50 mmHg), in sinus
tachycardia (120/min), with cold extremities and clinical signs of left and right heart
failure: jugular vein distension, lower limbs edema, and pulmonary crackles.
The chest X ray showed pulmonary edema. Blood test showed normal creatinin level,
normal liver function test, very high ferritin level: 24 000µg/l, and an elevated BNP level
(2560 ng/l). Cardiac ultrasound (figure 1) showed a dilated left ventricle with severely
impaired function (LVEF: 20%), right ventricle (RV) was slightly dilated with
moderately to severely impaired function (TAPSE: 10 mm, S: 9 cm/s). Cardiac MRI
showed signs of hemochromatosis: a prolonged T2*: 6.6 ms (figure 2). Cardiac biopsy
confirmed the diagnosis of secondary hemochromatosis by showing significant presence
of intracellular iron granules, positive to special iron staining. Despite high dose of
Dobutamine, the patient hemodynamical status deteriorated and an intra aortic balloon
(IABP) was installed, and enabled better progression. She regained a good diuresis and
was stable on inotropes and IABP but the weaning from these therapeutic options was
difficult. Beside inotropes, intravenous diuretics, and oral iron chelators (Deferiprone),
the patient was started on intravenous high dose of Deferoxamine (60 mg/Kg) since day
Zero of admission. We registered the patient on the high priority transplantation list, and
we discussed left ventricular assist device implantation (LVAD). On day 21 of
Deferoxamine the patient started to improve with progressive weaning from the IABP at
day 18 of support and then from Dobutamin. Ferritin level was decreased to 3 000 ng/l.
Repeated cardiac ultrasound showed improved ejection fraction (35%). The patient was
discharged home on both association Deferiprone plus Deferoxamine via a subcutaneous
pump, beside regular heart failure treatment, although the doses of beta blockers and
ACE inhibitors could not be titrated due to the relatively low blood pressure. On her last
follow up, 6 months post discharge, the patient is doing well, with no recurrent
hospitalizations for heart failure, she is in NYHA I-II. The last cardiac ultra sound at 6
months (figure 3) showed a LVEF of 50%, normal RV function, and no pulmonary
hypertension.
Discussion:
This case is a typical illustration of reversible cardiac involvement in secondary
hemochromatosis, manifested by cardiogenic shock. We disposed from the major
therapeutical options available starting from optimal iron chelation, optimal heart failure
medical treatment, mechanical assistance via intra aortic balloon, till candidacy to heart
transplantation. Interestingly our patient progressively responded well to medical
treatment despite her advanced heart failure and her critical situation. There is very few
data concerning the treatment of cardiogenic shock in secondary hemochromatosis
complicating thalassemia major.
Heart disease remains the predominant cause of death in β-thalassemia major (TM) [1–4]
During the past few decades, an impressive improvement in TM patients’ survival has
been noticed. In the mid-1960s, the best survival was 16 years old. Nowadays the
survival at the age of 35 years is 50% according to the UK thalassemia registry2.
Cardiac complications are still the leading cause of mortality, accounting for 71% of
deaths [5]. After heart failure onset, with intensified blood transfusions and regular iron
chelation in addition to conventional heart failure therapy, the 5-year survival is 48%[5].
TM is a genetic condition with severe reduction or absent production of the β-globin
chain constituent of hemoglobin (Hb) A, resulting in an excess of α-globin chains, and
consequent ineffective erythropoiesis and profound life threatening anemia [6].
Before the introduction of regular blood transfusions, patients developed a form of
high-output heart failure as a consequence of prolonged tissue hypoxia, resulting from
chronic anemia. In the era of systematic transfusion therapy, myocardial iron overload is
traditionally thought to be the main cause of thalassemia cardiomyopathy [5].
In terms of ventricular function, 2 different phenotypes are present [5]: (i) a dilated
cardiomyopathy phenotype, characterized by left ventricular dilatation and reduced
contractility, (ii) a restrictive cardiomyopathy phenotype, characterized by restrictive left
ventricular filling with subsequent pulmonary hypertension, right ventricular dilatation,
and heart failure.
Changes in the heart in addition to ventricular systolic impairment include the following:
(1) Decreased left atrial function[7], (2) Impaired right RV function, caused by the
increased vulnerability of the RV to iron deposition. Tissue Doppler imaging velocity and
strain imaging suggest early RV impairment in iron overload [8]. (3) Impaired
endothelial function in iron overload [9].
Myocardial iron deposition can be reproducibly quantified using myocardial T2* and this
is the most significant variable for predicting the need for ventricular dysfunction
treatment. Myocardial iron content cannot be predicted from serum ferritin or liver iron,
and conventional assessments of cardiac function can only detect those with advanced
disease [10].
Cardiac iron overload is defined by T2* on cardiovascular magnetic resonance
(CMR): 1) severe cardiac iron loading , T2* <10 ms and 2) mild to moderate cardiac iron
loading T2*10 to 20 ms [8].
Recognition of severe cardiac siderosis by T2* CMR and intervention with suitable
treatment, before the onset of symptomatic HF, is associated with improvements
in ventricular function.[11]
Studies suggest that a ferritin level >2500 μg/L indicates a raised risk but there is no
threshold effect, and risk is increased even down to ferritin levels of 1000 μg/L [12].
The first iron chelator approved for clinical use was Deferoxamine (DFO), that needs to
be given parentally, either subcutaneously, or by intravenous infusion [13].
Once severe cardiac iron loading is present, months to years of careful therapy is needed
to clear the iron.
Deferiprone (DFP) is an oral iron chelator that has significant compliance advantages
over Deferoxamine. Deferiprone is commonly used in combination with Deferoxamine
for enhanced iron clearance [13]. The combination of Deferoxamine with the Deferiprone
led to the reduction of myocardial iron load as well as the improvement of both left
ventricular ejection fraction and endothelial function as compared with
Deferoxamine.[14]
A study by Porter et al. clearly shows that DFO intensification with or without DFP is
effective in improving LVEF and myocardial T2* in this severely affected patients. DFO
was allowed up to 24 h/day and up to 60 mg/kg [15].
The acute mortality of New York Heart Association stage IV heart failure in thalassemia
remains high, probably in excess of 50% in hospital mortality, simply because support for
the heart and other failing organs, especially the kidneys and liver, often cannot be
continued long enough for iron chelation to stabilize myocardial function, a process that
may take many months [8]. In critical patients, like our case, immediate commencement
of 24-hour-per-day continuous intravenous iron chelation treatment with Deferoxamine
50 mg.kg−1.d [16] allows higher survival. Deferiprone should be introduced as soon as
possible at a dose of 75 mg.kg−1.d−1 [17]. Stabilization can occur within 14 days after
commencement of continuous iron chelation treatment but can also take months.
Consideration should be given to mechanical support devices to support both ventricles,
bearing in mind the RV is often compromised. There is no published evidence for this
approach [8].
Few reports exist concerning heart transplantation in recipients with end-stage heart
failure caused by iron overload occurring with beta-thalassaemia, or haemochromatosis.
A paper by Koerner et al reported seven transplanted cases for primary and secondary
hemochromatosis [18]. One of these candidates had to be bridged, first with a right
ventricular, then with a biventricular assist device. Five of the seven patients survived,
following transplantation. These results demonstrate the feasibility of transplantation in
patients with such heart failure [18].
Conclusion:
We reported an interesting case of advanced heart failure presenting with cardiogenic
shock in a 34 years old TM patient, responding successfully to adequate medical therapy
and short duration circulatory assistance. Early detection of myocardial iron overload is
crucial to avoid cardiomyopathy progression by intensifying the iron chelation regimen.
References:
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GC, Romeo MA, Forni GL, Gamberini MR, Ghilardi R, Piga A, Cnaan A. Survival and
complications in patients with thalassemia major treated with transfusion and
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Figures:
Figure 1:
The first cardiac ultra sound showed a dilated and severely impaired left ventricle (to the
left), and a moderately to severely impaired RV (to the right), TAPSE: 10 (up), tissue
Doppler velocity at the tricuspid annuls: 9 cm/ s (down).
Figure 2: cardiac magnetic resonance confirmed the diagonosis of cardiac
hemochromatosis, revealed by an extremely short T2* (6.6 ms).
Figure 3: cardiac ultrasound 6 months later, showed a significant improvement of the
LVEF, with residual slight impairment of the LV function at the left of the picture; on the
right, we notice a normal RV, function normal TAPSE: 19 mm(up), normal tissue
Doppler velocity at the tricuspid annuls: 13 cm/s (down).