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Paolo Ricchi,1Massimiliano Ammirabile2and Aurelio Maggio3
1. Assistant, Department of Oncohaematology, Microcythaemia Centre ‘A Mastrobuoni’, Antonio Cardarelli Hospital; 2. Fellow, Department of Oncohaematology,
Microcythaemia Centre ‘A Mastrobuoni’, Antonio Cardarelli Hospital; 2. Director, Division of Haematology II, Villa Sofia-Cervello Hospital
Free cholesterol is a constituent of cell membranes. Apart from
nucleus-free erythrocytes, all cells of the human body are able to
synthesise cholesterol de novo. More than 100 enzymatic processes
are involved in the complete biosynthesis of cholesterol, which is a
complex and energy-consuming process.
For this reason, several tissues prefer to assume cholesterol from
plasma lipoproteins rather than from their own intracellular synthesis.
Cholesterol devoted to plasma lipoprotein is synthesised in the liver
and in the distal part of the small intestine.1Chylomicron remnants
are the vehicle of cholesterol intake from the diet to the liver. The
hepatic cholesterol pools originating from chylomicron remnants and
de novo synthesised cholesterol are combined and excreted as very-
low-density lipoprotein (VLDL). Low-density lipoprotein (LDL), the
ultimate catabolic product of VLDL, is the main source of cholesterol
for human tissue, especially those with high cell turnover.2
Total cholesterol (TC) consists largely of the cholesterol in LDL particles
(LDL cholesterol) plus the cholesterol in high-density lipoprotein
particles (HDL cholesterol).
Cholesterol is not only a fundamental element of cell membranes
but also the principal precursor for steroid and sexual hormone
biosynthesis. Furthermore, cholesterol, through its intermediary
products such as farnesyl diphosphate and geranylgeranyl
diphosphate, is involved in the regulation of ras-protein intracellular
signal transduction.1
Hypercholesterolaemia in Thalassaemia
A large body of evidence from prospective and retrospective studies has
clearly shown that patients affected by thalassaemia have reduced
levels of TC with respect to healthy age- and sex-matched controls.3–10
Hypocholesterolaemia has been reported in all phenotypes of
β-thalassaemia and has also been described in various
haematological disorders associated with high erythropoietic
activity.11–14 Table 1 shows cholesterol levels found in different reports
exploring lipid profiles in young and adult patients affected by
all phenotypes of thalassaemia.
The majority of these studies have evaluated cholesterol level in
young patients with severe thalassaemia (thalassaemia major and
intermedia). As shown in Table 1, low levels of plasma cholesterol
are evident among all ages of patients with thalassaemia major
and intermedia.
Almost all studies agree with the observation that of all the forms
of thalassemia, thalassaemia intermedia patients show the most
marked alterations in lipid profile. Conversely, no studies have
identified a cholesterol cut-off value that could clearly distinguish
patients with thalassaemia intermedia from those affected by
thalassaemia major.
Furthermore, hypocholesterolaemia is only one aspect in the more
complex alteration of lipid profile involving LDL and HDL level
observed in all thalassemia patients. In fact, most of the above-
mentioned studies reported that thalassaemia patients also have
lower HDL and LDL levels than those observed in control patients.
Many of these studies have also tried to identify within-patient
factors correlating with cholesterol level;4,8,9 data analysis of most
reported studies failed to show any influence on cholesterol level of
age, sex, liver injury, haemoglobin, ferritin levels and the presence or
absence of the spleen. However, in the study by Ricchi et al.,8a lack
of effect of single genotypes on cholesterol levels in thalassaemia
major and intermedia patients was also reported.
Abstract
In this review, the role of hypocholesterolaemia as a potential source of several clinical features of patients affected by thalassaemia is
assessed. The primary focus is on the extent of the phenomenon among different forms of thalassaemia in order to highlight the particularly
reduced level in patients with thalassaemia intermedia. In addition, we explore how the reduced levels of cholesterol could influence the
atherogenic process and many typical clinical features of patients affected by thalassaemia.
Keywords
Hypocholesterolaemia, thalassaemia, atherogenesis, endocrinopathy
Disclosure:
The authors have no conflicts of interest to declare.
Received:
29 October 2009
Accepted:
22 February 2010
Citation:
European Haematology, 2010;4:20–23
Correspondence:
Paolo Ricchi, UOC Microcitemia, Azienda Ospedaliera di Rilievo Nazionale ‘A Cardarelli’, Via A Cardarelli 9, 80131 Naples, Italy.
E: paolo.ricchi@ospedalecardarelli.it
20 ©TOUCH BRIEFINGS 2010
Hypocholesterolaemia in Thalassaemia –
Pathogenesis, Implications and Clinical Effects
Haemoglobinopathies
Ricchi_EU Haematology 03/03/2010 12:40 Page 20
Hypocholesterolaemia in Thalassaemia – Pathogenesis, Implications and Clinical Effects
EUROPEAN HAEMATOLOGY
21
Pathogenesis
The pathogenetic mechanism for hypocholesterolaemia was
investigated in a interesting study conducted using a model of artificial
microemulsion termed LDE (a cholesterol-rich microemulsion), whose
composition resembled that of LDL.
It was demonstrated that LDL clearance, the mechanism that
removes LDL from the circulation, was enhanced in heterozygous
β-thalassaemia patients.15
However, despite the fact that hypocholesterolaemia in thalassaemia
was first described many years ago, there is no definitive explanation
for the mechanism underlying this clinical condition in severe
forms of thalassaemia. Two main pathogenetic mechanisms have
been proposed: the presence of enhanced cholesterol consumption
required for cell membrane formation,16–18 and the presence of a
hyperplastic and overactive reticuloendothelial system, which may
be responsible for an increased uptake of LDL.19,20
The first ‘mechanism’ seems to be the more complete and would also
explain the difference always reported in cholesterol level among
patients with thalassaemia intermedia and major. In fact, in the
studies by Ricchi8and by Hartman9it was clearly demonstrated
that patients with thalassaemia intermedia have both lower
cholesterol and lower haemoglobin (Hb) levels than patients with
thalassaemia major. In both studies, patients were accurately selected
by eliminating biases (severe liver disorders, hyperthyroidism,
fat malabsorption and other factors that could per se modify
cholesterol levels).
In the study by Ricchi et al.,8it was clearly indicated that pre-
transfusional Hb level was considered, which represents the lowest
peak of Hb for chronically transfused patients who usually remain at
higher values until their next transfusion.
According to current guidelines, patients with thalassaemia major
have pre-transfusional Hb ranging from 9.5 to 10g/dl, with the aim
being to reduce erythroid marrow activity.21 These data may strongly
support the hypothesis that the consistently high Hb levels in
chronically transfused patients (with thalassaemia major) may mean
that this group of patients can sustain a more complete degree of
marrow suppression with respect to that present in thalassaemia
intermedia patients.
Therefore, in patients with thalassaemia intermedia, a particularly
accelerated erythropoiesis and enhanced cholesterol consumption
for red cell membrane formation could be responsible for the lower
levels of cholesterolaemia. In support of this hypothesis, several
clinical and biochemical observations indicate a marked erythropoietic
marrow expansion in patients with thalassaemia intermedia.22,23
In fact, such patients, in the absence of surgery, pregnancy or
concomitant illnesses, usually do not receive blood transfusions.
Consistent with this situation, levels of circulating soluble transferrin
receptor, the best estimate of total erythropoiesis in the absence
of iron deficiency,24 were found to be lower in patients with
thalassaemia major than in patients with thalassaemia intermedia.25,26
Interestingly, in the study by Ricchi et al.,8patients with severe
forms of thalassaemia intermedia had particularly low levels of
cholesterol.8Finally, in a study evaluating hypocholesterolaemia
among thalassaemia intermedia patients, a significant inverse
correlation was found between cholesterol level and soluble
transferrin receptor.27
Further studies are needed to better elucidate the relationship between
Hb and cholesterol level and other parameters of erythropoietic activity,
such as soluble transferrin receptor, reticulocyte count and
extramedullary erythropoiesis in patients affected by thalassaemia.
Implications and Clinical Effects
Despite the fact that hypocholesterolaemia was first described many
years ago, its impact on the atherogenic process in patients with
severe thalassaemia has been very rarely addressed. While a lower
incidence of atherosclerosis-related disease and hypertension has
been reported in thalassaemia trait carriers,28,29 no study has yet fully
evaluated the prevalence of atherosclerotic disease in patients with
thalassaemia major and intermedia, or assessed whether the reduced
level of cholesterol really protects thalassaemic patients from the
development of atherogenesis.
The most frequent cause of death in patients with thalassaemia major
is heart disease related to myocardial iron overload, which is
responsible for more than half of all deaths as assessed by recent
studies of survival.
Due to the introduction of more effective chelation therapy, the mean life
expectancy of patients with thalassaemia major is increasing, and
cardiac mortality caused by iron accumulation in the heart is decreasing.
On the other hand, in the non-thalassaemic adult population, blood levels
of total cholesterol are widely used to predict ischaemic heart disease,
and treatment with statin, which lowers LDL cholesterol, substantially
reduces the incidence of ischaemic heart disease.
However, in recent years increasing evidence has suggested that not
only LDL level but also oxidative alteration of LDL are the key steps in
Table 1: Plasma Cholesterol Values from
Thalassaemic Patients
TM TI T Minor
Hartman n 47 9
TC (mg/dl) 106±23 74±24
Age (years) 11±4.2 (4–19) 10.3±5.1 (4–20)
Ricchi n 55 30
TC (mg/dl) 110.9±20.7 96.1±18.8
Age (years) 35 (22–40) 32 (20–39)
Livrea n 35
TC (mg/dl) 107.7±19.8*
Age (years) 32±14 (10–60)
Amendola n 23
TC (mg/dl) 117.3±30.3
Age (years) 29±12
Goldfarb n 39 27 23
TC (mg/dl) 118.6±25.2* 104.3±30.2* 150.8±41.1*
Age (years) 23.1±7.6 16±7.3
Faizeh n 30
TC (mg/dl) 119.1±37.7
Age (years) 8.8±4.05 (1.5–16)
*Actual cholesterol values were reported as mmol/l. The following formula was used to
convert data into mg/dl: mmol/l ÷ 0,0258.
n = number of patients; TC = total cholesterol; TM = thalassaenia major; TI = thalassaemia
intermedia; T Minor = thalassaemia minor.
Ricchi_EU Haematology 03/03/2010 12:41 Page 21
the series of events leading to atherogenesis-related vascular
modifications.30–32 Modified LDL is internalised in monocyte-derived
macrophages through cell surface scavenger receptors, an event that
leads to foam cell arrangement. Infiltration and deposition of these
cells in the arterial wall are considered the initiating steps in the
development of atherosclerotic plaque.
In β-thalassaemia, qualitative modification of LDL status has also been
observed; in fact, alteration of iron homeostasis, interactions between
damaged erythrocytes and LDL,33,34 depletion of antioxidant defences19,20
and a reduction in the size of HDL particles35 might endorse oxidative
damage to circulating LDL.
On the other hand, large increases in iron concentration are seen in
human atherosclerotic lesions in comparison with levels in healthy
arterial tissue.36 A further complicating element is that hepcidin, a
peptide involved in iron homeostasis and that endorses retention of
iron within the plaque,37–39 in patients with severe thalassaemia has a
strong inverse relationship with both erythropoietin and soluble
transferrin receptor, markers of erythropoietic activity.25 Thus, as
hepcidin is elevated in thalassaemia major patients as a consequence
of the transfusional regimen, it could be responsible for a particularly
increased atherogenic process in this population.
Accordingly, in a report from a Turkish group increased abdominal
aortic stiffness was found in young patients with thalassaemia major
that correlated with body iron stores.40
Thus, in thalassaemia patients the atherogenic process could be
enhanced in part by the increased iron stores and the induced oxidative
status, and in part counterbalanced by the reduced level of cholesterol;
however, the final balance probably promotes increased arterial disease.
Furthermore, macrophage accumulation of iron induced by hepcidin
could be responsible for the differences seen between patients with
thalassaemia intermedia and those with thalassaemia major, in the
sense that patients with thalassaemia major, as a consequence of
the increased levels of hepcidin, could have a greater propensity to
develop cardiovascular atherosclerosis.
Due to the improving survival of thalassaemic patients, more studies
are needed to evaluate precisely the prevalence of atherosclerotic
disease in adult patients with thalassaemia intermedia and major. To
this end, magnetic-resonance-based T2* measurement has recently
been demonstrated to be a good tool to evaluate and quantify not
only heart and liver iron accumulation but also iron deposition in
atherosclerotic plaque.41
In conclusion, patients with severe thalassaemia, notwithstanding
their low levels of cholesterol with respect to age- and sex-matched
controls3–10 owing to the described pathogenetic mechanism, should
be particularly prone to developing atherosclerotic plaque and its
clinical consequences.
The potential role of hypocholesterolaemia in the pathogenesis of
some clinical aspects of thalassaemia have been rarely discussed.
These include alterations in endocrine function, increased
susceptibility to infections and vascular complications such as
thrombophilia, which affect thalassaemia major and intermedia
patients in a different manner.42
Traditionally, most clinical features and complications of
endocrinopathies have been essentially linked to iron overload, which
disrupts hormonal secretion, resulting in hypoparathyroidism,
hypogonadism and hypothyroidism.43 In thalassaemia major patients,
the main risk factors associated with endocrine complications were
recently found to be high serum ferritin levels, poor compliance with
desferioxamine (DFO) therapy, early onset of transfusion therapy (only
for hypogonadism) and splenectomy (only for hypothyroidism).44
Furthermore, in a study evaluating cortisol and adrenocorticotropic
hormone response to surgical stress (splenectomy) in thalassaemia
major patients, a decreased adrenal reserve with increased pre-
operative adrenocorticotrophic hormone (ACTH) concentrations was
found in thalassaemic patients.45
However, cholesterol is the main precursor to steroid biosynthesis in
adrenal and sexual glands, and experimental studies suggest that HDL
is the favourite resource in the adrenal gland for steroid biosynthesis.46
There are no studies investigating whether such low cholesterol
and HDL levels might contribute to adrenal and sexual insufficiency,
particularly in thalassaemia intermedia patients.47
Hypocholesterolaemia, independently of its putative role in
determining adrenal insufficiency, may also contribute to further
amplify susceptibility to infection in thalassaemic patients. Reduced
levels of cholesterol may per se limit immune function: lipids, in
particular HDL, have been found to bind and neutralise
lipopolysaccharides (LPS) and endotoxins.48–50
In the non-thalassaemic population there is an increasing body of
evidence that hypocholesterolaemia is associated with nosocomial
infections and that hypocholesterolaemia is a risk factor for
mortality in hospitalised patients.51–57 It is therefore possible that
hypocholesterolaemia could be in part responsible for the
unfavourable outcome of severe infection and sepsis in
thalassaemia patients. Randomised clinical studies evaluating the
impact of administration of lipoprotein to septic thalassaemic
patients are mandatory.
Finally, coagulation abnormalities are often described in β-
thalassemia. In particular, a thrombophilic status characterised by
elevated levels of endothelial adhesion protein (intercellular cell
adhesion molecule-1 [ICAM-1], endothelial leukocyte adhesion
molecule-1 [ELAM-1], vascular cell adhesion molecule 1 [VCAM-1],
von Willebrand factor and thrombomodulin) has been well
documented, suggesting that endothelial activation may be involved
in vascular occlusion.58 On the other hand, in the non-thalassaemic
population there is evidence that HDL can also control the fibrinolytic
pathway and platelet function directly; in fact, HDL may affect
platelet function through interfacing with the glycoprotein IIb–IIIa
complex, thus competing with the binding of fibrinogen to platelets
and resulting in inhibition of platelet aggregation.59 No study has yet
evaluated whether hypocholesterolaemia further supports the well
recognised procoagulant status of thalassaemic patients.
Conclusion
Hypocholesterolaemia in the absence of a cholesterol metabolism
genetic disorder60 is a constant clinical feature of patients with severe
thalassaemia. The pathophysiology of hypocholesterolaemia in severe
forms of thalassaemia should be clarified by studies investigating
Haemoglobinopathies
EUROPEAN HAEMATOLOGY
22
Ricchi_EU Haematology 03/03/2010 12:41 Page 22
cholesterol metabolism and balance. However, being presumably
related to erythropoietic cell division, hypocholesterolaemia is most
prevalent in patients with thalassaemia intermedia, where it may be a
marker of disease severity but does not correlate with age, sex, liver
injury, Hb level and iron overload in thalassaemic patients. Such
reduced levels of cholesterol cannot protect thalassaemic patients
from the development of atherosclerotic disease because of the well-
recognised role of iron accumulation in the pathogenesis of the
atherogenic process; in this context, iron chelation could be an useful
tool to modify their risk of atherosclerosis.
Conversely, such low levels of cholesterol in thalassaemic patients
seem to reflect the inability of the organism to balance the increased
cholesterol requirement for red cell membrane formation; thus, it is
conceivable that the availability of cholesterol, ordinarily used in
steroid hormone synthesis to control infection and to control
hypercoagulability, could be at least in part reduced.
Additional studies are required to establish whether hypocholesterolaemia
promotes complications of thalassaemia and whether cholesterol
supplementation can be recommended for the management of
thalassaemia intermedia. n
Hypocholesterolaemia in Thalassaemia – Pathogenesis, Implications and Clinical Effects
EUROPEAN HAEMATOLOGY
23
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Paolo Ricchi is an Assistant in the Department
of Oncohaematology in the Microcythaemia Centre
‘A Mastrobuoni’, Antonio Cardarelli Hospital in
Naples. His research interests include antineoplastic
combined chemotherapy protocols, combined
modality therapy, chemoprevention, thalassaemia
and haemoglobinopathies.
Aurelio Maggio is Director of the Division of Haematology
II at Villa Sofia-Cervello Hospital in Palermo. He has
extensive experience in biomedical research involving
areas of medical genetics, haematology and gene therapy.
Dr Maggio is a Professor at the Haematology Post-
graduate School of the University of Palermo and is
actively invloved with professional thalassemia and
haemoglobinopathy. organisations.
Massimiliano Ammirabile is a Fellow in the Department
of Oncohaematology in the Microcythaemia Centre ‘A
Mastrobuoni’, Antonio Cardarelli Hospital in Naples. His
main research fields include haemochromatosis,
thalassaemia and haemoglobinopathies,
erythrocytosis, cholesterolaemia in thalassaemic
patients, haemostasis and thrombosis and genetic
and biomolecular resources.
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