Ricchi_EU Haematology 03/03/2010 12:41 Page 22
Haemoglobinopathies
the series of events leading to atherogenesis-related vascular Traditionally, most clinical features and complications of
modifications.
30–32
Modified LDL is internalised in monocyte-derived endocrinopathies have been essentially linked to iron overload, which
macrophages through cell surface scavenger receptors, an event that disrupts hormonal secretion, resulting in hypoparathyroidism,
leads to foam cell arrangement. Infiltration and deposition of these hypogonadism and hypothyroidism.
43
In thalassaemia major patients,
cells in the arterial wall are considered the initiating steps in the the main risk factors associated with endocrine complications were
development of atherosclerotic plaque. recently found to be high serum ferritin levels, poor compliance with
desferioxamine (DFO) therapy, early onset of transfusion therapy (only
In β-thalassaemia, qualitative modification of LDL status has also been for hypogonadism) and splenectomy (only for hypothyroidism).
44
observed; in fact, alteration of iron homeostasis, interactions between
damaged erythrocytes and LDL,
33,34
depletion of antioxidant defences
19,20
Furthermore, in a study evaluating cortisol and adrenocorticotropic
and a reduction in the size of HDL particles
35
might endorse oxidative hormone response to surgical stress (splenectomy) in thalassaemia
damage to circulating LDL. major patients, a decreased adrenal reserve with increased pre-
operative adrenocorticotrophic hormone (ACTH) concentrations was
On the other hand, large increases in iron concentration are seen in found in thalassaemic patients.
45
human atherosclerotic lesions in comparison with levels in healthy
arterial tissue.
36
A further complicating element is that hepcidin, a However, cholesterol is the main precursor to steroid biosynthesis in
peptide involved in iron homeostasis and that endorses retention of adrenal and sexual glands, and experimental studies suggest that HDL
iron within the plaque,
37–39
in patients with severe thalassaemia has a is the favourite resource in the adrenal gland for steroid biosynthesis.
46
strong inverse relationship with both erythropoietin and soluble There are no studies investigating whether such low cholesterol
transferrin receptor, markers of erythropoietic activity.
25
Thus, as and HDL levels might contribute to adrenal and sexual insufficiency,
hepcidin is elevated in thalassaemia major patients as a consequence particularly in thalassaemia intermedia patients.
47
of the transfusional regimen, it could be responsible for a particularly
increased atherogenic process in this population. Hypocholesterolaemia, independently of its putative role in
determining adrenal insufficiency, may also contribute to further
Accordingly, in a report from a Turkish group increased abdominal amplify susceptibility to infection in thalassaemic patients. Reduced
aortic stiffness was found in young patients with thalassaemia major levels of cholesterol may per se limit immune function: lipids, in
that correlated with body iron stores.
40
particular HDL, have been found to bind and neutralise
lipopolysaccharides (LPS) and endotoxins.
48–50
Thus, in thalassaemia patients the atherogenic process could be
enhanced in part by the increased iron stores and the induced oxidative In the non-thalassaemic population there is an increasing body of
status, and in part counterbalanced by the reduced level of cholesterol; evidence that hypocholesterolaemia is associated with nosocomial
however, the final balance probably promotes increased arterial disease. infections and that hypocholesterolaemia is a risk factor for
mortality in hospitalised patients.
51–57
It is therefore possible that
Furthermore, macrophage accumulation of iron induced by hepcidin hypocholesterolaemia could be in part responsible for the
could be responsible for the differences seen between patients with unfavourable outcome of severe infection and sepsis in
thalassaemia intermedia and those with thalassaemia major, in the thalassaemia patients. Randomised clinical studies evaluating the
sense that patients with thalassaemia major, as a consequence of impact of administration of lipoprotein to septic thalassaemic
the increased levels of hepcidin, could have a greater propensity to patients are mandatory.
develop cardiovascular atherosclerosis.
Finally, coagulation abnormalities are often described in β-
Due to the improving survival of thalassaemic patients, more studies thalassemia. In particular, a thrombophilic status characterised by
are needed to evaluate precisely the prevalence of atherosclerotic elevated levels of endothelial adhesion protein (intercellular cell
disease in adult patients with thalassaemia intermedia and major. To adhesion molecule-1 [ICAM-1], endothelial leukocyte adhesion
this end, magnetic-resonance-based T
2
* measurement has recently molecule-1 [ELAM-1], vascular cell adhesion molecule 1 [VCAM-1],
been demonstrated to be a good tool to evaluate and quantify not von Willebrand factor and thrombomodulin) has been well
only heart and liver iron accumulation but also iron deposition in documented, suggesting that endothelial activation may be involved
atherosclerotic plaque.
41
in vascular occlusion.
58
On the other hand, in the non-thalassaemic
population there is evidence that HDL can also control the fibrinolytic
In conclusion, patients with severe thalassaemia, notwithstanding pathway and platelet function directly; in fact, HDL may affect
their low levels of cholesterol with respect to age- and sex-matched platelet function through interfacing with the glycoprotein IIb–IIIa
controls
3–10
owing to the described pathogenetic mechanism, should complex, thus competing with the binding of fibrinogen to platelets
be particularly prone to developing atherosclerotic plaque and its and resulting in inhibition of platelet aggregation.
59
No study has yet
clinical consequences. evaluated whether hypocholesterolaemia further supports the well
recognised procoagulant status of thalassaemic patients.
The potential role of hypocholesterolaemia in the pathogenesis of
some clinical aspects of thalassaemia have been rarely discussed. Conclusion
These include alterations in endocrine function, increased Hypocholesterolaemia in the absence of a cholesterol metabolism
susceptibility to infections and vascular complications such as genetic disorder
60
is a constant clinical feature of patients with severe
thrombophilia, which affect thalassaemia major and intermedia thalassaemia. The pathophysiology of hypocholesterolaemia in severe
patients in a different manner.
42
forms of thalassaemia should be clarified by studies investigating
22
EUROPEAN HAEMATOLOGY
Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80  |  Page 81  |  Page 82  |  Page 83  |  Page 84  |  Page 85  |  Page 86  |  Page 87  |  Page 88  |  Page 89  |  Page 90  |  Page 91  |  Page 92  |  Page 93  |  Page 94  |  Page 95  |  Page 96  |  Page 97  |  Page 98  |  Page 99  |  Page 100