Ricchi_EU Haematology 03/03/2010 12:41 Page 21
Hypocholesterolaemia in Thalassaemia – Pathogenesis, Implications and Clinical Effects
Pathogenesis Table 1: Plasma Cholesterol Values from
The pathogenetic mechanism for hypocholesterolaemia was
Thalassaemic Patients
investigated in a interesting study conducted using a model of artificial
microemulsion termed LDE (a cholesterol-rich microemulsion), whose
TM TI T Minor
composition resembled that of LDL.
Hartman n 47 9
TC (mg/dl) 106±23 74±24
Age (years) 11±4.2 (4–19) 10.3±5.1 (4–20)
It was demonstrated that LDL clearance, the mechanism that
Ricchi n 55 30
removes LDL from the circulation, was enhanced in heterozygous
TC (mg/dl) 110.9±20.7 96.1±18.8
β-thalassaemia patients.
15
Age (years) 35 (22–40) 32 (20–39)
Livrea n 35
However, despite the fact that hypocholesterolaemia in thalassaemia TC (mg/dl) 107.7±19.8*
was first described many years ago, there is no definitive explanation Age (years) 32±14 (10–60)
for the mechanism underlying this clinical condition in severe
Amendola n 23
forms of thalassaemia. Two main pathogenetic mechanisms have
TC (mg/dl) 117.3±30.3
been proposed: the presence of enhanced cholesterol consumption
Age (years) 29±12
required for cell membrane formation,
16–18
and the presence of a
Goldfarb n 39 27 23
hyperplastic and overactive reticuloendothelial system, which may
TC (mg/dl) 118.6±25.2* 104.3±30.2* 150.8±41.1*
Age (years) 23.1±7.6 16±7.3
be responsible for an increased uptake of LDL.
19,20
Faizeh n 30
TC (mg/dl) 119.1±37.7
The first ‘mechanism’ seems to be the more complete and would also
Age (years) 8.8±4.05 (1.5–16)
explain the difference always reported in cholesterol level among
*Actual cholesterol values were reported as mmol/l. The following formula was used to
patients with thalassaemia intermedia and major. In fact, in the convert data into mg/dl: mmol/l ÷ 0,0258.
studies by Ricchi
8
and by Hartman
9
it was clearly demonstrated
n = number of patients; TC = total cholesterol; TM = thalassaenia major; TI = thalassaemia
intermedia; T Minor = thalassaemia minor.
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 among thalassaemia intermedia patients, a significant inverse
by eliminating biases (severe liver disorders, hyperthyroidism, correlation was found between cholesterol level and soluble
fat malabsorption and other factors that could per se modify transferrin receptor.
27
cholesterol levels).
Further studies are needed to better elucidate the relationship between
In the study by Ricchi et al.,
8
it was clearly indicated that pre- Hb and cholesterol level and other parameters of erythropoietic activity,
transfusional Hb level was considered, which represents the lowest such as soluble transferrin receptor, reticulocyte count and
peak of Hb for chronically transfused patients who usually remain at extramedullary erythropoiesis in patients affected by thalassaemia.
higher values until their next transfusion.
Implications and Clinical Effects
According to current guidelines, patients with thalassaemia major Despite the fact that hypocholesterolaemia was first described many
have pre-transfusional Hb ranging from 9.5 to 10g/dl, with the aim years ago, its impact on the atherogenic process in patients with
being to reduce erythroid marrow activity.
21
These data may strongly severe thalassaemia has been very rarely addressed. While a lower
support the hypothesis that the consistently high Hb levels in incidence of atherosclerosis-related disease and hypertension has
chronically transfused patients (with thalassaemia major) may mean been reported in thalassaemia trait carriers,
28,29
no study has yet fully
that this group of patients can sustain a more complete degree of evaluated the prevalence of atherosclerotic disease in patients with
marrow suppression with respect to that present in thalassaemia thalassaemia major and intermedia, or assessed whether the reduced
intermedia patients. level of cholesterol really protects thalassaemic patients from the
development of atherogenesis.
Therefore, in patients with thalassaemia intermedia, a particularly
accelerated erythropoiesis and enhanced cholesterol consumption The most frequent cause of death in patients with thalassaemia major
for red cell membrane formation could be responsible for the lower is heart disease related to myocardial iron overload, which is
levels of cholesterolaemia. In support of this hypothesis, several responsible for more than half of all deaths as assessed by recent
clinical and biochemical observations indicate a marked erythropoietic studies of survival.
marrow expansion in patients with thalassaemia intermedia.
22,23
Due to the introduction of more effective chelation therapy, the mean life
In fact, such patients, in the absence of surgery, pregnancy or expectancy of patients with thalassaemia major is increasing, and
concomitant illnesses, usually do not receive blood transfusions. cardiac mortality caused by iron accumulation in the heart is decreasing.
Consistent with this situation, levels of circulating soluble transferrin On the other hand, in the non-thalassaemic adult population, blood levels
receptor, the best estimate of total erythropoiesis in the absence of total cholesterol are widely used to predict ischaemic heart disease,
of iron deficiency,
24
were found to be lower in patients with and treatment with statin, which lowers LDL cholesterol, substantially
thalassaemia major than in patients with thalassaemia intermedia.
25,26
reduces the incidence of ischaemic heart disease.
Interestingly, in the study by Ricchi et al.,
8
patients with severe
forms of thalassaemia intermedia had particularly low levels of However, in recent years increasing evidence has suggested that not
cholesterol.
8
Finally, in a study evaluating hypocholesterolaemia only LDL level but also oxidative alteration of LDL are the key steps in
EUROPEAN HAEMATOLOGY
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