Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0039730 (thalassemia)
 10,305 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Because total cholesterol levels have been found to be lower in patients affected by thalassemia major and intermedia, we examined the plasma lipid pattern of 628 beta-thalassemia trait carriers and 4552 controls in order to evaluate whether the plasma lipid impairment is also present in the heterozygous state. Total cholesterol and low density lipoprotein (LDL)-cholesterol levels were significantly lower in beta-thalassemia trait carriers when compared to controls, whereas plasma triglycerides and high density lipoprotein (HDL)-cholesterol levels did not differ between the two groups. We suggest that accelerated erythropoiesis and increased uptake of LDL by macrophages and histiocytes of the reticuloendothelial system are the main determinants of low plasma cholesterol levels in heterozygous thalassemia.
Atherosclerosis 1989 Feb
PMID:Plasma lipids in beta-thalassemia minor. 271 66

Recombinant human growth hormone (rhGH) is now available for treatment of short stature due to growth hormone (GH) deficiency. It's potential use in other causes of short stature raises concerns about adverse effects of long term treatment on carbohydrate and lipoprotein metabolism. We describe the serial changes in lipids, lipoproteins and apolipoproteins, including apo(a) in 12 children with beta-thalassaemia major undergoing rhGH treatment for 24-36 months. All showed satisfactory increases in height and weight. A significantly higher mean plasma apo(a) was observed at 3 months (102.6 U/l) versus baseline (71.4 U/l, P < 0.01, geometric means). Subsequently apo(a) levels gradually decreased returning to pretreatment levels after 36 months of rhGH treatment. There were parallel rises and falls in the apo(a) isoforms of different sizes during treatment. There were only minimal changes in the other lipid related parameters. All children had markedly reduced cholesterol levels (3.0 +/- 0.49 mmol/l, mean +/- S.D.) characteristic of their underlying disease. In conclusion the elevation of apo(a) by GH is only transient, there is no differential effect of rhGH on the large and small isoforms of apo(a) and there are no clinically significant adverse effects of rhGH treatment on lipoprotein metabolism.
Atherosclerosis 1997 Feb 10
PMID:Growth hormone therapy transiently increases apolipoprotein(a) in short beta-thalassaemia major children with normal growth hormone reserve. 905 Jul 74

Patients with homozygous beta-thalassemia show an abnormal lipoprotein profile. In asymptomatic heterozygotes the lipid pattern is less markedly affected but interestingly related to a diminished cardiovascular risk. The extent and significance of these findings are still a matter of debate and no data are available on lipoprotein(a) plasma levels. Seventy patients with homozygous beta-thalassemia (HT-P), 70 beta-thalassemia trait carriers (TT-C) and 70 sex and age-matched controls were investigated and their plasma lipoprotein profile and apo(a) phenotypes determined. In a subgroup of these same subjects (12 HT-P, 12 TT-C and 24 controls) and in 12 bone marrow-transplanted homozygous beta-thalassemic patients (BMT-P) plasma lipoprotein composition was assessed. HT-P disclosed significantly lower total-cholesterol, LDL-cholesterol, HDL-cholesterol, apo A-I, apo B plasma levels and higher triglyceride concentration than TT-C (-7, -11, -8, -8, -13 and +11%, respectively) or controls (-39, -50, -46, -32, -30 and + 35%, respectively). All lipoprotein subclasses were triglyceride-enriched, while LDLs were also protein-enriched and HDLs protein-depleted. TT-C disclosed a small but significant reduction in apo A-I and apo B plasma levels but only minor lipoprotein abnormalities with respect to the controls. BMT-P lipoprotein composition was intermediate between HT-P and normal subjects. Apo(a) plasma levels did not differ among the groups. A higher prevalence of 'small' apo(a) isoforms was present in HT-P. Within the same 'isoform group', apo(a) plasma levels were significantly lower in HT-P than in TT-C or controls. Since liver cirrhosis is almost always present in HT-P, it is conceivable that an altered hepatic apo(a) synthesis or catabolism due perhaps to diminished apolipoprotein glycation may be involved. In TT-C a partially improved cardiovascular risk profile was apparent (low hematocrit, low LDL-cholesterol and apo B), thus justifying the claim for a low prevalence of ischemic heart disease, but no Lp(a) plasma level modification could be detected.
Atherosclerosis 1997 May
PMID:Plasma lipoprotein composition, apolipoprotein(a) concentration and isoforms in beta-thalassemia. 918 Feb 53

The alteration of the oxidant/antioxidant balance may affect the susceptibility of low density lipoproteins (LDL) to oxidation in haemolytic disorders such as thalassemia. Thirty patients affected by beta-thalassemia intermedia were examined, and compared with age-matched healthy controls. The mean amount of vitamin E in the thalassemic LDL was lower than control (p < 0.0001), either when it was calculated on the base of LDL protein (61% decrease) or cholesterol (25% decrease). The LDL resistance to Cu2+-induced oxidation, evaluated as the length of the lag phase before the onset of conjugated diene (CD) lipid hydroperoxide production, was 20% lower than control. Other parameters of LDL susceptibility to oxidation, such as the rate of lipid peroxidation, Rp, and the total amount of conjugated dienes produced, CDmax, were only slightly lower than control, which can be explained by a lower content of peroxidable lipids in the thalassemic LDL. Total LDL cholesterol was 1.08 x 10(3) and 2.07 x 10(3) mol/mol LDL in thalassemic and in control LDL, respectively. The length of the lag phase in thalassemic LDL shows a strongly positive correlation with its vitamin E content (r = 0.732; p < 0.0001). The r2-value of 0.53 provides evidence that more than 50% of the lag phase is determined by vitamin E. Oxidizability of LDL lipids may explain 22-24% of the lag phase, as calculated by the inverse correlation between the length of the lag phase and CDmax (r = -0.474; p = 0.008; r2 = 0.22) and Rp (r = -0.499; p = 0.005; r2 = 0.24). In multiple regression analysis, the lag phase was predictable to 66% by vitamin E plus CDmax, and to 60% by vitamin E plus Rp. Plasma vitamin E was 53% lower in thalassemia patients compared to control and positively correlated with vitamin E in the LDL (r = 0.677; p < 0.0001). None of the correlations above were observed in control subjects. In conclusion, beta-thalassemia is associated with very low levels of vitamin E in plasma and in LDL, a condition that renders these particles more susceptible to in vitro oxidative modification and may account for atherogenesis-related vascular diseases described in thalassemia. The present data on a statistically significant correlation between abnormally low vitamin E and oxidizability of LDL contribute substantially to the hypothesis that vitamin E is a pathophysiologically important determinant of antioxidative protection of LDL.
Atherosclerosis 1998 Apr
PMID:Oxidation resistance of LDL is correlated with vitamin E status in beta-thalassemia intermedia. 962 86

The recent discovery of the specific molecular defects in many patients with hereditary spherocytosis and hereditary elliptocytosis/pyropoikilocytosis partially clarifies the molecular pathology of these diseases. HE and HPP are caused by defects in the horizontal interactions that hold the membrane skeleton together, particularly the critical spectrin self-association reaction. Single gene defects cause red cells to elongate as they circulate, by a unknown mechanism, and are clinically harmless. The combination of two defective genes or one severe alpha spectrin defect and a thalassaemia-like defect in the opposite allele (alphaLELY) results in fragile cells that fragment into bizarre shapes in the circulation, with haemolysis and sometimes life-threatening anaemia. A few of the alpha spectrin defects are common, suggesting they provide an advantage against malaria or some other threat. HS, in contrast, is nearly always caused by family-specific private mutations. These involve the five proteins that link the membrane skeleton to the overlying lipid bilayer: alpha and beta spectrin, ankyrin, band 3 and protein 4.2. Somehow, perhaps through loss of the anchorage band 3 provides its lipid neighbours (Peters et al, 1996), microvesiculation of the membrane surface ensues, leading to spherocytosis, splenic sequestration and haemolysis. Future research will need to focus on how each type of defect causes its associated disease, how the spleen aggravates membrane skeleton defects (a process termed 'conditioning'), how defective red, cells are recognized and removed in the spleen, and why patients with similar or even identical defects can have different clinical severity. Emphasis also needs to be given to improving diagnostic tests, particularly for HS, and exploring new options for therapy, like partial splenectomy, which can ameliorate symptoms while better protecting patients from bacterial sepsis and red cell parasites, and perhaps from atherosclerosis (Robinette & Franmeni, 1977) and venous thrombosis (Stewart et al, 1996).
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PMID:Red blood cell membrane disorders. 1105 1

Iron is an essential element for normal cellular function and general health. However, iron may play a pathologic role in certain cardiac conditions including reperfusion injury, hemochromatosis, beta-thalassemia and coronary atherosclerosis. It also may play a role in injury due to anthracycline cardiotoxicity. Removal of iron via phlebotomy for hemochromatosis and chelation therapy for beta-thalassemia are proven treatments. Cell culture, and isolated organ and animal studies suggest that depleting iron stores may prevent reperfusion injury, restenosis and even atherogenesis. This article will review mechanisms by which iron overload states and normal iron stores contribute to cardiovascular pathophysiology and the accumulating evidence that iron chelation may prevent restenosis and atherogenesis.
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PMID:Iron-mediated cardiovascular injury. 1094 90

One of the genetic features of the Sardinian population is the high prevalence of hemoglobin disorders. It has been estimated that 13% to 33% of Sardinians carry a mutant allele of the alpha-globin gene (alpha-thalassemia trait) and that 6% to 17% are beta-thalassemia carriers. In this population, a single mutation of beta-globin gene (Q39X, beta(0) 39) accounts for >95% of beta-thalassemia cases. Because previous studies have shown that Sardinian beta-thalassemia carriers have lower total and low density lipoprotein (LDL) cholesterol than noncarriers, we wondered whether this LDL-lowering effect of the beta-thalassemia trait was also present in subjects with familial hypercholesterolemia (FH). In a group of 63 Sardinian patients with the clinical diagnosis of FH, we identified 21 unrelated probands carrying 7 different mutations of the LDL receptor gene, 2 already known (313+1 g>a and C95R) and 5 not previously reported (D118N, C255W, A378T, T413R, and Fs572). The 313+1 g>a and Fs572 mutations were found in several families. In cluster Fs572, the plasma LDL cholesterol level was 5.76+/-1.08 mmol/L in subjects with beta(0)-thalassemia trait and 8.25+/-1.66 mmol/L in subjects without this trait (P<0.001). This LDL-lowering effect was confirmed in an FH heterozygote of the same cluster who had beta(0)-thalassemia major and whose LDL cholesterol level was below the 50th percentile of the distribution in the normal Sardinian population. The hypocholesterolemic effect of beta(0)-thalassemia trait emerged also when we pooled the data from all FH subjects with and without beta(0)-thalassemia trait, regardless of the type of mutation in the LDL receptor gene. The LDL-lowering effect of beta(0)-thalassemia may be related to (1) the mild erythroid hyperplasia, which would increase the LDL removal by the bone marrow, and (2) the chronic activation of the monocyte-macrophage system, causing an increased secretion of some cytokines (interleukin-1, interleukin-6, and tumor necrosis factor-alpha) known to affect the hepatic secretion and the receptor-mediated removal of apolipoprotein B-containing lipoproteins. The observation that our FH subjects with beta(0)-thalassemia trait (compared with noncarriers) have an increase of blood reticulocytes (40%) and plasma levels of interleukin-6 (+60%) supports these hypotheses. The lifelong LDL-lowering effect of beta(0)-thalassemia trait might slow the development and progression of coronary atherosclerosis in FH.
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PMID:Influence of beta(0)-thalassemia on the phenotypic expression of heterozygous familial hypercholesterolemia : a study of patients with familial hypercholesterolemia from Sardinia. 1063 24

Thalassemic (TM) patients are subjected to peroxidative tissue injury because of continuous blood transfusions. It has been documented that circulating LDL from TM patients show marked oxidative modification, that could represent an event leading to atherogenesis. We investigated in 75 beta-TM patients the levels of oxidized LDL antibody (OLAB) to asses their correlation with total cholesterol, LDL and HDL cholesterol, triglycerides Apo A-1 and Apo B. OLAB/mg chol-LDL is greater in TM patients than healthy controls (p<0.001). No correlation was found between OLAB and age, sex of patients, mean blood consumption, mean serum ferritin, mean transaminases, PT, PTT, and fibrinogen. A significant positive correlation was found between OLAB and triglycerides in TM patients (p<0.001). Also a significant correlation was found between OLAB/mg chol-LDL and level of triglycerides in TM patients, but not with total cholesterol, LDL and HDL chols, Apo A-1 and Apo B. On the contrary in the healthy controls this correlation between OLAB and OLAB/mg chol-LDL versus triglycerides was negative and not significant. High levels of OLAB/mg chol-LDL in patients with beta-thalassemia, in absence of evident signs of atherosclerosis, suggest some regulatory mechanisms on the lipid peroxidation which modulate the deposition of ox-LDL in the macrophages and support the hypothesis that both serum iron and triglycerides are involved in the pathogenesis of LDL oxidation.
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PMID:Oxidized LDL antibodies (OLAB) in patients with beta-thalassemia major. 1222 55

The coexistence of a pseudoxanthoma elasticum (PXE)-like syndrome in beta-thalassemia and other hemoglobinopathies is a recently established clinical entity that has been observed with a significant frequency and related to some severe, even life-threatening complications. We present here a thalassemia intermedia patient who developed unstable angina in a setting of severe anemia and PXE-related coronary arterial calcification. Besides the clinical significance of this PXE-like syndrome, its acquired nature may introduce some new thoughts regarding the pathogenesis of atherosclerosis.
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PMID:Unstable angina associated with coronary arterial calcification in a thalassemia intermedia patient with a pseudoxanthoma elasticum-like syndrome. 1263 Dec 61

Iron is essential for all human cells as well as neoplastic cells and invading microbes. Natural and synthetic iron chelators could affect biological processes involving iron and other metal ions in health and disease states. Iron overload is the most common metal toxicity condition worldwide. There are currently two iron chelating drugs, which are mostly used for the treatment of thalassaemia and other conditions of transfusional iron overload. Deferoxamine was until recently the only approved iron chelating drug, which is effective but very expensive and administered parenterally resulting in low compliance. Deferiprone (L1 or 1,2-dimethyl-3-hydroxypyrid-4-one) is the world's first and only orally active iron chelating drug, which is effective and inexpensive to synthesise thus increasing the prospects of making it available to most thalassaemia patients in third world countries who are not currently receiving any form of chelation therapy. Deferiprone has equivalent iron removal efficacy and comparable toxicity to deferoxamine. There are at least four other known iron chelators, which are currently being developed. Even if successful, these are not expected to become available for clinical use in the next five years and to be as inexpensive as deferiprone. The variation in the chemical, biological, pharmacological, toxicological and other properties of the chelating drugs and experimental chelators provide evidence of the difference in the mode of action of chelators and the need to identify and select molecular structures and substituents based on structure/activity correlations for specific pharmacological activity. Such information may increase the prospects of designing new chelating drugs, which could be targeted and act on different tissues, organs, proteins and iron pools that play important role not only in the treatment of iron overload but also in other diseases of iron and other metal imbalace and toxicity including free radical damage. Chelating drugs could also be designed, which could modify the enzymatic activity of iron and other metal containing enzymes, some of which play a key role in many diseases such as cancer, inflammation and atherosclerosis. Other applications of iron chelating drugs could involve the detoxification of toxic metals with similar metabolic pathways to iron such as Al, Cu, Ga, In, U and Pu.
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PMID:The design and development of deferiprone (L1) and other iron chelators for clinical use: targeting methods and application prospects. 1527 56


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