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)

In previous trials, the orally active iron chelator deferiprone (L1) has been associated with sporadic agranulocytosis, milder forms of neutropenia and other side-effects. To determine the incidence of these events, we performed a multicentre prospective study of the chelator. Blood counts were performed weekly, and confirmed neutropenia mandated discontinuation of therapy. Among 187 patients with thalassaemia major, the incidence of agranulocytosis (neutrophils < 0.5 x 109/l) was 0.6/100 patient-years, and the incidence of milder forms of neutropenia (neutrophils 0.5-1.5 x 109/l) was 5.4/100 patient-years. All cases of neutropenia resolved after interruption of therapy. Neutropenia occurred predominantly in non-splenectomized patients. Nausea and/or vomiting occurred early in therapy, was usually transient and caused discontinuation of deferiprone in three patients. Mild to moderate joint pain and/or swelling did not require permanent cessation of deferiprone and occurred more commonly in patients with higher ferritin levels. Mean alanine transaminase (ALT) levels rose during therapy. Increased ALT levels were generally transient and occurred more commonly in patients with hepatitis C. Persistent changes in immunological studies were infrequent, although sporadic abnormalities occurred commonly. Mean zinc levels decreased during therapy. Ferritin levels did not change in the overall group but decreased in those patients with baseline levels > 2500 microgram/l. This study characterized the safety profile of deferiprone, and, under the specific conditions of monitoring, demonstrated that agranulocytosis is less common than previously predicted.
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PMID:Safety profile of the oral iron chelator deferiprone: a multicentre study. 1069 60

Impairment of haemoglobin synthesis occurs in the genetic diseases known as thalassaemia. The consequent chronic anaemia leads to increased dietary iron absorption which results in iron overload. Treatment through regular blood transfusions increases oxygen capacity, but also adds iron from haemoglobin. An essential treatment, in parallel with transfusions, is the use of chelating agents to remove the excess iron. Thalassaemia patients are particularly at risk of free radical damage. Human lymphocytes from normal individuals can be investigated in vitro as a model system in the presence of free radicals in the Comet assay. This assay measures DNA damage, particularly DNA strand breakage. We examined cells from an Australian thalassaemic patient (sickle/beta thal double heterozygote-sickle phenotype) who had not yet received chelation therapy to determine if the cells were more sensitive to simulated iron overload and to haemosiderins. Lymphocytes from the patient were received as frozen samples after 28 h on dry ice and then placed in liquid nitrogen. Normal lymphocytes frozen under the same conditions and normal nonfrozen lymphocytes were compared. The lymphocytes from a normal female did not respond in vitro to ferric chloride (FeCl(3)) or haemosiderin but did to ferrous chloride (FeCl(2)) and ferrous sulphate (FeSO(4)). Deferoxamine appeared to reduce the response to FeCl(2) and FeSO(4) but deferiprone did not. When the lymphocytes from the nonchelated patient were treated with FeSO(4) and hydrogen peroxide, deferoxamine and deferiprone both reduced the response. Over the same dose range of iron salt (FeSO(4)), the lymphocytes from the thalassaemic patient were more sensitive, with much higher background levels of damage and induced damage. When deferiprone and deferoxamine were compared over a nontoxic range, deferiprone appeared to produce a greater reduction of damage in lymphocytes of the thalassaemia patient. Ferritin iron appears to be more available than haemosiderin iron in reactions leading to DNA damage. Haemosiderin containing higher amounts of the goethite-like (alpha-FeOOH) iron oxide phase leads to lower levels of DNA damage.
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PMID:Effect of iron salts, haemosiderins, and chelating agents on the lymphocytes of a thalassaemia patient without chelation therapy as measured in the comet assay. 1099 72

In sub-Saharan Africa, anaemia in pregnancy results from multiple causes including malaria, iron deficiency and haemoglobinopathies. In a cross-sectional study among 530 pregnant women in Ghana in November-December 1998, red blood cell indices were analysed with respect to malaria, serum concentrations of ferritin and C-reactive protein (CRP), and the haemoglobin and alpha-globin genotypes. Anaemia (haemoglobin [Hb] < 11 g/dL) was found in 54% of the women; 63% harboured malaria parasites at predominantly low numbers. Ferritin levels were considerably influenced by malaria and inflammatory processes (CRP > 0.6 mg/dL). Depending on the definition applied, the prevalence of iron deficiency ranged between 5% and 46%. The HbAS trait was observed in 14%, HbAC and elevated HbF in 7% each, and sickle cell disease in 1%. Heterozygous beta-thalassaemia was present in 1% of the women and alpha(+)-thalassaemia in 33% (29% heterozygous, 4% homozygous). Women with HbAS had higher malaria parasite densities than those with HbAA. In individuals with highly elevated HbF (> 10%), parasitaemia occurred in 27% only. Low gravidity, second trimester of pregnancy, malaria, raised CRP levels, and homozygous alpha(+)-thalassaemia were independent risk factors for anaemia in multivariate analysis. alpha(+)-Thalassaemia, however, was associated with a lesser degree of malarial anaemia when compared to non-thalassaemic women. Iron deficiency appears not to be a major health problem in this population. Haemoglobinopathies are common but, except for homozygous alpha(+)-thalassaemia, do not substantially contribute to anaemia in pregnancy. alpha(+)-Thalassaemia ameliorates malarial anaemia in pregnant women.
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PMID:Anaemia in pregnant Ghanaian women: importance of malaria, iron deficiency, and haemoglobinopathies. 1113 70

In 1997, the Italian Ministry of Health created a special programme for the controlled distribution of deferiprone to collect data and to evaluate its safety and effectiveness in long-term use. Five hundred and thirty-two thalassaemia patients from 86 treatment centres were enrolled in this programme. One hundred and eighty-seven patients (32%) experienced a total of 269 events that led to a temporary interruption or, in some cases, to a discontinuation of treatment. The incidence of agranulocytosis and milder neutropenias were 0.4/100 and 2.1/100 patient-years respectively. Neutropenia occurred predominantly in younger and non-splenectomized patients. Transient alanine transaminase increase, gastrointestinal discomfort and arthralgia were the other most commonly reported events. Ferritin levels showed a significant decrease in time after 3 years of therapy. This is the largest number of deferiprone-treated patients to have been reported to date. These data show that the drug was effective in reducing serum ferritin levels and the incidence of adverse events was not greater than the frequency reported in clinical trials.
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PMID:The safety and effectiveness of deferiprone in a large-scale, 3-year study in Italian patients. 1210 Jan 70

Treatment of patients with beta-thalassemia major has improved dramatically during the past 40 years; however, the current clinical status of these patients remains poorly characterized. We performed a cross-sectional study of 342 patients in the Registry of the National Institutes of Health-sponsored Thalassemia Clinical Research Network. Evidence of hepatitis C exposure was present in 35% of tested patients, was associated with age, and had a rate of spontaneous viral clearance of 33%. Ferritin levels ranged from 147 to 11 010 ng/mL (median, 1696 ng/mL). Median hepatic iron content was 7.8 mg/g dry weight and 23% of patients had values of 15 mg/g dry weight or higher. No patients 15 years or younger and 5% of patients aged 16 to 24 years had heart disease requiring medication. Ten percent had cirrhosis on biopsy. Endocrinologic complications were common among adults. Seventy-four (22%) patients had recent implantable central venous access devices (CVADs) placed. Among 80 episodes of bacteremia in 38 patients, 90% were attributable to the CVAD. Among 330 patients who had received deferoxamine chelation therapy, 224 (68%) reported no complications. We conclude that hepatitis C, iron-related organ dysfunction, and complications of iron chelation therapy are strongly age-dependent in North American patients with beta-thalassemia.
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PMID:Complications of beta-thalassemia major in North America. 1498 52

Magnetic resonance imaging (MRI) appears to be useful for monitoring iron overload in thalassaemia. We studied 106 patients with beta-thalassaemia: 80 with thalassaemia major (TM) and 26 with thalassaemia intermedia (TI). Thirty-five patients with sickle cell disease (SCD) were also evaluated. Serum ferritin, liver and myocardial T2-relaxation time and liver iron concentration (LIC) were measured. LIC values, based on biopsies from 29 patients, showed a close inverse correlation with the respective liver T2-values, along with a strong positive correlation with ferritin levels in all patients. Heart T2-values correlated with left ventricular ejection fraction in TM and SCD, but not in TI patients. Both liver and heart T2-values were significantly lower in TM patients than those of TI, and SCD patients. Ferritin levels showed a strong correlation with liver T2-values in all three groups of patients. Similarly, a negative correlation was found between serum ferritin levels and heart T2-values in TM, but not in TI and SCD patients. Heart and liver T2-values showed a significant correlation only in TM patients. These results suggest that the MRI technique (T2 relaxation time) used in our study, is a reliable, safe and non-invasive method for the assessment of the deposition of iron in the liver; results for the heart become reliable only when there is heavy iron deposition.
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PMID:Magnetic resonance imaging in the evaluation of iron overload in patients with beta thalassaemia and sickle cell disease. 1532 28

Iron overload is not uncommon in sickle cell disease (SCD) and requires regular chelation therapy in several instances. The present study evaluates the effect of deferiprone in 15 adult patients with SCD (ten beta(s)/beta(0)thalassemia and five beta(s)/beta(s)) and iron overload. Deferiprone was given at a dose of 75 mg/kg daily for 12 months. The evaluation considered pre- and post-treatment values of serum ferritin, urinary iron excretion, and T2 values of liver and heart obtained by magnetic resonance imaging (MRI). Eleven patients had a liver biopsy prior to starting therapy to evaluate iron concentration (LIC). Twelve patients completed the study with satisfactory compliance. In ten of them (83.3%) the serum ferritin levels decreased significantly at the end of the trial; in eight patients (66.6%) the reduction of serum ferritin was accompanied by a significant increase of their liver T2 values. All patients had a significant increase of urinary iron excretion in response to the drug. Ferritin levels and liver T2 values correlated with liver iron concentration; on the contrary, ferritin levels and liver T2 values failed to show any correlation with heart T2 values. Heart T2 values did not also show any correlation with left ventricular ejection fraction. Deferiprone was well tolerated and did not cause any significant adverse effects. These results suggest that deferiprone may effectively decrease the iron deposition in patients with SCD; moreover, T2 MRI proves to be a reliable and rapid, noninvasive method for assessing the liver iron load in patients with SCD.
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PMID:Deferiprone as an oral iron chelator in sickle cell disease. 1580 85

Bone marrow transplantation (BMT) is the only complete cure for b-thalassemia. Iron depletion therapy is still required to remove excess iron, accumulated before BMT. Hepatic and myocardial iron load were evaluated using T2* magnetic resonance in 8 ex-thalassemic patients after BMT, aged 19.5 +/- 4.25 years, who were in iron depletion therapy. Average hepatic T2* was 18.8 +/- 11.0 msec (4.1-35.0 msec). In 4 out of 8 patients iron overload was detected, not exceeding however 4 mg/gr dry tissue. Average heart T2* was 31.0 +/- 4.6 msec (25.6-35.2 msec), not significantly different (P = 0.18) from our age-matched normal population (33.0 +/- 4.0). Normal left ventricular ejection fraction was found in 7 out of 8 patients (mean 64.5 +/- 7.0%) with the remaining having a marginal value of 54.1%. Ferritin level before BMT was 1748 +/- 451 mug/l and dropped to 536 +/- 260 microg/l at the end of iron depletion therapy after BMT. Current ferritin level was 271 +/- 253 microg/l and although it was significant lower compared to both ferritin before BMT (P < 0.001) and after iron depletion (P < 0.001), evidence of residual hepatic iron load was identified by T2*. Hepatic and myocardial T2* magnetic resonance can be used as a more reliable index than ferritin for evaluation of iron depletion therapy in ex-thalassemic patients after BMT.
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PMID:Myocardial and hepatic T2* magnetic resonance evaluation in ex-thalassemic patients after bone-marrow transplantation. 1723 81

As a consequence of the high prevalence of TorqueTeno virus (TTV) in blood donors, thalassemia patients frequently acquire various genotypes of this virus through therapeutic blood transfusions. At present, the clinical consequences of TTV infection remain indeterminate for these patients. Here, several hundred thalassemia patients were tested for the presence of TTV and its genotypes using a combination of PCR and clone-based DNA sequencing. Approximately 10% (12/118) of the patients aged 2-20 years remained negative for TTV including eight genotypes of SENV. Ferritin, aspartate-aminotransferase (AST) and alanine-aminotransferase (ALT) levels were invariably lower in TTV-negative patients (P = 0.02, <0.01, and 0.06, respectively) than in TTV-positive patients. Patients with TTV-HCV co-infection showed elevated ferritin and ALT levels compared with patients with TTV infection alone (P < 0.02 and P < 0.01). AST and ALT levels were within the normal range for all TTV-negative patients, whereas abnormal levels of AST and ALT were seen in a significant proportion of TTV-positive patients (30.7% and 33.6%, respectively) and patients with TTV-HCV co-infections (70.0% and 56.6%, respectively). Only TTV-positive patients (28.0%) and patients with TTV-HCV co-infections (36.3%) had hyper-ferritin levels (> or =3,000 ng/ml). The genotype(s) of TTV responsible for the liver dysfunction could not be determined. However, high levels of AST and ALT were found to be correlated with detection of a higher number of TTV genotypes in the patients. The data suggests that frequent and persistent TTV infection through blood transfusion is associated with hepatic dysfunction and/or damage in transfusion dependent thalassemia patients.
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PMID:Clinical outcome of frequent exposure to Torque Teno virus (TTV) through blood transfusion in thalassemia patients with or without hepatitis C virus (HCV) infection. 1809 40

Seasonal iron overload in Svalbard reindeer was studied by light and electron microscopy and by X-ray microanalysis. The hepatic iron overload was of two types. The first type was characterized by massive siderosis of both parenchymal and non-parenchymal cells caused by a diet very rich in iron but low in energy and protein. Hepatocytes contained a moderate amount of free ferritin particles in the cytosol together with numerous siderosomes. This pattern is similar to that seen in primary haemochromatosis and thalassaemia. Kupffer cells contained large quantities of cytosolic ferritin, siderosomes and lysosomes with disintegrating red blood cells as seen in thalassaemia. The second type was characterized by massive non-parenchymal siderosis caused by an energy- and protein-poor diet with normal iron concentration. Hepatocytes contained little cytosolic ferritin and few siderosomes, but there were abundant electron-dense bodies without iron (i.e., autophagosomes). Kupffer cells were as described above. Ferritin was also present within the duodenal mucosa of these animals, located within enterocytes and lamina propria macrophages, as well as in the extracellular space and capillary and lacteal lumina. Ferritin was also present in the acinar cells of submucosal Brunner's glands. Changes consistent with exchange of ferritin particles between different cell types were observed. The role of ferritin as a possible iron transporter in this condition is discussed.
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PMID:Iron distribution in the liver and duodenum during seasonal iron overload in Svalbard reindeer. 1934 12


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