Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “THALASSEMIA”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,333 records · Page 74Linked to original sources
PubMed2005

Treatment of hepatitis C virus infection in thalassemia.

Treatment of hepatitis C virus (HCV) in the general population has improved over the last decade. Patients treated with peginterferon alfa (PegIFN) and ribavirin (RBV) combination therapy demonstrate overall 50-55% sustained viral response (SVR) with rates as high as 80% in patients with genotypes 2 and 3. Because RBV induces hemolysis and subsequently increases blood transfusion requirements, combination therapy has been considered contraindicated for hemoglobinopathies. This report reviews the response to interferon alfa and RBV (IFN/RBV) and PegIFN/RBV combination therapies in patients treated in the Northern California Comprehensive Thalassemia Center. A total of six thalassemia major patients were treated with IFN/RBV (n = 5; age: 4-38 years) or with PegIFN/RBV (n = 1; age: 26 years). Quantitative HCV RNA polymerase chain reaction and liver iron level assessment were completed. Transfusion volumes were obtained from patients' medical records. On IFN/RBV combination, four of five patients demonstrated SVR. The one patient on PegIFN/RBV showed end-treatment viral response after 6 months of therapy (genotype 3), but subsequently relapsed. Liver iron pretreatment level ranged from 0.2 to 22 mg/g dry weight, with a mean +/- SD of 7.9 +/- 7.7. Transfusion requirement increased by a median of 43.5% (range: 32-137%). Five of the six patients had liver iron measurements within 1 year following completion of treatment, with quantitative liver iron increasing in two patients by 2.5 mg/g dry weight, decreasing in two patients by 3 and 14 mg/g dry weight, and remaining unchanged in one patient. All patients were able to complete combination therapy, although dose reductions were required. Patients with thalassemia and high iron overload can obtain SVR after combination therapy with rates similar to those in the general population and without significant complications. Although transfusion requirements increased in most patients, iron burden was not necessarily increased.

Adolescent↗
PubMed2005

Measuring chromosome breaks in patients with thalassemia.

Iron-mediated oxidative stress plays an important role in the pathophysiology of thalassemia. Oxidative stress can cause lesions in DNA, including double-strand breaks. DNA damage, which is a cause of cancer (although not the only one), is recognized as deleterious. Unlike cancer, DNA damage can be assayed easily and relatively inexpensively in humans. In this study, a sensitive micronucleus assay was used to measure the frequency of chromosomal breaks in patients with alpha- and beta-thalassemia. The micronucleus test is based on the observation that a secondary nucleus (micronucleus) is formed around a chromosomal fragment, outside the main nucleus of a dividing cell. Micronuclei are readily apparent in red blood cells (RBCs), which otherwise lack DNA. We combined an immunomagnetic separation technique with single-laser flow cytometry to isolate and analyze reticulocytes in peripheral blood for the presence of micronuclei before these cells are removed by the spleen. Blood samples were obtained from patients with thalassemia and healthy volunteers. After immunomagnetic enrichment of CD71-positive reticulocytes, the cells were stained for micronuclei using the DNA dye 7-aminoactinomycin D (7-AAD) and evaluated by flow cytometry. Our findings indicate that higher levels of micronuclei frequencies are present in thalassemic RBCs.

Cell Separation↗
PubMed2005

Exploring the role of hepcidin, an antimicrobial and iron regulatory peptide, in increased iron absorption in beta-thalassemia.

To develop new treatments for beta-thalassemia, it is essential to identify the genes involved in the relevant pathophysiological processes. Iron metabolism in thalassemia mice being investigated, focusing on the expression of a gene called hepcidin (Hamp), which is expressed in the liver and whose product (Hamp) is secreted into the bloodstream. In mice, iron overload leads to overexpression of Hamp, while Hamp-knockout mice suffer from hemochromatosis. The aim of this study is to investigate Hamp in the mouse model of beta-thalassemia and to address the potential gene transfer of Hamp to prevent abnormal iron absorption.

Animals↗
PubMed1979

Platelet dysfunction in homozygous beta-thalassemia.

This report details the results of studies performed in nine patients with homozygous beta-thalassemia evaluating platelet function and prostaglandin formation. Platelet malonyldialdehyde (MDA) formation in the presence of N-ethyl maleimide (NEM 1 mM) or thrombin (0.5 u/ml) was used as an indicator of platelet prostaglandin synthesis. The data on the nine patients revealed two distinct subgroups of patients. Six of nine thalassemics, demonstrated platelet abnormalities. Their mean bleeding time was 7.5 +/- 2.5 min (1 SD), significantly prolonged (P less than 0.005) when compared to a value of 3.5 +/- 1.0 min in normal controls. MDA formation in the presence of NEM was significantly decreased (P less than 0.005) to 2.41 +/- 0.49 (1 SD) when compared to a control value of 3.24 +/- 0.33 nmoles MDA/10(9) platelets. Similarly, the mean value for thrombin induced MDA was 0.98 +/- 0.18 nmoles which was decreased (P less than 0.02) when compared to a value of 1.26 +/- 0.2 in the controls. Platelet aggregations with adenosine diphosphate (ADP), epinephrine, and collagen were abnormal in all six patients. However, when platelets from these patients were mixed with platelets from donors who had ingested aspirin 2-8 hr before donation mutual correction and secondary irreversible aggregation of the mixture resulted. No mutual correction was observed when the thalassemic platelets were preincubated with aspirin in vitro before mixing with platelets from donors who had recently ingested aspirin. Although the total amount of platelet malonyldialdehyde formed by the thalassemic platelets in response to NEM and thrombin was decreased when compared to normal controls, this reduction was not the cause of the platelet aggregation abnormalities. This appears to be so because the amount of MDA, and, thus, prostaglandin endoperoxides synthesized by these platelets in response to external stimuli was sufficient to cause irreversible aggregation of platelets from donors who had recently ingested aspirin, and were, therefore, unable to synthesize their own endogenous platelet endoperoxides. In the remaining three patients, bleeding times, platelet aggregation, and MDA formation was normal. No correlation was observed between the platelet abnormalities noted and the magnitude of iron overload, presence of fibrin degradation products, liver function abnormalities, or the use of iron chelators in the individual patient. Family studies were normal. Although the platelet dysfunction does not appear to be of major significance in the usual patient with thalassemia major under normal circumstances, antiplatelet aggregating agents should be used with caution. Aspirin inhibits platelet endoperoxide and prostaglandin formation and this effect may potentiate the platelet dysfunction present in some patients with thalassemia major.

Adolescent↗
PubMed1986

The effect of transfusion on lung capacity, diffusing capacity, and arterial oxygen saturation in patients with thalassemia major.

Our previous cross-sectional study of patients with thalassemia major suggested progressive lung changes characterized by low total lung capacity, hypoxemia, and elevated transfer factor for carbon monoxide. We reevaluated nine of the patients for three reasons: to determine the relationship of the previous findings to the immediate effects of blood transfusion; to assess the longitudinal progression of the lung changes; and to evaluate the effect of splenectomy on lung volume changes in these patients, all of whom underwent splenectomy in the interval between the two studies. We found that during the 5- to 6-yr period between studies total lung capacity had decreased significantly (p less than 0.05) from a mean 86% predicted to a mean 79% predicted. However, vital capacity increased significantly (p less than 0.05) from a mean 81% predicted to 88% with no significant change in functional residual capacity. There was no significant immediate effect of transfusion on total lung capacity, vital capacity, or functional residual capacity. However, the diffusion constant for carbon monoxide increased significantly (p less than 0.005) immediately following transfusion and there was a positive correlation between the increase and the amount of blood transfused (r = 0.74, p less than 0.05). Arterial oxygen saturation was below 95% in five of eight patients and increased significantly with transfusion (p less than 0.05). We conclude: 1) thalassemia major and/or its treatment is associated with hypoxemia and a progressive reduction in total lung capacity. 2) Despite the progressive reduction in total lung capacity, splenectomy in patients with thalassemia major increases expiratory reserve volume and thereby increases vital capacity.

Adolescent↗
PubMed1993

Correction of hyperinsulinemia by glyburide treatment in nondiabetic patients with thalassemia major.

Hyperinsulinemia and insulin resistance precede the development of diabetes in patients with thalassemia major on hypertransfusion/desferoxamine therapy. To examine whether these early metabolic defects could be reversed, seven nondiabetic patients with thalassemia (17 +/- 4 y) were studied for 12 mo before and during 12 mo of low-dose treatment with glyburide (1.25 to 3.75 mg/d), a second-generation oral hypoglycemic agent. Plasma glucose responses to oral glucose (1.75 g/kg body weight) were normal before and after glyburide. Plasma insulin responses were markedly increased before glyburide therapy (area under insulin response curve 86 +/- 15 and 96 +/- 15 versus 40 +/- 5 nmol/min/L in normal controls, p < 0.001). However, insulin responses to glucose fell significantly after 3 mo of glyburide (to 52 +/- 7 nmol/min/L, p < 0.05 versus pretreatment) and were normalized after 12 mo (42 +/- 7 nmol/min/L, p = NS versus controls). The rate of insulin-stimulated glucose metabolism during euglycemic insulin clamps (40 mU/m2/min) was low in the patients before treatment (163 +/- 10 versus 215 +/- 17 mg/m2/min in controls, p < 0.05) and increased to 205 +/- 30 mg/m2/min after 3 mo of glyburide. The treatment was well tolerated. In conclusion, in nondiabetic, hyperinsulinemic, thalassemic patients, chronic glyburide therapy normalizes insulin responses to oral glucose. To the extent that insulin hypersecretion contributes to the development of diabetes in thalassemia, glyburide therapy may provide a means of postponing this complication of the disease.

Adolescent↗
PubMed1981

Studies on the possible mechanism for deficiency of nonsuppressible insulin-like activity in thalassemia major.

Previous studies have shown that serum levels of the somatomedin, nonsuppressible insulin-like activity (NSILA-S), are extremely low in patients with thalassemia major. Since these patients are not GH deficient, several other possible mechanisms for the reduced levels of NSIL-S have been explored. No evidence for the presence of NSILA inhibitors was obtained either in mixing experiments of normal serum and thalassemic sera or after acid gel chromatography of thalassemic sera. The high iron and ferritin levels of thalassemia had no effects on the NSILA-S bioassay itself or on the binding of GH to its hepatic receptors. GH molecules secreted as a result of exercise-induced GH stimulation tests were shown to be both immunologically and biologically reactive. No circulating GH-binding proteins were present in thalassemic sera. Since the liver function in the group of patients included in this study was only slightly abnormal, it is considered unlikely that generalized hepatic damage due to the severe iron overload of thalassemia is a major cause. These results suggest that neither NSILA-S inhibitors, abnormal GH molecules, nor hepatic damage contribute to the failure of these patients to produce NSILA-S and that a specific defect may exist at the hepatic GH receptor or postreceptor level.

Adolescent↗
PubMed1986

Impaired growth hormone (GH) response to GH-releasing hormone in thalassemia major.

The response of GH to acute administration of GH-releasing hormone (GHRH) was evaluated in 19 patients with thalassemia major and 8 normal children. In 13 of the 19 patients, GHRH induced a definite increase (greater than 5 ng/ml) in plasma GH levels, with peaks occurring 5-45 min postinjection. In 6 patients there was little or no GH rise after GHRH treatment. Overall, the mean GH response to GHRH of patients with thalassemia was lower than that of normal children. These data indicate that in thalassemia major, in addition to the described defect at the hepatic GH receptor or postreceptor level which impedes generation of somatomedins, there may be a marked impairment in somatotroph function. In one patient in whom the GH response to GHRH was superimposable on that of normal subjects, there was a blunted GH response to insulin hypoglycemia. This finding indicates that functional damage in hypothalamic structures for GH control can also occur in thalassemic patients.

Adolescent↗
PubMed2001

Transient hypoparathyroidism due to amphotericin B-induced hypomagnesemia in a patient with beta-thalassemia.

OBJECTIVE: To report a case of transient hypoparathyroidism that developed in a beta-thalassemic patient due to amphotericin B-induced hypomagnesemia. CASE SIJMMARY: A 21-year-old man with beta-thalassemia was treated with amphotericin B for Candida albicans intravenous line sepsis. After five days of treatment (cumulative dose 160 mg), he developed hypomagnesemia, which caused hypoparathyroidism and hypocalcemia; all three abnormalities resolved after the drug was withdrawn. DISCUSSION: Patients with beta-thalassemia may develop endocrinologic abnormalities due to excessive iron deposition. Some may have subclinical hypoparathyroidism that clinically emerges after even a mild homeostasis disturbance. Amphotericin B is associated with variable adverse effects including renal tubular insult, which may induce hypomagnesemia following relatively short treatment. The resolution of hypomagnesemia, hypocalcemia, and hypoparathyroidism in our patient after discontinuation of amphotericin B treatment suggests that the endocrine dysfunction was due to a drug-related adverse effect and not to parathyroid dysfunction caused by iron deposition. CONCLUSIONS: This case demonstrates a known but rarely reported adverse effect of amphotericin B, namely hypomagnesemia, that may occur even at a low cumulative dose. It also emphasizes that patients with an underlying disease, such as thalassemia, may be more susceptible to hypoparathyroidism and hypocalcemia during treatment with amphotericin B.

Adult↗
PubMed2001

History and origin of beta-thalassemia in Turkey: sequence haplotype diversity of beta-globin genes.

In the present study we report the sequence haplotypes associated with 22 beta-globin gene mutations present in Turkey. Nine nucleotide polymorphisms and an (AT)xTy motif located at the 5' end of the beta-globin gene form the sequence haplotypes that were investigated in 204 unrelated beta-thalassemia and wild-type chromosomes from Turkey. Twelve sequence haplotypes were observed in the chromosomes analyzed and haplotypic heterogeneity was found in the wild-type beta-globin genes. Samples from the Black Sea region demonstrated a remarkable level of haplotypic heterogeneity in contrast to the homogeneity present in Central Anatolian samples. Of the 22 beta-globin mutations analyzed, 18 were related with single sequence haplotypes. This simple association led to the attempt to determine the origin of these mutations by comparing their frequencies in Turkey with those in other countries and/or the world distribution of the haplotypes carrying them. However, the presence of several exceptions for the "one haplotype/one mutation" rule showed that the beta-globin gene cluster is far from static. Each of the IVS-I-110 (G-->A), Cd 39 (C-->T), IVS-I-6 (T-->C), and -30 (T-->A) beta-globin mutations was associated with a minimum of two sequence haplotypes. This fact is best explained by the likelihood of strong recombination mechanisms taking place, rather than by assuming multiple origins for each of these alleles. According to our results, malarial selection for the oldest beta-thalassemia allele in Anatolia (i.e., IVS-I-110 G-->A) may have occurred between 6500 and 2000 B.C. From that date on, most of the common beta-thalassemia mutations in Turkey were established, and by the 13th century A.D. most of them were brought to frequencies close to those observed at present.

Gene Frequency↗
PubMed2004

Beta-thalassemia microelectronic chip: a fast and accurate method for mutation detection.

BACKGROUND: beta-Thalassemia is one of the most common genetic diseases in humans. We developed an automated electronic microchip for fast and reliable detection of the nine most frequent mutations accounting for >95% of the beta-thalassemia alleles in the Mediterranean area. METHODS: We developed a microchip-based assay to identify the nine most frequent mutations (cd39C>T, IVS1-110G>A, IVS1-1G>A, IVS1-6T>C, IVS2-745C>G, cd6delA, -87C>G, IVS2-1G>A, and cd8delAA) by use of the Nanogen Workstation. The biotinylated amplicon was electronically addressed on the chip to selected pads, where it remained embedded through interaction with streptavidin in the permeation layer. The DNA at each test site was then hybridized to a mixture of fluorescently labeled wild-type or mutant probes. RESULTS: Assays conditions were established based on the analysis of 700 DNA samples from compound heterozygotes or homozygotes for the nine mutations. The assays were blindly validated on 250 DNA samples previously genotyped by other methods, with complete concordance of results. Alternative multiplexed formats were explored: the combination of multiplex PCR with multiple addressing and/or hybridization allowed analysis of all nine mutations in the same sample on one test site of the chip. CONCLUSIONS: The open flexible platform can be designed by the user according to the local prevalence of mutations in each geographic area and can be rapidly extended to include the remaining mutations causing beta-thalassemia in other regions of the world.

Fluorometry↗
PubMed2000

Genetic modifying factors in beta-thalassemia.

The beta-thalassemia is probably the most extensively studied genetic disease. Essentially any molecular defect that has been first described in association with the globin genes has been later implicated as a molecular determinant of newly discovered genes. Accordingly, the thalassemias have always represented a model genetic disease, especially in relation to the development of programs for population screening, genetic counseling and prenatal diagnosis. Here we will review the present knowledge on the genetics of thalassemia and of the relevant modifying factors. Major categories of the carrier state, the genotypes, the clinical phenotypes and the correlation between genotype and phenotype will be discussed.

Erythrocyte Indices↗
PubMedDate not supplied

Turner's syndrome and hypogonadotrophic hypogonadism: thalassemia major and hemochromatosis.

We report here the first case of an association between thalassemia major, hemochromatosis, hypogonadotrophic hypogonadism and Turner's syndrome. The patient is an Albanese girl born in 1980; thalassemia major was diagnosed at 1 year and she was started on a transfusion program; in 1987 iron chelation therapy was started. Six years ago, at 7 years of age, her short stature was observed and she was referred to the endocrinology clinic for evaluation; the basal and stimulation tests done at that time failed to reveal growth hormone deficiency, hypothyroidism or any other disease. Nevertheless, at 12 years old, she was still prepubertal and there was a bone age delay of 1.5 years; a gonadotropin-releasing hormone (GnRH) stimulation test showed no response of either FSH (basal: 0.2 mU/ml; peak: 0.8 mU/ml) or LH (basal: < 0.1 mU/ml; peak: 0.6 mU/ml), suggesting hypogonadotrophic hypogonadism. Small dysmorphies called our attention to the possibility of Turner's syndrome which was confirmed by the karyotype (45 XO/46 XX). In this patient, thalassemia major and its lifelong consequences, namely the hemochromatosis-related hypogonadotrophic hypogonadism, masked the usual hormonal findings of Turner's syndrome.

Adolescent↗
PubMedDate not supplied

Inappropriate leptin secretion in thalassemia: a potential cofactor of pubertal timing derangement.

The objective of the present study was to gain a better understanding of the role played by scarce leptin production in the deranged sexual development observed in patients with thalassemia. We studied 101 patients at different stages of puberty. Patients of both sexes were divided into three groups according to Tanner stages: T1-2 (20 males and 12 females), T3-4 (9 males and 4 females) and T5 (48 males and 8 females). Serum levels of leptin, ferritin, testosterone and estradiol were assessed. Leptin levels were adjusted for body mass index (BMI) using reference ranges stratified on the basis of gender and pubertal development. Deviations from the mean reference values were evaluated by calculating the standard deviation scores. Mean leptin standard deviation scores were significantly lower than expected in pubertal stage T1-2 and T3-4 in males and T3-4 and T5 in females. The peak leptin level was delayed in boys (13 years). In girls, parallelism between leptin and BMI was present until age 7-10 years; thereafter, although BMI constantly increased, leptin levels fell dramatically. Mean ferritin levels were significantly higher in pubertal stage T1-2 among males and in T5 among females. These findings show that in thalassemia adipose tissue is unable to assure adequate leptin production just when the highest leptin secretion is required and suggest that this inappropriate leptin secretion may be a cofactor of the derangement in pubertal timing observed in patients with thalassemia.

Adolescent↗
PubMed2005

A patient with Klinefelter's syndrome and thalassemia intermedia.

Klinefelter's syndrome (KS) is associated with a wide spectrum of clinical features, such as tall stature, eunuchoid proportions, testes disproportionately small for the level of pubertal development, gynecomastia and behavioral problems. The association of KS with thalassemia intermedia has not been previously reported. A male patient with thalassemia intermedia was diagnosed with KS at the age of 14 years when endocrine evaluation for delayed puberty showed hypergonadotrophic hypogonadism. Thyroid function was normal; however, basal and GnRH-stimulated gonadotropin concentrations were raised while serum testosterone was low. Karyotype analysis revealed KS (47,XXY). Testosterone replacement therapy started soon after diagnosis and now at the age of 20 years the patient's height is 178.3 cm, the U/L ratio is 0.91. Testicular volume is 12 ml (Prader orchidometer) and his pubic hair is stage 4. To our knowledge this is the first case of a patient suffering from KS and thalassemia intermedia reported in the literature.

Adolescent↗
PubMed1995

Delayed puberty in males with beta-thalassemia major: pulsatile gonadotropin-releasing hormone administration induces changes in gonadotropin isoform profiles and an increase in sex steroids.

Patients with beta-thalassemia major often have pubertal delay, the etiology of which has not been fully elucidated. We investigated the pituitary-gonadal response to short-term subcutaneous pulsatile gonadotropin-releasing hormone (GnRH) administration (150 ng/kg body weight every 120 min for 7 days) in five young males (aged 13.6-19.0 years) affected by beta-thalassemia major and presenting signs of delayed puberty. Immunoreactive and bioactive gonadotropin levels were determined and their isoform profiles were examined, before and after GnRH treatment, in a pool of samples collected every 15 min for 240 min. Testosterone, androstenedione, 17-hydroxyprogesterone, dehydroepiandrosterone and 17 beta-estradiol were measured as markers of gonadal function on days 0, 1, 3, 5 and 7 of treatment. Five patients (aged 16.9-26.8 years) with confirmed diagnosis of idiopathic hypogonadotropic hypogonadism who were starting pulsatile GnRH therapy were also studied in the same protocol. Increased sex steroid levels were observed in both groups as a result of treatment. On day 7, the thalassemic patients had increased bioactive luteinizing hormone (LH) and follide-stimulating hormone (FSH), although immunoreactive LH and FSH were comparable to day 0. Moreover, fewer acidic and more basic immunoreactive and bioactive isoforms were noted in LH profiles on day 7. Similar results were observed in hypogonadal patients, who also had increased immunoreactive LH and FSH values. We suggest that the early stage of delayed puberty in thalassemia might be characterized by a neuroendocrine dysfunction resulting in an impaired hypothalamic GnRH release, which is inadequate for a proper pituitary stimulation. Pulsatile GnRH treatment seems to re-establish partially the correct pituitary-gonadal function.

17-alpha-Hydroxyprogesterone↗
PubMed1988

Inadequate utilization of routine electronic RBC counts to identify beta thalassemia carriers.

We investigated physician awareness of the diagnosis of beta thalassemia minor as suggested by RBC indices obtained from routine electronic counts; and, the knowledge of the carriers of their genetic trait. Out of 17,000 counts, 324 were compatible with the diagnosis of beta thalassemia minor, but, only 175 (54 per cent) were identified by physicians as possibly thalassemic and in 47 of these (27 per cent) was the diagnosis verified. Twenty-four of 39 interviewed patients in whom the diagnosis of beta thalassemia minor was established knew about their carrier state.

Adult↗
PubMed1995

Thalassemia incidentally found by marked erythrocytosis due to an ochre mutation at codon 35 in a Japanese man.

We present a patient with beta-thalassemia minor diagnosed on the basis of the incidental findings of marked hypochromic and microcytic erythrocytosis. Hemoglobin analysis revealed increased hemoglobin (Hb) A2 levels and decreased beta/alpha synthesis ratio in both the propositus and his mother. Further molecular studies identified a single base substitution of TCA to TAA within codon 35 in heterozygous state, which creates a premature terminator resulting in a defect of effective beta globin synthesis. This is the first report of beta-thalassemia due to a nonsense mutation at codon 35 of beta-thalassemia gene in the Japanese population.

Adult↗