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PubMed2006

Liver fibrosis and iron levels during long-term deferiprone treatment of thalassemia major patients.

Deferiprone (L1) is an orally active iron-chelation agent that is being evaluated as a treatment for iron overload in thalassemia major. Although some reports have concluded that LI may exacerbate hepatic fibrosis and the deterioration of liver function in thalassemia patients, other studies have reported no detrimental effects. In view of these serious concerns regarding the hepatic toxicity of LI, a Taiwanese group of beta-thalassemia (thal) patients with the longest known duration of LI therapy and who had provided liver biopsies, were enrolled in this study. From April 1999 to July 2004, the 17 enrolled thalassemia major patients had been on L1 therapy for as long as 19 to 60 months. Two liver biopsies from each of the 17 patients were received at the China Medical University Hospital, Taichung, Taiwan. Serum alanine aminotransferase (ALT), viral serological studies for hepatitis B and hepatitis C, iron scores and fibrosis scores were available at the beginning of the study and at the time of the second biopsy. Overall, the 17 patients received L1 therapy continuously for a mean period of 3.3 years. With the exception of two patients, fibrosis scores decreased in all patients after LI therapy. Three patients had increased iron scores after therapy of L1 and 11 patients had increased ALT levels; increased ALT levels occurred more frequently in hepatitis C positive patients. In this study, most thalassemia major patients had no progression of hepatic fibrosis or increased liver iron stores during long-term LI therapy.

Adolescent↗
PubMedDate not supplied

Prevalence and hematological characteristics of beta-thalassemia trait in Gaziantep urban area, Turkey.

Thalassemia is one of the most common hereditary disorders in the Mediterranean region and studies have shown that the prevalence of beta-thalassemia trait is high in the southern part of Turkey. Gaziantep is a city located near this region and, therefore, the authors investigated the prevalence and hematological characteristics of the beta-thalassemia traits in primary school students in Gaziantep. Sixty primary schools were selected from a list of all primary schools using a systematic sampling method. Data were collected by a face-to-face questionnaire. Osmotic fragility testing (OFT) using single-tube 0.36% NaCl solution was used for the screening of beta-thalassemia. Students who were positive in regard to OFT went through a series of testing, including a complete blood count, serum ferritin levels, serum iron, and hemoglobin electroforesis. Chi-square test was used in statistical analysis. Of the 2439 students enrolled to the study from the selected 60 classrooms, 1353 (55.5%) were male and 1086 (44.5%) were female. The OFT was positive in 115 (4.7%) of the participants. CEA and confirmatory HPLC results of the students who were positive OFT indicated that 70 (60.8%) had normal results, 33(28.7%) showed high HbA2 levels, 7 (6.1%) showed high HbA2 and HbF levels, 5(5.2%) showed high HbA2 and Fe-deficiency anemia, and none showed increased HbF levels. The overall prevalence of beta-thalassemia trait was 1.84%. No gender differentials and highest rates among the Kahramanmaras (3.5%) and Sanliurfa (1.7%) born students were the other significant findings of this study. Implementation of a routine carrier-screening program offering genetic counseling, prenatal diagnosis, and selective termination of affected fetuses would be a wise approach to eliminate this disease from the region.

Adolescent↗
PubMed2006

Bias-corrected diagnostic performance of the naked-eye single-tube red-cell osmotic fragility test (NESTROFT): an effective screening tool for beta-thalassemia.

It is being increasingly recognized that a majority of the countries in the thalassemia-belt need a cost-effective screening program as the first step towards control of thalassemia. Although the naked eye single tube red cell osmotic fragility test (NESTROFT) has been considered to be a very effective screening tool for beta-thalassemia trait, assessment of its diagnostic performance has been affected with the reference test- and verification-bias. Here, we set out to provide estimates of sensitivity and specificity of NESTROFT corrected for these potential biases. We conducted a cross-sectional diagnostic test evaluation study using data from 1563 subjects from Central India with a high prevalence of beta-thalassemia. We used latent class modelling after ensuring its validity to account for the reference test bias and global sensitivity analysis to control the verification bias. We also compared the results of latent class modelling with those of five discriminant indexes. We observed that across a range of cut-offs for the mean corpuscular volume (MCV) and the hemoglobin A2 (HbA2) concentration the average sensitivity and specificity of NESTROFT obtained from latent class modelling was 99.8 and 83.7%, respectively. These estimates were comparable to those characterizing the diagnostic performance of HbA2, which is considered by many as the reference test to detect beta-thalassemia. After correction for the verification bias these estimates were 93.4 and 97.2%, respectively. Combined with the inexpensive and quick disposition of NESTROFT, these results strongly support its candidature as a screening tool-especially in the resource-poor and high-prevalence settings.

Adolescent↗
PubMed2001

The beta-thalassemia mutation spectrum in the Iranian population.

Beta-thalassemia is the most common hereditary disease in Iran. More than two million carriers of beta-thalassemia live in Iran. Since the Iranian population is a mixture of different ethnic groups, it is necessary to determine the frequency and distribution of mutations in the different parts of the country. For this purpose, we divided Iran in to eight different regions according to the geographic and ethnic distribution of the population. Over a 10-year period 1,217 beta-thalassemia chromosomes of 164 affected patients and 889 unrelated carriers were studied using the amplification refractory mutation system-polymerase chain reaction technique. We detected 81% beta-thalassemia mutations in the studied chromosomes. IVS-II-I (G --> A) was the predominant mutation found in our study (34%). Its relative frequency in the north was much higher than other regions, and it lessened toward the south, where the IVS-I-5 (G --> C) mutation was more common. IVS-I-5 (G --> C) (7.55%), codons 8/9 (+ G) (4.76%), and IVS-I-110 (G --> A) (4.76%) were the other most common mutations. The results presented here can be used as a basis of prenatal diagnosis of beta-thalassemia in different regions of Iran.

DNA Mutational Analysis↗
PubMed2002

The beta+-IVS-I-6 (T-->C) mutation accounts for half of the thalassemia chromosomes in the Palestinian populations of the mountain regions.

A study of the spectrum of beta-thalassemia mutations in the southern part of the West Bank of the Palestinian Authority revealed the presence of 10 different beta-globin mutations. The study included 41 patients and 54 carriers of beta-thalassemia and sickle cell anemia. The spectrum of mutations observed was typically Mediterranean. However, their relative frequencies was unique. The predominant allele was IVS-I-6 (T-->C), with an exceptionally high frequency of 48.5% for this mutation. The homozygous IVS-I-6 patients had widely variable clinical presentations, from typical transfusion-dependent thalassemia major to non-transfusion-dependent thalassemia intermedia phenotype. Since it is so widespread in these West Bank populations, the IVS-I-6 mutation may date back to ancient times. The nonsense mutation at codon 37 (G-->A) was found at a relatively high frequency of 11.3%, supporting the hypothesis that it originated in this region. The other mutations, at decreasing frequencies ranging from 9.5-1.5%, were: IVS-I-110 (G-->A), frameshift codon 5 (- CT), IVS-I-1 (G-->A), IVS-II-1 (G-->A), Hb S [beta6(A3)Glu-->Val], frameshift codons 8/9 (+G), codon 39 (C-->T), and -30 (T-->A). Our findings will improve health care for the Palestinian population, and also has implications for the study of the origin and spread of thalassemia in the Middle East.

Adolescent↗
PubMed2002

Beta-thalassemia in the Korean population.

Beta-Thalassemia is uncommon in the Korean population, however, it must be considered in the differential diagnosis of hypochromic anemia. The molecular characterization of beta-thalassemia is absolutely necessary for molecular diagnosis as well as any genetic epidemiological study in this region. We analyzed the molecular basis of beta-thalassemia in 38 Korean families. Using direct sequencing of genomic DNA amplified through polymerase chain reaction and haplotype analysis, 35 beta-thalassemic genes were characterized, all of which were heterozygous. Twelve different mutations were identified. The most common mutations noted included the initiation codon ATG-->AGG (beta0) (28.9%), codon 17 (beta0) (A-->T) (18.4%), and IVS-II-1 (beta0) (G-->A) (10.5%). Interestingly, mutations causing dominantly inherited beta-thalassemia were also common (15.7%). All four cases with the IVS-II-1 (G-->A) mutation were linked to the silent mutation of codon 91 (C-->T) of the beta-globin gene. The initiation codon A7G-->AGG and IVS-II-1 (G-->A) with codon 91 (C-->T) mutations were found in the Far East only, and may be inherited from a common origin for each mutation, at least in Koreans. The codon 17 (A-->T) and codons 41/42 (beta0) (-TTCT) were suggested to be introduced by gene-flow from southern China. Otherwise, only Hb Korea [codons 33/34 (beta0) (-GTG)] and a novel beta-thalassemic mutation, codons 89/90 (beta0) (-GT), were identified in Koreans. This mutation spectrum is characteristic of the low prevalence area of beta-thalassemia in Korea, it is, however, quite different from the adjacent countries, Japan and China.

Adult↗
PubMed2003

Molecular genetic testing of beta-thalassemia patients of Indian origin and a novel 8-bp deletion mutation at codons 36/37/38/39.

Hemoglobinopathies are the most commonly inherited genetic disorders in India. Certain communities in India have a high predisposition to beta-thalassemia. To offer prenatal diagnosis and to prevent the birth of an affected child, mutation testing in clinically diagnosed beta-thalassemia patients/carriers is a prerequisite. Over a period of 4 years, we have conducted DNA analysis in 385 carriers for 15 beta-thalassemia mutations, HbD, HbE, and HbS. Using reverse dot blot (RDB) and amplification refractory mutation system (ARMS), we have been able to identify mutations in 381 of 385 thalassemia chromosomes. The study included the analysis of five common mutations found in Asian Indians, namely IVS1-5 (G-C), 619-bp deletion, IVS1-1 (G-T), and the frameshifts at CD8/9(+G) and CD41/42(-CTTT). The occurrence of these five mutations was seen in 299 (91.2%) carriers referred to us, the percentage of mutations varying between 4.0 and 68.9%. We also found Cd16 (-C) in 2.1%, CD30 (G-C) in 1.5%, and CD 15(G-A) in 0.6%; these are considered common mutations in the Indian population, as well. The beta-thalassemia anomaly in 4 (0.6%) carriers remained uncharacterized by RDB and ARMS analysis. During delineation of the mutations in uncharacterized carriers by single-stranded conformational polymorphism (SSCP) and sequencing analysis, we have also been able to identify two unusual mutations, one involving an initiation codon and the second involving a novel 8-bp deletion, in Indian families of Uttar Pradesh origin.

Base Sequence↗
PubMed2003

Validation of dHPLC for molecular diagnosis of beta-thalassemia in Southern Italy.

Beta-thalassemia, the most common hereditary anemia in the Mediterranean area, results from over 200 causative mutations in the beta-globin locus. The aim of this study was to validate a denaturing high-performance liquid chromatography (dHPLC)-based assay for postnatal and prenatal molecular diagnosis of beta-thalassemia in Southern Italy. Sixty beta-thalassemic patients, affected either by thalassemia intermedia or thalassemia major, were analyzed in a blind study. We also carried out prenatal molecular diagnosis in 12 couples at-risk for having affected offspring. Chorionic villi samples were subjected to dHPLC analysis upon molecular characterization of the parental beta-globin alleles. Direct sequence analysis was used to validate each result, showing an accuracy rate of 100% for dHPLC. Overall, our protocol was able to identify the responsible mutations in all 96 analyzed subjects (including 12 prenatals in at-risk pregnancies), detecting the eight most common mutations in Southern Italy. Three rare mutations (one of which, reported here for the first time) that standard mutation detection methods failed to reveal, were also identified. dHPLC assay proved to be a reliable, rapid, and sensitive method for detecting both common and rare mutations within the beta-globin gene. Because of this property our protocol has the potential to be implemented for mutational screening in different areas of high prevalence for beta-thalassemia.

Chorionic Villi Sampling↗
PubMed1978

Relationship between tocopherols and serum lipid levels in children with beta-thalassemia major.

Serum tocopherol levels were found to be below normal (less than 0.5 mg/100 ml) in nine (50%) of 18 children with beta-thalassemia major receiving inadequate treatment with blood transfusions. The mean tocopherol levels were significantly lower in the children with beta-thalassemia (0.57 mg/100/ml +/- 0.20) than in the controls (1.08 mg/100 ml +/- 0.24). Serum total lipid levels were found to be low in children with beta-thalassemia. The difference between the mean total lipid level in the beta-thalassemic patients (365 mg/100 ml +/- 75) as compared to that of the controls (581 mg/100 ml +/- 94) was highly significant (P less than 0.01). The ratio of serum tocopherol to 1 g total lipids was lower in children with beta-thalassemia (1.41 mg/100 ml +/- 0.43) than in the controls (1.88 mg/100 ml +/- 0.46) and the difference was significant. Yet, only three out of the 18 children with beta-thalassemia showed a ratio of less than 0.8 mg/100 ml tocopherol per 1 g total lipid which may be considered indicative of tocopherol deficiency.

Adolescent↗
PubMed1999

Usefulness of certain red blood cell indices in diagnosing and differentiating thalassemia trait from iron-deficiency anemia.

Iron-deficiency anemia and thalassemia are among the most common microcytic anemias. Differentiating these anemias by means of hemogrant indices is imprecise. Powerful statistical computer programming now enables sensitive discriminant analyses to aid in the diagnosis. Laboratory results from 383 adults were examined retrospectively and grouped according to their original diagnoses: normal (n = 78); beta-thalassemia (n = 134); alpha-thalassemia (n = 106); and iron-deficiency anemia (n = 65). Statistical analysis of results evaluated only RBC indices: RBC count, hemoglobin level, mean corpuscular volume, mean corpuscular hemoglobin, and RBC distribution width. Stepwise multivariate discriminant analysis determined those indices that best differentiated the 4 groups. The Fisher linear discriminant function for each group was calculated and tested casewise. Discriminant analysis identified mean corpuscular hemoglobin, RBC count, mean corpuscular volume, and RBC distribution width as the best set of indices for differentiating the 4 diagnoses. Casewise testing of the calculated Fisher linear discriminant function resulted in mean-weighted sensitivity of 80.4%. The present study demonstrates that a set of linear discriminant functions based on routine hemogram data can effectively differentiate between alpha-thalassemia, beta-thalassemia, and iron-deficiency anemia, with a high degree of accuracy.

Anemia, Iron-Deficiency↗
PubMed1978

Population screening for beta-thalassemia minor. Report of cooperative trials based on two approaches.

In a cooperative intrastate program based upon experience with sickle-cell anemia screening, the authors explored the feasibility of applying hemoglobin electrophoresis for detection of beta-thalassemia gene carriers. Initially, blood samples collected in capillary tubes were analyzed by cellulose acetate electrophoresis with densitometric quantitation of hemoglobin A2 (Hb A2), followed by selective spectrophotometric quantitation. This approach proved insufficiently specific or reproducible. Follow-up hematologic and family studies of presumptive beta-thalassemia gene carriers indicated that coordinate measurement of erythrocytic indices and Hb A2 values would have discriminated a subpopulation with a high incidence of beta-thalassemia trait more specifically. This approach was tested prospectively by the use of 731 venous blood samples collected in a county with a large population of Mediterranean ancestry. Of 31 individuals (4.2%) with presumptive thalassemia trait, 13 returned for a repeat testing, and the initial results for 11 were confirmed. These findings lend support to an empirical screening sequence suggested by Pearson (erythrocytic indices followed by Hb A2 quantitation), but they also indicate that a significant subpopulation of beta-thalassemia gene carriers with limited phenotypic expression may elude detection in any single-pass approach.

Blood Protein Electrophoresis↗
PubMed1983

Thalassemia minor: routine erythrocyte measurements and differentiation from iron deficiency.

The clinical differentiation of the causes of microcytosis is difficult because of the lack of a method for the diagnosis of alpha thalassemia. A number of laboratory tests have been proposed for the differentiation of alpha thalassemia from iron deficiency, including decision functions based on the red blood cell indices generated by electronic cell counters. The accuracy of these screening methods was assessed in 93 patients with microcytosis known to be secondary to either iron deficiency or beta thalassemia minor and, prospectively, in 26 patients with microcytosis in whom globin chain synthesis ratio was used to diagnose thalassemia. The functions evaluated were: RBC volume distribution curve; osmotic fragility; erythrocyte count; discriminant function = MCV - (5 X Hgb) - RBC - 8.4; ratio of MCH/RBC; ratio of MCV/RBC; and 0.01 X MCH X (MCV)2. A simplified method of measuring anisocytosis using the RBC volume distribution curve was significantly more accurate (P less than 0.01) in distinguishing iron deficiency from thalassemia than any of the other decision functions. Analysis of red blood cell volume distribution, although not sufficiently accurate for definitive diagnosis, appears to be a useful technic in the initial screening of patients with microcytosis and in determining which additional testing should be done.

Adult↗
PubMed1987

Reconstruction of human alpha thalassemia-2 genotypes in monkey cells.

The human adult alpha globin genes, alpha 2 and alpha 1, are contained within two tandemly arranged duplication units. Each unit spans 4 kb of DNA, and contains three homology blocks (X, Y, Z) separated by non-homologous sequences. Segmental DNA recombination processes between the two units have resulted in high frequencies of two types of deletions in certain human populations, each deletion removing one alpha globin gene from chromosome 16, (alpha-thalassemia 2). In order to study the molecular mechanisms of alpha-thalassemia 2, and of homologous DNA recombination in general in mammalian cells, we have reconstructed these two alpha-thalassemia 2 genotypes in monkey cells. The two duplication units have been cloned in an SV40 origin-containing vector, and transfected into COS 7 cells. Newly replicated plasmid DNA was isolated and analyzed by Southern blot hybridization. Homologous DNA recombination occurs with high frequencies (10-20% per kb of homology), and this generates both types of alpha-thalassemia 2 deletions on the episomes in the monkey cells. Removal of the 5' end of either one, or both, of the X blocks prior to DNA transfection affects the relative frequencies of the two alpha-thalassemia 2 genotypes in a novel way. We consider and discuss these results in terms of several alternative models. Our data suggest the existence of hot spot(s) for initiation of homologous DNA recombination, or recombination promoting element(s), in a specific region of the human adult alpha globin locus. A DNA sequence that defines the boundaries of the two duplication units, and has been implicated in the initiation of gene conversion of the two X blocks, is contained within this region.

Animals↗
PubMed1993

Case report: effects of iron deficiency and the -88 C-->T mutation on HbA2 levels in beta-thalassemia.

Hemoglobin A2 levels in members of an African American family with -88 C-->T beta(+)-thalassemia were measured, and two patients in whom iron deficiency anemia developed were evaluated during treatment. Iron deficiency may diminish the level of HbA2 in healthy control subjects and in patients with heterozygous beta-thalassemia; in addition, it may reduce the amount of variant hemoglobin in certain hemoglobinopathies. Although iron deficiency appeared to be associated with a reduction in HbA2 quantity in the patient with heterozygous beta-thalassemia, the level of HbA2 did not fall below the range characteristic of beta-thalassemia. It had been proposed that mutations in the beta-globin gene promoter may be associated with higher-than-expected levels of HbA2. However, this "mild" beta-globin gene promoter mutation did not seem to result in HbA2 concentrations higher than anticipated in the heterozygous beta-thalassemias.

Anemia, Hemolytic↗
PubMed2000

Correlative analysis of the sagittal profile of the spine in patients with beta-thalassemia and in healthy persons.

This prospective study compares several roentgenographic parameters of the thoracic and lumbar spine in patients with beta-thalassemia and in healthy persons who served as controls. Eighty-four patients with beta-thalassemia and 84 age- and gender-matched healthy persons were examined clinically and radiologically (thoracic kyphosis, lumbar lordosis, and vertebral and sacral inclination). Although there was a significant difference in the vertebral inclination from T6 to L1, L4, and L5 between patients and controls, thoracic kyphosis and lumbar lordosis did not differ in the two groups. The apical vertebra of the thoracic kyphosis in patients and controls was T7 and T6, respectively, whereas L4 was the apical vertebra of the lumbar lordosis in both groups. There were no age- or gender-related differences in the magnitude of sacral inclination, thoracic kyphosis, or lumbar lordosis in the patients with beta-thalassemia compared with controls. Lumbar lordosis was significantly correlated with sacral inclination in both patients with beta-thalassemia and controls. Beta-thalassemia does not affect sagittal profile of the thoracic and lumbar spine but it is associated by structural changes on the frontal plane of the spine that are expressed as a high prevalence of scoliosis.

Adolescent↗
PubMed1990

Low fractions of mono- and diconjugated bilirubin in patients with beta-thalassemia: an approach to characterize hepatic conjugation capacity.

Unconjugated and mono- and diconjugated bilirubin was determined by alkaline methanolysis and thin-layer chromatography in serum from 16 pediatric patients with homozygous beta-thalassemia (aged 1-23 years), in 14 age-matched controls, and in 26 healthy adults. Total bilirubin amounted to 21 +/- 20 mumol/L in patients with thalassemia compared with 7 +/- 4 mumol/L in healthy children and 11 +/- 3 mumol/L in healthy adults. The fractions of bilirubin conjugates in the various groups were 8 +/- 4% (patients with thalassemia), 18 +/- 5% (age-matched controls; p less than 0.001), and 16 +/- 5% (healthy adults; p less than 0.001). The low fraction of bilirubin conjugates in patients with thalassemia showed no correlation to any other physical or laboratory finding. It is concluded that subnormal values of bilirubin conjugates in thalassemia indicate defective bilirubin conjugation.

Adolescent↗
PubMedDate not supplied

Selenium and glutathione peroxidase with beta-thalassemia major.

BACKGROUND: Chronic iron-overload is a major cause of organ failure and mortality worldwide, but its pathogenesis remains to be elucidated. OBJECTIVES: To examine the relationship between various measures of body iron burden, selenium concentrations and glutathione peroxidase (GPx) activity in patients with beta-thalassemia major. METHODS: An age- and gender-matched case control study was conducted to examine the relationship between various measures of body iron burden (serum ferritin, transferrin saturation, total serum iron), plasma concentrations of selenium and glutathione peroxidase (GPx) activity in patients with homozygous beta-thalassemia major (N = 20) and healthy controls (N = 10). Ten patients received the experimental oral chelator L1 and ten received chelation therapy with subcutaneous desferal. RESULTS: Significantly decreased plasma concentrations of selenium (microg/L) were observed in patients chelated with L1 (1.4 +/- 0.2) or desferal (1.4 +/- 0.1), in comparison to healthy controls (1.8 +/- 0.1, p < 0.01). Significantly decreased plasma activity of GPx (microg/L) was observed in patients chelated with L1 (166 +/- 43) or desferal (178 +/- 46), in comparison to healthy controls (296 +/- 22, p < 0.001). Significantly increased concentrations of all measures of body iron burden were observed in beta-thalassemia patients, in comparison to healthy controls (p < 0.001). CONCLUSION: Patients with beta-thalassemia major and chronic iron-overload have decreased concentrations of the essential element selenium and the protective selenium-dependent antioxidant enzyme GPx. Additional research examining the effects of dietary antioxidant supplementation with selenium on these aforementioned parameters in patients with beta-thalassemia major and iron-overload is warranted.

Adult↗
PubMed1992

Thalassemias: simple screening for hereditary anemias.

The most prevalent hemoglobinopathies in the world, thalassemias are hereditary microcytic anemias. Each year, 100,000 children throughout the world are born with thalassemia major, a fatal blood disease. Thalassemia minor is the carrier state for this catastrophic disease. Health practitioners can easily identify patients who may have thalassemia minor through evaluation of routine red-blood-cell indices, and diagnosis can be confirmed by Hgb A2 evaluation. Once individuals know they have thalassemia minor, a lifetime of unnecessary treatment for anemia can be avoided. Patient education should also include information about preconception counseling and partner screening. Recognition of the potential for congenital diseases and subsequent screening or referral are the responsibilities of all health care practitioners who see clients before and during their reproductive years.

Algorithms↗