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Query: UMLS:C0039730 (thalassemia)
 10,305 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

New developments in the epidemiology, treatment and prognosis of thalassemia have dramatically altered the approach to the care of affected patients, and these developments are likely to have an even greater impact in the next few years. Demographic changes have required an awareness and understanding of the unique features of thalassemia disorders that were previously uncommon in North America but are now seen more frequently in children and recognized more consistently in adults. New methods for measuring tissue iron accumulation and new drugs to remove excessive iron are advancing two of the most challenging areas in the management of thalassemia as well as other transfusion-dependent disorders. Improved survival of patients with thalassemia has given new importance to adult complications such as endocrinopathies and hepatitis that have a major impact on the quality of life. This chapter describes how these changes are redefining the clinical management of thalassemia. In Section I, Dr. Renzo Galanello describes recent advances in iron chelation therapy. Several new chelators are either licensed in some countries, are in clinical trials or are in the late stages of preclinical development. Some of these iron chelators, such as deferiprone (DFP) and ICL670, are orally active. Others, such as hydroxybenzyl-ethylenediamine-diacetic acid (HBED) and starch deferoxamine, require parenteral administration but may be effective with less frequent administration than is currently required for deferoxamine. Chelation therapy employing two chelators offers the possibility of more effective removal of iron without compromising safety or compliance. Other strategies for chelation therapy may take advantage of the ability of particular chelators to remove iron from specific target organs such as the heart and the liver. In Section II, Dr. Dudley Pennell addresses cardiac iron overload, the most frequent cause of death from chronic transfusion therapy. The cardiac complications related to excessive iron may result from long-term iron deposition in vulnerable areas or may be due to the more immediate effects of nontransferrin-bound iron. Cardiac disease is reversible in some patients with intensive iron chelation therapy, but identification of cardiac problems prior to the onset of serious arrhythmias or congestive heart failure has proven difficult. New methods using magnetic resonance imaging (MRI) have recently been developed to assess cardiac iron loading, and studies suggest a clinically useful relationship between the results using these techniques and critical measures of cardiac function. Measurements such as T2* may help guide chelation therapy in individual patients and may also enhance the assessment of new chelators in clinical trials. The use of MRI-based technology also holds promise for wider application of non-invasive assessment of cardiac iron in the management of patients with thalassemia. In Section III, Dr. Melody Cunningham describes some of the important complications of thalassemia that are emerging as patients survive into adulthood. Hepatitis C infection is present in the majority of patients older than 25 years. However, antiviral therapy in patients with thalassemia has been held back by the absence of large clinical trials and concern about ribavirin-induced hemolysis. More aggressive approaches to the treatment of hepatitis C may be particularly valuable because of the additive risks for cirrhosis and hepatocellular carcinoma that are posed by infection and iron overload. Thrombosis is recognized with increasing frequency as a significant complication of thalassemia major and thalassemia intermedia, and pulmonary hypertension is now the focus of intense study. Risk factors for thrombosis such as splenectomy are being identified and new approaches to anticoagulation are being initiated. Pregnancies in women with thalassemia are increasingly common with and without hormonal therapy, and require a better understanding of the risks of iron overload and cardiac disease in the mother and exposure of the fetus to iron chelators. In Section IV, Dr. Elliott Vichinsky describes the dramatic changes in the epidemiology of thalassemia in North America. Hemoglobin E-beta thalassemia is seen with increasing frequency and poses a particular challenge because of the wide variability in clinical severity. Some affected patients may require little or no intervention, while others need chronic transfusion therapy and may be appropriate candidates for hematopoietic stem cell transplantation. Enhancers of fetal hemoglobin production may have a unique role in Hb E-beta thalassemia since a modest increase in hemoglobin level may confer substantial clinical benefits. Alpha thalassemia is also being recognized with increasing frequency in North America, and newborn screening for Hemoglobin Barts in some states is leading to early detection of Hb H disease and Hb H Constant Spring. New data clarify the importance of distinguishing these two disorders because of the increased severity associated with Hb H Constant Spring. The use of intrauterine transfusions to sustain the viability of fetuses with homozygous alpha thalassemia has created a new population of patients with severe thalassemia and has raised new and complex issues in genetic counseling for parents with alpha thalassemia trait.
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PMID:Thalassemia. 1556 74

The life expectancy of patients with thalassemia major has significantly increased in recent years, as reported by several groups in different countries. However, complications are still frequent and affect the patients' quality of life. In a recent study from the United Kingdom, it was found that 50% of the patients had died before age 35. At that age, 65% of the patients from an Italian long-term study were still alive. Heart disease is responsible for more than half of the deaths. The prevalence of complications in Italian patients born after 1970 includes heart failure in 7%, hypogonadism in 55%, hypothyroidism in 11%, and diabetes in 6%. Similar data were reported in patients from the United States. In the Italian study, lower ferritin levels were associated with a lower probability of experiencing heart failure and with prolonged survival. Osteoporosis and osteopenia are common and affect virtually all patients. Hepatitis C virus antibodies are present in 85% of multitransfused Italian patients, 23% of patients in the United Kingdom, 35% in the United States, 34% in France, and 21% in India. Hepatocellular carcinoma can complicate the course of hepatitis. A survey of Italian centers has identified 23 such cases in patients with a thalassemia syndrome. In conclusion, rates of survival and complication-free survival continue to improve, due to better treatment strategies. New complications are appearing in long-term survivors. Iron overload of the heart remains the main cause of morbidity and mortality.
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PMID:Survival and complications in thalassemia. 1633 50

The pathophysiology of thalassemia is, to a certain extent, associated with the generation of labile iron in the pathological red blood cell (RBC). The appearance of such forms of iron at the inner and outer cell surfaces exposes the cell to conditions whereby the labile metal promotes the formation of reactive oxygen species (ROS) leading to cumulative cell damage. Another source of iron accumulation results from increased absorption due to decreased expression of hepcidin. The presence of labile plasma iron (LPI) was carried out using fluorescent probes in the FACS. RNA expression of hepcidin was measured in two models of thalassemic mice. Hepcidin expression was also measured in human hepatoma HepG2 cells following incubation with thalassemic sera. LPI was identified and could be quantitatively measured and correlated with other parameters of iron overload. Hepcidin expression was downregulated in the livers of thalassemic mice, in major more than in intermedia. Thalassemic sera down regulated hepcidin expression in HepG2 liver cells. A possible way to decrease iron absorption could be by modulating hepcidin expression pharmacologically, by gene therapy or by its administration. Treatment with combination of antioxidants such as N-acetylcysteine for proteins and vitamin E for lipids in addition to iron chelators could neutralize the deleterious effects of ROS and monitored by quantitation of LPI.
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PMID:Role of iron in inducing oxidative stress in thalassemia: Can it be prevented by inhibition of absorption and by antioxidants? 1633 57

Hepatocellular carcinoma (HCC) is a complication of cirrhosis. Due to blood transfusions, patients with beta-thalassemia (thal) are often infected with either hepatitis C virus (HCV) or hepatitis B virus (HBV). In the past, many patients did not survive long enough to develop HCC. The recent improvements in prognosis have helped in the diagnosis of HCC that has developed. The aim of this study was to evaluate HCC incidence in beta-thal. We performed liver ultrasound (US) on all adults without a previous diagnosis of HCC. Risk factors (iron overload, HCV infection, HBV infection, cirrhosis) were evaluated. One hundred and eight thalassemia patients have been evaluated; of whom three were excluded (two patients as they were under the age of 18 years and one patient because he had a previous history of HCC). Seventy-two patients [31 had thalassemia major (TM), 41 had thalassemia intermedia (TI)] with risk factors (iron overload in 72, HCV infection in 46, HBV infection in two, cirrhosis in 10) and 33 (four with TM and 29 with TI) without risk factors underwent liver US. Overall, two patients were found to have a newly developed HCC. Of these two patients, one was treated with surgery and the other with percutaneous radiofrequency. Further follow-up did not show any evidence of recurrence after 23 and 15 months, respectively. Ultrasound screening can allow early detection and treatment of HCC in thalassemia patients.
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PMID:A prospective study of hepatocellular carcinoma incidence in thalassemia. 1654 Apr 24

Infections are major complications and constitute the second most common cause of mortality and a main cause of morbidity in patients with thalassaemia, a group of genetic disorders of haemoglobin synthesis characterised by a disturbance of globin chain production. Thalassaemias are among the most common genetic disorders in the world. Predisposing factors for infections in thalassaemic patients include severe anaemia, iron overload, splenectomy, and a range of immune abnormalities. Major causative organisms of bacterial infections in thalassaemic patients are Klebsiella spp in Asia and Yersinia enterocolitica in western countries. Transfusion-associated viral infections (especially hepatitis C) can lead to liver cirrhosis and hepatocellular carcinoma. A unique and challenging infection detected in Asian patients is pythiosis, caused by a fungus-like organism, the mortality rate of which is very high. Because the prognosis for thalassaemia has much improved, with many patients surviving to the fifth decade of life in developed countries, it is mandatory to reduce mortality by recognising and presumptively treating infections in these patients as quickly as possible.
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PMID:Infections and thalassaemia. 1655 47

Beta-thalassaemia represents a group of diseases, in which ineffective erythropoiesis is accompanied by iron overload. In a mouse model of beta-thalassaemia, we observed that the liver expressed relatively low levels of hepcidin, which is a key factor in the regulation of iron absorption by the gut and of iron recycling by the reticuloendothelial system. It was hypothesised that, despite the overt iron overload, a putative plasma factor found in beta-thalassaemia might suppress liver hepcidin expression. Sera from beta-thalassaemia and haemochromatosis (C282Y mutation) patients were compared with those of healthy individuals regarding their capacity to induce changes the expression of key genes of iron metabolism in human HepG2 hepatoma cells. Sera from beta-thalassaemia major patients induced a major decrease in hepcidin (HAMP) and lipocalin2 (oncogene 24p3) (LCN2) expression, as well as a moderate decrease in haemojuvelin (HFE2) expression, compared with sera from healthy individuals. A significant correlation was found between the degree of downregulation of HAMP and HFE2 induced by beta-thalassaemia major sera (r = 0.852, P < 0.0009). Decreased HAMP expression was also found in HepG2 cells treated with sera from beta-thalassaemia intermedia patients. In contrast, the majority of sera from hereditary haemochromatosis patients induced an increase in HAMP expression, which correlated with transferrin (Tf) saturation (r = 0.765, P < 0.0099). Our results suggest that, in beta-thalassaemia, serum factors might override the potential effect of iron overload on HAMP expression, thereby providing an explanation for the failure to arrest excessive intestinal iron absorption in these patients.
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PMID:Downregulation of hepcidin and haemojuvelin expression in the hepatocyte cell-line HepG2 induced by thalassaemic sera. 1693 99

Thalassemic diseases including homozygous beta-thalassemia and beta-thalassemia/Hb E (beta-Thal/Hb E) are prevalent in Southeast Asia. Iron overload is a common complication in beta-thalassemia patients which induces intracellular oxidative stress and lipid peroxidation (LPO). LPO end products generate miscoding etheno adducts in DNA which after their repair are excreted in urine. We investigated whether urinary levels of 1,N6-ethenodeoxyadenosine (epsilondA) and 3,N4-ethenodeoxycytidine (epsilondC) can serve as putative cancer risk markers in beta-Thal/Hb E patients. epsilondA and epsilondC levels were assayed in collected urine samples by immunoprecipitation-HPLC-fluorescence and 32P-postlabeling TLC, respectively. Mean epsilondA (fmol/micromol creatinine) levels in urine of beta-Thal/Hb E patients ranged from 4.8 to 120.4 (33.8+/-3.9; n=37) and were 8.7 times higher compared to asymptomatic controls (1.4-13.8; 3.9+/-0.8; n=20). The respective epsilondC levels ranged from 0.15 to 32.5 (5.2+/-1.3; n=37) and were increased some 13 times over controls (0.04-1.2; 0.4+/-0.7; n=20). epsilondC levels were correlated positively with NTBI (r=0.517; P=0.002), whereas epsilondA showed only a trend (r=0.257; P=0.124). We conclude that the strongly increased urinary excretion of etheno adducts indicates elevated LPO-induced DNA damage in internal organs such as the liver. These highly promutagenic lesions may contribute to the increased risk of thalassemia patients to develop hepatocellular carcinoma.
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PMID:Increased urinary 1,N6-ethenodeoxyadenosine and 3,N4-ethenodeoxycytidine excretion in thalassemia patients: markers for lipid peroxidation-induced DNA damage. 1834 16

Chronic hepatitis C virus (HCV) infection is a major cause of morbidity and mortality worldwide. Progression to cirrhosis and hepatocellular carcinoma occurs in 20% of infected adults. The natural history following childhood infection is less well defined, although cirrhosis in children is described. Since blood product screening for HCV infection was introduced in 1990, most children who acquire HCV do so by vertical transmission from an infected mother. Transmission to offspring occurs in approximately 5%. Most children with HCV infection are asymptomatic. Diagnosis is made by testing those at risk for HCV RNA by polymerase chain reaction (PCR) and HCV antibody (anti-HCV) by enzyme immunoassay (EIA). The clinical impact of HCV infection is assessed by monitoring symptoms and signs, blood testing of liver enzymes, ultrasound imaging, and by liver biopsy. Improved efficacy and tolerability of treatment strategies in adults have had a significant impact on the management of children with HCV infection. The emphasis is now on promoting awareness, early diagnosis, and treatment. Treatment strategies have evolved from monotherapy with interferon alfa (IFNalpha), to combination therapy with ribavirin. Pegylated IFNalpha is superior to conventional IFNalpha, and forms the basis of current recommendations. The genotype of HCV influences treatment efficacy. Treatment is generally well tolerated in children, although adverse effects are common. Preparation and support throughout treatment for the whole family is needed. A proportion of children with HCV infection have co-morbidity, including viral co-infection or hematologic disease. Although treatment may be contraindicated, risks and benefits must be considered before denying treatment. Anemia is more common in those with HIV co-infection, renal insufficiency, thalassemia, or cirrhosis, and may be aggravated by treatment. Children with thalassemia may have iron overload, and transfusion requirements may increase during treatment. Further refinements of combination therapy and development of new drugs are in progress. Vaccine candidates are undergoing phase I and II treatment trials.
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PMID:Management strategies for hepatitis C virus infection in children. 1899 46

TATA-binding protein (TBP) is the first basal factor that recognizes and binds a TATA box on TATA-containing gene promoters transcribed by RNA polymerase II. Data available in the literature are indicative of admissible variability of the TATA box. The TATA box flanking sequences can influence TBP affinity as well as the level of basal and activated transcription. The possibility of mediated involvement in in vivo gene expression regulation of the TBP interactions with variant TATA boxes is supported by data on TATA box polymorphisms and associated human hereditary pathologies. A table containing data on TATA element polymorphisms in human gene promoters (about 40 mutations have been described), associated with particular pathologies, their short functional characteristics, and manifestation mechanisms of TATA-box SNPs is presented. Four classes of polymorphisms are considered: TATA box polymorphisms that weaken and enhance promoter, polymorphisms causing TATA box emergence and disappearance, and human virus TATA box polymorphisms. The described examples are indicative of the polymorphism-associated severe pathologies like thalassemia, the increased risk of hepatocellular carcinoma, sensitivity to H. pylori infection, oral cavity and lung cancers, arterial hypertension, etc.
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PMID:TATA box polymorphisms in human gene promoters and associated hereditary pathologies. 1926 66

In thalassemia patients, iron overload can stimulate lipid peroxidation (LPO), thereby generating miscoding DNA adducts. Adducted DNA was measured in the lymphocytes of beta-Thal/Hb E patients and healthy controls and in the organs of thalassemic mice. epsilondA, epsilondC and M(1)dG residues were quantified by (32)P-postlabeling-TLC/HPLC. M(1)dG levels in lymphocyte DNA from patients were 4 times as high as in controls, while the increase in epsilondA and epsilondC was not significant. Adducted DNA accumulated in the liver of thalassemic mice having >2.7 mg Fe/g tissue dry weight; DNA adducts and iron were highly correlated. epsilondA was not specifically generated in certain mouse liver cell types as revealed by immunohistochemical staining. We found elevated LPO-induced DNA damage in the liver of thalassemic mouse and in lymphocytes, implicating that massive DNA damage occurs in the liver of thalassemia patients. We conclude that promutagenic LPO-derived DNA lesions are involved in the onset of hepatocellular carcinoma in these patients.
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PMID:Accumulation of lipid peroxidation-derived DNA lesions in iron-overloaded thalassemic mouse livers: comparison with levels in the lymphocytes of thalassemia patients. 1948 8


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