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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

We studied a patient with mild beta-thalassaemia major under treatment with the oral chelator deferiprone (DFP or L1) for about 10 yr (L1 veteran). Due to poor compliance with desferrioxamine, the patient started compassionate use of DFP at an age of 23 yr with a serum ferritin of 5200 microg/L. Monitoring iron overload by SQUID biosusceptometry revealed a dramatic decrease of liver iron concentrations from 4500 to 950 microg/g(liver) within 9.5 yr. A good clinical response to chelation treatment with DFP was observed together with an improvement of liver and cardiac function and a reduction in the hepatitis virus load.
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PMID:Long-term treatment with deferiprone in a L1 veteran. 1587 57

Hepatitis C virus is considered to be the main aetiological agent responsible for the occurrence of post-transfusion hepatitis. Patients with thalassaemia acquire hepatitis most often from viruses contracted through blood transfusions. The present study was undertaken to evaluate the prevalence of hepatitis C virus (HCV) in thalassaemic patients with multiple blood transfusions. The association of HCV seropositivity with number of blood transfusions and liver enzyme profile was also analysed. The study group consisted of fifty patients (40 males and 10 females) attending the thalassaemic unit of Lok Nayak Hospital, a tertiary care hospital at Delhi, within the age group of 1-25 years. Thirty patients (60%) were found to be seropositive for HCV antibodies while one patient (2%) was co-infected with HCV antibodies and hepatitis B surface antigen. Study of liver enzyme profile showed aspartate aminotransferase levels to be significantly higher, although the level of serum alanine aminotransferase, alkaline phosphatase, total protein, bilirubin and albumin were not significantly altered in these patients. It is inferred from this study that 60% of the thalassaemics were infected with HCV and this was directly related to the number of blood transfusions received by them. The regularised national blood policy followed by blood banks for providing safe blood along with better screening method of donated blood in blood banks would bring down the incidence of hepatitis C in such high risk group.
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PMID:Anti-HCV seropositivity among multiple transfused patients with beta thalassaemia. 1600 15

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

To assess the effects of liver iron overload and fibrosis after treatment with a chelating agent in hepatitis C virus (HCV)-infected thalassemia, from April 1999 to July 2004, 45 patients with thalassemia major (age range 9-33 years, mean 19.3) received daily deferiprone (L1) for 23-60 months (75 mg/kg). The patients were divided into two groups on the basis of their hepatitis status (27 with, 18 without). Their serum was analyzed for alanine aminotransferase (GPT), aspartate aminotransferase (GOT), bilirubin (total/direct), r-glutamyl transpeptidase (r-GT), alkaline phosphatase (Alk-P), and ferritin. Liver iron overload and fibrosis were defined by a senior pathologist. No significant differences were demonstrated in serum levels of GPT, GOT, bilirubin, r-GT, Alk-P or ferritin; comparison was made for each group before and after L1 treatment. Iron scores were 2.3 +/- 0.9 and 2.8 +/- 0.9 for the hepatitis C negative and positive groups, respectively (p = 0.07), with liver fibrosis scores of 1.0 +/- 0.5 and 0.4 +/- 0.52 (p = 0.56). The two scores were not higher for the positive group. There was no evidence of: 1) greater iron overload and fibrosis in the HCV-infected thalassemic patients; 2) L1 inducing progressive hepatic fibrosis or worsening iron overload in HCV-infected thalassemic patients after long-term therapy; 3) further damage to liver cells associated with L1 treatment.
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PMID:Effect of deferiprone on liver iron overload and fibrosis in hepatitis-C-virus-infected thalassemia. 1679 45

The role and value of endoscopic retrograde cholangiopancreatography (ERCP) in the pediatric age group is not well established, because pancreatic and biliary diseases are less common in children. This however is not the case in areas like the Eastern Province of Saudi Arabia where sickle cell disease (SCD) and other hemoglobinopathies are common, with increased frequency of cholelithiasis and choledocholithiasis. The purpose of this study was to evaluate the indications, findings, safety and therapies of ERCP in children. One hundred and twenty five children had diagnostic and/or therapeutic ERCP as part of their management at our hospital. Their medical records were reviewed for: age at diagnosis, sex, Hb electrophoresis, indication for ERCP, findings, therapy and complications. There were 77 males and 48 females. Their age at presentation ranged from 5-18 year (mean 13.25 year). The majority of them had sickle cell disease (77.6%). The indications for ERCP were: obstructive jaundice (67.2%), recurrent biliary colic with or without jaundice (10.4%), acute and chronic pancreatitis (7.2%), postoperative bile leak (2.4%), cholangitis with obstructive jaundice (2.4%), hepatitis of unknown etiology (3.2%), cirrhosis of unknown etiology (4%), thalassemia with jaundice (0.8%), hemobilia (0.8%), acute cholecystitis with jaundice (0.8%), and sickle cell disease with ulcerative colitis and obstructive jaundice (0.8%). In six children, ERCP was done following laparoscopic cholecystectomy. ERCP was carried out under sedation in 91 (72.8%) children and under general anesthesia in 34. It was successful in 121 (96.8%) children while cannulation of the Ampulla failed in four. ERCP was normal in 43 children, but eight of them showed evidence of recent stone passage and in six, there were gallstones. In the remaining children, ERCP revealed: normal CBD with stones (18 patients), dilated CBD with stones (17 patients), dilated CBD without stones (19 patients), dilated biliary tree with stones (10 patients), dilated biliary tree without stones (six patients), bile leak (two patients), dilated biliary tree with stones and choledocho-duodenal fistula (one patient), choledochal cyst (two patients), septate gallbladder (one patient), normal ERCP with multiple pancreatic cysts (one patient) and biliary stricture (one patient). The following procedures were carried out: 35 had endoscopic sphincterotomy and stone extraction, 20 had endoscopic sphincterotomy, four had CBD stenting, one underwent removal of a stent, two had insertion of a nasobiliary tube and one had biliary endoprosethesis. There was no mortality. One had bleeding from the site of sphincterotomy which stopped after adrenaline injection. Four patients (3.2%) developed transient mild pancreatitis which settled conservatively. ERCP in the pediatric age group is safe both as a diagnostic and therapeutic procedure. ERCP can provide valuable information which aid in the diagnosis of biliary and pancreatic diseases in children as well as therapy with the technical feasibility of endoscopic sphincterotomy. This is specially so in the era of laparoscopic cholecystectomy, where ERCP should be the treatment of choice in children with CBD stones who are going or have previously undergone laparoscopic cholecystectomy.
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PMID:Diagnostic and therapeutic ERCP in the pediatric age group. 1714 28

Cases of fatal, acute, irreversible renal failure and cytopenias, including agranulocytosis and thrombocytopenia, have been disclosed in a postmarketing report on deferasirox, a few months after the European Union authorities and about a year after the FDA proceeded to its accelerated approval. No details on the incidence rate or the cause of these toxicities have yet been reported. Other toxic side effects include skin, gastric, auditory and ocular abnormalities, and hepatitis. Regular serum creatinine, blood counts and other toxicity monitoring as well as withdrawal of deferasirox from the patients affected and those with serum ferritin < 0.5 mg/l was recommended. Toxicity, inability to clear cardiac iron and high cost (60 euros/g) question the future universal role of deferasirox, by comparison with the safety and efficacy records of deferiprone, deferoxamine and their combination in the treatment of transfusional iron overload. Also questioned are the procedures adopted by regulatory authorities and the marketing methods of pharmaceutical companies on orphan drugs, which are of no benefit to thalassaemia patients in developing countries.
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PMID:Deferasirox: uncertain future following renal failure fatalities, agranulocytosis and other toxicities. 1748 Jan 73

This prospective study analyzes the clinical features and histopathological findings in liver biopsies of pediatric patients presenting to the hospital with liver disease during a 10 year period. Only those patients in whom liver biopsy was performed for a tissue diagnosis were included. Fifty patients were investigated, all below the age of 12 years, of whom 36 were male and 14 female. Thirty-two were of neonatal-infantile group, 11 had a diagnosis of neonatal giant cell he hepatitis of infections origin and an intact biliary tree. Two had septic shock and one had leishmaniasis. The remaining 18 patients of the neonatal-infantile group constituted five case of glycogen storage disease, six of infantile obstructive cholangiopathy (biliary atreasia), four of fatty change and one each of congenital hepatic fibrosis, neuroblastoma and nonspecific reactive hepatitis. The eighteen older children had the following diagnoses: thalassemia in five, sickle cell disease in four, two each of Reye syndrome and hepatoblastoma. The remaining were one each of glycogen storage disease, Rotor syndrome, cirrhosis, fatty change and non-Hodgkin lymphoma (NHL). These findings are presented and discussed.
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PMID:Pediatric liver disease in the eastern province of Saudi Arabia: A clinicopathological study. 1758 93

We report on an 11-year-old girl with concomitant Ebeta thalassemia (EbetaT) and Wilson disease (WD). She was diagnosed with EbetaT at 2 years of age, but the coexistence of WD could only be established at 11 years. The diagnosis of the later was based on the clinical presentation of hepatitis and severe Coomb's negative hemolytic anemia, coupled with laboratory evidence of WD. To our knowledge, this is the first report on the cooccurrence of EbetaT and WD. As both the conditions are associated with variable degrees of hemolysis, WD in the setting of EbetaT may remain masked and consequently remain undiagnosed for a long time. Sudden, severe hemolysis in a patient of thalassemia may be explained by the coexistence of additional pathology, in this case WD.
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PMID:Acute Wilson disease associated with E beta-thalassemia. 1913 82

This literature review is a comprehensive summary of premarital (prenuptial) screening programmes for the most prevalent hereditary haemoglobinopathies, namely thalassaemia and sickle cell disease, and the important infections HIV (human immunodeficiency virus) and hepatitis viruses B and C (HBV and HCV). It describes the background to premarital screening programmes and their value in countries where these diseases are endemic. The use of premarital screening worldwide is critically evaluated, including recent experiences in Saudi Arabia, followed by discussion of the outcomes of such programmes. Despite its many benefits, premarital testing is not acceptable in some communities for various legal and religious reasons, and other educational and cultural factors may prevent some married couples following the advice given by counsellors. The success of these programmes therefore depends on adequate religious support, government policy, education and counselling. In contrast to premarital screening for haemoglobinopathies, premarital screening for HIV and the hepatitis viruses is still highly controversial, both in terms of ethics and cost-effectiveness. In wealthy countries, premarital hepatitis and HIV testing could become mandatory if at-risk, high-prevalence populations are clearly identified and all ethical issues are adequately addressed.
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PMID:Premarital screening programmes for haemoglobinopathies, HIV and hepatitis viruses: review and factors affecting their success. 1934 27


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