Deferasirox (ICL670) is a once-daily oral iron chelator developed for the treatment of chronic iron overload from blood transfusions. A comparative phase 3 trial was conducted to demonstrate the efficacy of deferasirox in regularly transfused patients with ␤-thalassemia aged 2 years or older. Patients were randomized and received treatment with deferasirox (n ‫؍‬ 296) or deferoxamine (n ‫؍‬ 290), with dosing of each according to baseline liver iron concentration (LIC). The primary endpoint was maintenance or reduction of LIC; secondary endpoints included safety and tolerability, change in serum ferritin level, and net body iron balance. In both arms, patients with LIC values of 7 mg Fe/g dry weight (dw) or higher had significant and similar dose-dependent reductions in LIC and serum ferritin, and effects on net body iron balance. However, the primary endpoint was not met in the overall population, possibly due to the fact that proportionally lower doses of deferasirox relative to deferoxamine were administered to patients with LIC values less than 7 mg Fe/g dw. The most common adverse events included rash, gastrointestinal disturbances, and mild nonprogressive increases in serum creatinine. No agranulocytosis, arthropathy, or growth failure was associated with deferasirox administration. Deferasirox is a promising once-daily oral therapy for the treatment of transfusional iron overload. (Blood. 2006;107:3455-3462)

Most deaths in beta-thalassemia major result from cardiac complications due to iron overload. Differential effects on myocardial siderosis may exist between different chelators. A randomized controlled trial was performed in 61 patients previously maintained on subcutaneous deferoxamine. The primary end point was the change in myocardial siderosis (myocardial T2*) over 1 year in patients maintained on subcutaneous deferoxamine or those switched to oral deferiprone monotherapy. The dose of deferiprone was 92 mg/kg/d and deferoxamine was 43 mg/kg for 5.7 d/wk. Compliance was 94% ؎ 5.3% and 93% ؎ 9.7% (P ‫؍‬ .81), respectively. The improvement in myocardial T2* was significantly greater for deferiprone than deferoxamine (27% vs 13%; P ‫؍‬ .023). Left ventricular ejection fraction increased significantly more in the deferipronetreated group (3.1% vs 0.3% absolute units; P ‫؍‬ .003). The changes in liver iron level (؊0.93 mg/g dry weight vs ؊1.54 mg/g dry weight; P ‫؍‬ .40) and serum ferritin level (؊181 g/L vs ؊466 g/L; P ‫؍‬ .16), respectively, were not significantly different between groups. The most frequent adverse events were transient gastrointestinal symptoms for deferipronetreated patients and local reactions at the infusion site for deferoxamine. There were no episodes of agranulocytosis. Deferiprone monotherapy was significantly more effective than deferoxamine over 1 year in improving asymptomatic myocardial siderosis in beta-thalassemia major. (Blood. 2006;107: 3738-3744)

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The mechanism(s) determining the progression from fatty liver to steatohepatitis is currently unknown. Our goal was to define the relative impact of iron overload, genetic mutations of HFE, and insulin resistance on the severity of liver fibrosis in a population of subjects with nonalcoholic fatty liver disease (NAFLD) who had low prevalence of obesity and no overt symptoms of diabetes. In a cohort of 263 prospectively enrolled patients with NAFLD, 7.4% of patients had signs of peripheral iron overload and 9% had signs of hepatic iron overload, but 21.1% had hyperferritinemia. The prevalence of C282Y and H63D HFE mutations was similar to the general population and mutations were not associated with iron overload. Although subjects were on average only moderately overweight, insulin sensitivity, measured both in the fasting state and in response to oral glucose, was lower. Univariate analysis demonstrated that the presence of severe fibrosis was independently associated with older age, female sex, overweight, aspartate/alanine aminotransferase ratio, serum ferritin level, fasting glucose and insulin levels, decreased insulin sensitivity, and with histologic features (degree of necroinflammation and steatosis). After adjustment for body mass index (BMI), age, sex, and degree of steatosis, ferritin levels (odds ratio [OR] ‫؍‬ 1.77; 95% CI ‫؍‬ 1.21-2.58; P ‫؍‬ .0032) and the oral glucose insulin sensitivity (OR ‫؍‬ 0.53; CI ‫؍‬ 0.33-0.87; P ‫؍‬ .0113) were independent predictors of severe fibrosis. In conclusion, the current study indicates that insulin resistance is a major, independent risk factor for advanced fibrosis in patients with NAFLD. Increased ferritin levels are markers of severe histologic damage, but not of iron overload. Iron burden and HFE mutations do not contribute significantly to hepatic fibrosis in the majority of patients with NAFLD. (HEPATOLOGY 2004;39:179 -187.) N onalcoholic fatty liver disease (NAFLD) is growing in importance, causing in a wide spectrum of hepatic injury, ranging from fatty liver to steatohepatitis and cirrhosis. 1 Whereas pure fatty liver has a benign clinical course, nonalcoholic steatohepatitis (NASH) is a recognized cause of progressive liver fibrosis that eventually leads to cirrhosis, liver failure, and hepatocellular carcinoma. 2-4 NAFLD and NASH are the two most common chronic liver diseases in Western countries, with an estimated prevalence in the general population of 10% to 20% and 2% to 3%, respectively. 2,5-7 A two-hit theory 8 has been proposed to explain the progression from simple steatosis to NASH, fibrosis, or cirrhosis. The first hit is represented by excessive hepatic fat accumulation primarily owing to insulin resistance and is supported by the close relation observed between NAFLD and several features of the metabolic syndrome (visceral obesity, type II diabetes mellitus, and dyslipidemia). 9 -11 The second hit is related mainly to increased intrahepatic oxidative stress, which promotes hepatic fibrosis through the production of reactive oxygen sp...

Deferoxamine (DFO) therapy has been associated with improved survival of thalassemia patients. However, cardiac disease remains the main cause of death in those patients. In 1995, the oral chelator deferiprone became available for clinical use. We compared the occurrence of cardiac disease in patients treated only with DFO and in those whose therapy was switched to deferiprone during the period of observation, from January 31, 1995, to December 31, 2003. All patients with thalassemia major treated in 7 Italian centers who were born between 1970 and 1993 and who had not experienced a cardiac event prior to January 1995 were included. DFO only was given to 359 patients, and 157 patients received deferiprone for part of the time. A total of 3610 patient-years were observed on DFO and 750 on deferiprone. At baseline, the 2 groups were comparable for age and sex, while ferritin levels were significantly higher in patients switched to deferiprone. Fifty-two cardiac events, including 10 cardiac deaths, occurred during therapy with DFO. No cardiac events occurred during deferiprone therapy or within at least 18 months after the end of it. In the setting of a natural history study, deferiprone therapy was associated with significantly greater cardiac protection than deferoxamine in patients with thalassemia major. (Blood. 2006;107:3733-3737)

Anaemia is a chief determinant of globalill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P <10−8, which together explain 4–9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.

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.

High frequency of erythrocyte (red blood cell [RBC]) genetic disorders such as sickle cell trait, thalassemia trait, homozygous hemoglobin C (Hb-C), and glucose-6-phosphate dehydrogenase (G6PD) deficiency in regions with high incidence of Plasmodium falciparum malaria and casecontrol studies support the protective role of those conditions. Protection has been attributed to defective parasite growth or to enhanced removal of the parasitized RBCs. We suggested enhanced phagocytosis of rings, the early intraerythrocytic form of the parasite, as an alternative explanation for protection in G6PD deficiency. We show here that P falciparum developed similarly in normal RBCs and in sickle trait, beta-and alpha-thalassemia trait, and HbH RBCs. We also show that membrane-bound hemichromes, autologous immunoglobulin G (IgG) and complement IntroductionHigh frequency of hemoglobinopathies such as sickle cell trait, thalassemia trait, homozygous hemoglobin C (Hb-C) and Hb-E; glucose-6-phosphate dehydrogenase (G6PD) deficiency; and Southeast Asian ovalocytosis (SAO) in regions with past or present high incidence of Plasmodium falciparum malaria and case-control studies support the protective role of those conditions (see Roberts et al 1 ; Weatherall 2 ; Greene 3 ; and Serjeantson et al 4 for reviews). Protection has been attributed in some studies to defective invasion or growth of the parasite in the mutant erythrocytes (red blood cells [RBCs]), 5-7 while other studies found normal parasite invasion and growth. 8,9 Since the original proposal by Haldane, 10 microcitemia and increased osmotic resistance, enhanced oxidant radical production due to unpaired globin chains, increased sickling, ionic unbalances or membrane rigidity, or molecular defects in band 3 have been suggested as underlying mechanisms explaining impaired growth of the parasite in the mutant RBCs. [1][2][3][4][5][11][12][13] Other studies have found increased deposition of nonspecific autologous antibodies on malaria-parasitized mutant RBCs and suggested phagocytic elimination as the possible mechanism of protection in nonimmune subjects. 14-16 Recently, we found that several strains of P falciparum developed similarly in normal and G6PD-deficient RBCs. 9 However, ring-parasitized G6PD-deficient RBCs bound more opsonins such as autologous immunoglobulin G (IgG) and complement C3c fragments, and were phagocytosed more intensely than their normal counterparts. 9 We suggested enhanced ring phagocytosis as an alternative explanation for malaria protection in G6PD-deficient individuals, and discussed why removal of early parasite forms could be advantageous to the host. 9 We show here that P falciparum invaded and matured similarly in normal and mutant RBCs (heterozygous sickle cell anemia [HbAS]; heterozygous beta-thalassemia [beta-thal trait]; homozygotes for alpha-plus thalassemia [alpha-thal trait]; compound heterozygotes for alpha-zero and alpha-plus thalassemia [HbH disease]) up to the third cycle of invasion. We also show that membrane-bound hemichromes, ag...