RESUMO
HFE gene mutations have been shown to be responsible for hereditary hemochromatosis. Their effect on iron load in [3-thalassemia patients and carriers remains controversial. We aimed to determine the prevalence of HFE gene mutations [C282Y and H63D] in [3-thalassemia patients and carriers and to investigate its effect on their serum ferritin levels. A total of 100 [3-thalassemia subjects; 75 patients and 25 carriers were screened for HFE gene mutations by PCR-RFLP. Serum ferritin measured by ELISA was evaluated in relation to HFE mutations. Twenty-eight [3-thalassemia patients [37.3%] were heterozygotes for H63D mutation [H/D], 8 [10.7%] were D/D and 39 [52%] were negative [H/H]. Among carriers, 4 [16%] were D/D and 21 [84%] were H/H homozygotes. C282Y mutant allele was not detected in any of the subjects. Serum ferritin levels were significantly higher in p-thalassemia patients heterozygotes or homozygotes for H63D mutation compared to those without mutation [p = 0.000]. Carriers homozygotes for H63D mutation showed significantly higher serum ferritin levels compared to those without mutation [p < 0.001]. Homozygosity for H63D mutation tends to be associated with higher ferritin levels in beta-thalassemia patients and carriers suggesting its modulating effect on iron load in these cases
RESUMO
Low levels of fetal hemoglobin [HbF] in sickle cell disease [SCD] patients [pts] are associated with a variety of vaso-acciusive complications and an increased risk of early death. Raising HbF levels can reduce the effect of the disease. Hydroxyurea [HU] reduces the production of HbS containing red cells and favours the production of HbF containing red cells. It has been used successfully in the management of adults with SCD and there is growing data on its efficacy and safety in pediatric age group. This study reviews our clinical experience with HU in the treatment of pediatric pts with SCD attending the Pediatric Hematology Clinic of Cairo University. Sixty SCD pts from 2001 to 2007 who received HU over the period of 6 years [yrs] and who continued therapy for at least 6 months were included. Four pts were excluded because of noncompliance to treatment. Response to HU was assessed both clinically and by laboratory findings. Pts were considered responders if they showed >/= 50% improvement in clinical and laboratory data. These data included number of blood transfusions/yr, vasoocciusive crisis [VOC]/yr requiring admission to the emergency unit, hospital admissions/yr. Laboratory data included Hb [g/dl], MCV [fl], HbF%, total leucocytic count [TLC], x10[3]ml absolute neutrophil count [ANC], platelets x10[3]ml and reticulocytic count [%] and serum ferritin level [ng/ml]. Fifty six pts [44 children and 12 adults [>18 yrs] were included. Their mean age was 14.05 +/- 5.3 yrs [range of 6-28 yrs]. Thirty seven were females and 19 males. Twenty four [42.9%] were sickle-beta thalassemia while 32 [57.1%] were homozygous sickle cell anemia [SS]. The main indications for starting HU therapy were frequent VOC, transfusion dependency and acute chest syndrome [91%, 86% and 16% respectively]. Other indications included hepatic crisis [5%], bone infarction [7%], sequestration crisis [5%] and pulmonary hypertension in one case. HU was started in a dose of 15mg/kg/day with careful monthly monitoring for side effects. There was no attempt to achieve maximum tolerated dose. Dose increase or decrease was done depending on clinical and laboratory response with a maximum dose of 30mg/kg/day. The mean dose of HU was 15.8mg/kg/day [range 10-30 mg/kg/day] and the mean duration of therapy was 3.25 yrs [range of 0.5-6 yrs]. Forty four pts [78.6%] were found to be responders. There was a significant [p<0.05] improvement in all clinical parameters. Responders showed a significant decrease in TLC, ANC, reticulocytic count and serum ferritin [P values 0.002, 0.019, 0.000, 0.001 respectively]. Significant increase in HbF and MCV [p=0.000, 0.001 respectively] was also observed. HU toxicity was defined by>3 fold increase in ALT, platelet count<80,000 p1, ANC<1500 or increase in serum creatinine>50%above baseline. Twenty pts [35.7%] showed signs of HU toxicity: elevated ALT [n=9], neutropenia [n=7], thrombocytopenia [n=1], unexplained jaundice [n=1] and both neutropenia and jaundice [n=2]. Thirteen pts continued therapy with reduction of the dose or temporary stopping of HU while 7 stopped HU. It was noticed that all pts who developed hepatotoxicity were HCV positive p=0.036]. It was also shown that hepatotoxicity was significantly higher among those receiving Deferiprone with HU [n=20] [p=0.001]. There was no relation between response to HU and patients' age, sex, spleen status or phenotype. HU provides the best available strategy to achieve clinical and hematological improvement in SCD in pediatrics, but requires periodic monitoring of blood count and ALT levels especially for HCV positive pts and those on Deferiprone therapy