ORIGINAL ARTICLE: Pro-hepcidin and iron metabolism parameters in multi-time blood donors

A high number of blood donations may cause iron depletion. The pathophysiology behind this process may involve hepcidin, a recently discovered peptide that acts by inhibiting iron absorption and promoting iron retention in reticuloendothelial macrophages. The aim of this study was to determine serum pro-hepcidin levels and iron metabolism parameters in multi-time blood donors. The study group consisted of 132 multi-time male blood donors and 25 healthy male volunteers (nondonors). Complete blood cell count and iron status including serum iron, ferritin, soluble transferrin receptor (sTfR), total iron binding capacity (TIBC), unsaturated iron binding capacity (UIBC), erythropoietin and pro-hepcidin (ELISA) were assessed. In blood donors, ferritin level drops markedly in relation to donation frequency (P < 0.001). In contrast, TIBC and UIBC levels increase progressively corresponding to annual donation frequency. Pro-hepcidin concentration increases significantly with the number of donations per year (P = 0.0290). In blood donors having donated blood with the highest frequency per year, pro-hepcidin levels were positively correlated with haemoglobin (R = 0.31, P < 0.05) and negatively with sTfR (R = −0.31, P < 0.05). Pro-hepcidin levels increase in relation to blood donation frequency per year. Longitudinal studies focusing on changes in serum hepcidin levels are required to address the question whether hepcidin may contribute to iron metabolism disturbances in multi-times blood donors.     

Pulmonary hypertension in non-transfusion-dependent thalassemia: Correlation with clinical parameters,liver iron concentration,and non-transferrin-bound iron

Abstract

Background

Pulmonary hypertension is a major cardiac complication in non-transfusion-dependent thalassemia (NTDT). Several clinical and laboratory parameters, including iron overload, have been shown to have a positive correlation with the incidence of pulmonary hypertension. Non-transferrin-bound iron (NTBI) is a form of free-plasma iron that is a good indicator of iron overload.

Objectives

The aim of this study was to determine the prevalence of pulmonary hypertension in patients with NTDT and to investigate its correlation with the clinical parameters, liver iron concentration (LIC) and NTBI.

Methods

Patients with NTDT were evaluated using echocardiography, and magnetic resonance imaging for cardiac T2* and LIC. Pulmonary hypertension was de?ned as peak tricuspid regurgitation velocity ≥2.9 m/s measured using trans-thoracic echocardiography. Clinical parameters and the status of iron overload as determined by LIC, serum ferritin, and NTBI level were evaluated for their association with pulmonary hypertension.

Results

Of 76 NTDT patients, mean age 23.7 ± 8.5 years, seven patients (9.2%) had pulmonary hypertension. Previous splenectomy (71.4 vs. 24.6%, P-value 0.019), higher cumulative red blood cell (RBC) transfusions (received ≥10 RBC transfusions 85.7 vs. 33.3%, P-value 0.011), higher nucleated RBCs (353 ± 287 vs. 63 ± 160/100 white blood cells, P-value <0.001), and a high NTBI level (5.7 ± 3.0 vs. 3.3 ± 2.8 µmol/l, P-value 0.034) were associated with pulmonary hypertension. There was no significant correlation between LIC or serum ferritin and pulmonary hypertension.

Conclusion

Pulmonary hypertension in NTDT is common, and is associated with splenectomy and its related factors. NTBI level shows a significant correlation with pulmonary hypertension.     

Observational study comparing long-term safety and efficacy of Deferasirox with Desferrioxamine therapy in chelation-naïve children with transfusional iron overload

Objectives: An observational study was conducted to explore postmarketing safety and efficacy of Deferasirox (DFX) in comparison with conventional Desferrioxamine (DFO) in chelation‐naïve children with transfusional iron overload. Methods: Transfusion‐dependent children (aged ≤5 yr) who had serum ferritin above 1000 μg/L and had been prescribed either first‐line DFX or DFO for at least 12 months to maintain serum ferritin between 500 and 1000 μg/L were included. Initial DFX dose was 20 mg/kg/d for 7 d a week, and DFO dose was 25–35 mg/kg/d subcutaneously, given for 5 d a week. Dose adjustments were based on serum ferritin changes and safety markers. The primary efficacy endpoint was change in serum ferritin from baseline. The effect of transfusional iron loading rate (ILR) and different doses of chelators on serum ferritin was also assessed. Results: A total of 111 patients were observed for a median of 2.29 yr on DFX (n = 71) and 2.75 yr on DFO (n = 40). Absolute change in serum ferritin from baseline to the last available observation was not significant with DFX (91 μg/L, P = 0.5) but significantly higher with DFO (385 μg/L, P < 0.005). ILR and DFX doses had a major impact on serum ferritin changes in DFX cohort. The height‐ and weight‐standard deviation scores did not differ significantly in both cohorts during the study. Fluctuations in liver enzymes and non‐progressive increase in serum creatinine were the most common adverse events (DFX; 9.8%, 18.0% and DFO; 5.0%, 7.5%, respectively). Conclusion: DFX is well tolerable and at least as effective as DFO to maintain safe serum ferritin levels and normal growth progression in chelation‐naïve children.     

Elevated total iron-binding capacity as a predictor of response to deferasirox therapy in the setting of chronic iron overload

It is difficult to predict the efficacy of deferasirox (DFX) as its pharmacokinetics varies among patients. The area under the curve (AUC) is reportedly useful for determining adequate DFX dosage; however, serum concentration measurements are often challenging. Effective DFX dosage is thus defined by assessing the efficacy of this agent in clinical practice. To analyze a predictive response marker to DFX therapy for use in adjusting the effective dosage during the early treatment phase, we retrospectively evaluated 39 DFX-treated patients. We defined response as a >40 % decrease in serum ferritin concentration from the pretreatment level. A maximum elevation of the total iron-binding capacity (TIBC) correlated with response in a multivariate analysis of iron metabolic markers (R ² = 0.37, p < 0.001). A receiver operating characteristic curve analysis revealed that TIBC elevation had an AUC of 0.85 (p < 0.001) and the optimal cut-off value of TIBC elevation was 150 µg/dl. TIBC elevation of >150 µg/dl is a favorable predictor of effective ferritin reduction in DFX therapy (hazard ratio 29.6, 95 % confidence interval 4.8–183.6; p < 0.001). DFX therapy with TIBC monitoring may enable the determination of the minimum effective DFX dosage.     

Bone marrow iron distribution,hepcidin, and ferroportin expression in renal anemia

Abstract

Objectives

The hepcidin–ferroportin system is involved in both conditions associated with iron-restricted erythropoiesis in renal anemia: iron deficiency and anemia of chronic disorders. As serum hepcidin could aid diagnosis, we investigated its relationships with bone marrow iron distribution, hepcidin–ferroportin expression in bone marrow cells, and peripheral iron indices in non-dialysis chronic kidney disease (CKD) patients.

Methods

Fifty-four epoetin and iron naive CKD patients entered this prospective, observational study. According to bone marrow iron distribution (iliac crest biopsy, Perls' stain), 26 had iron deficiency anemia, 21 anemia of chronic disorders and 7 had normal iron stores. Medullar hepcidin and ferroportin expression (immunofluorescence (IF), semiquantitative scales) and serum hepcidin (Hep25 – ELISA) were the main studied parameters.

Results

Low hepcidin and high ferroportin expression by erythroblast and macrophage were seen in iron deficiency anemia, while the opposites were true in anemia of chronic disorders. In regression analysis, higher Hep25 and ferritin predicted hepcidin expression (R²=0.48; P < 0.0001), while lower ferritin and Hep25 - predicted ferroportin expression (R² = 0.29; P = 0.003) by erythroblast; inflammation had no contribution. In ROC analysis, serum hepcidin and ferritin had similar moderate utility in differentiating iron deficiency anemia from anemia of chronic disorders (AUC 0.63 95% CI 0.47–0.79 and 0.76 95% CI 0.61–0.90, respectively).

Conclusions

Thus, in anemic epoetin naive non-dialysis CKD patients, hepcidin and ferroportin expression by erythroblast and macrophage are closely related to bone marrow iron distribution. Although the hepcidin–ferroportin system seems regulated by ferritin-driven Hep25, serum hepcidin and peripheral iron indices are of little help in describing bone marrow iron status.     

Hepcidin levels predict nonresponsiveness to oral iron therapy in patients with iron deficiency anemia

Levels of hepcidin, a major regulator of iron homeostasis, may identify patients with iron deficiency anemia (IDA) who will not respond to oral iron therapy. In this study, IDA patients underwent a 14‐day trial (run‐in) course of ferrous sulfate therapy. Nonresponders (Hgb increase <1 g/dL with 67% compliance rate) were randomized to IV ferric carboxymaltose (FCM; two injections of 750 mg) or further oral iron for 14 days. Screening hepcidin levels were 38.4 versus 11.3 ng/mL, P = 0.0002 in nonresponders versus responders to a trial of oral iron. Hepcidin of > 20 ng/mL, showed sensitivity of 41.3%, specificity of 84.4%, and positive predictive value of 81.6% for predicting nonresponsiveness to oral iron. PPVs for ferritin> 30 ng/mL or transferrin saturation (TSAT)>15% were 59.2 and 55%, respectively. Negative predictive values for hepcidin, ferritin, and TSAT were 46.3, 22.7, and 19.7, respectively. FCM versus oral iron showed Hgb increases of ≥1 gm/dL in 65.3% versus 20.8% (P < 0.0001) and Hgb increases of 1.7 ± 1.3 versus 0.6 ± 0.9 g/dL (P = 0.0025), respectively. We conclude that hepcidin predicts nonresponsiveness to oral iron in patients with IDA and is superior to TSAT or ferritin for this purpose. Nonresponse to oral iron therapy does not rule out IDA, since two‐thirds of patients subsequently responded to intravenous iron. Am. J. Hematol. 88:97–101, 2013. © 2012 Wiley Periodicals, Inc.     

Impact of prohepcidin levels and iron parameters on early post-transplantation toxicities

Abstract

Objective: Recent reports show the adverse impact of pre-transplantation iron overload on the outcome of haematopoietic stem cell transplantation (HSCT). We studied the pre-transplantation serum iron (SI) parameters including prohepcidin levels — a regulatory peptide of systemic iron homeostasis — and their role in early post-transplantation toxicities in allogeneic HSCT recipients.

Patients and methods: One hundred consecutive patients [36 women and 64 men; median age 27·5 years (range 16–63 years)] who underwent allogeneic HSCT between September 2003 and October 2007 at Gazi University were included in the study.

Results: Pre-transplantation serum prohepcidin levels did not show correlation with SI parameters and interleukin-6 levels (P>0·05). Prohepcidin levels were inversely correlated with the National Cancer Institute grade of mucositis (P?=?0·060), neutropenic fever (P<0·001), and the number of days with febrile neutropenia (P?=?0·003). SI levels were correlated with the severity of hepatotoxicity (P?=?0·015) while pre-transplantation transferrin saturation levels were positively correlated with the severity of hepatotoxicity (P?=?0·055), pulmonary toxicity (P?=?0·032), and sinusoidal obstruction syndrome (P?=?0·049). Pre-transplantation serum ferritin levels were positively correlated with the development of sinusoidal obstruction syndrome (P?=?0·010) and inversely correlated with the day of neutrophil engraftment (P?=?0·012). Overall survival was 41·26% with a median follow-up time of 13 months (range 0·0–60 months). Pre-transplantation serum prohepcidin levels and iron overload were not associated with survival in Cox regression analysis.

Conclusion: Our results suggest that pre-transplantation iron parameters and prohepcidin levels might predict some of the early post-transplantation toxicities, however, without an impact on overall survival.     

Pattern of iron chelation therapy in Egyptian beta thalassemic patients: Mansoura University Children's Hospital experience

Background: The simultaneous use of deferoxamine (DFO) and deferiprone (DFP) has an additive effect in iron excretion in transfusion-dependent thalassemic patients.

Aim of the work: To evaluate the efficacy and safety of a prospective alternating therapy with DFO and DFP in patients with β-thalassemia major (TM) and increased serum ferritin with DFO monotherapy alone.

Patient and methods: Sixty patients with β-TM (mean age ± SD, 13.05 ± 6.1, range 10–20 years) with iron overload (serum ferritin > 2000 ng/ml) were studied. They received DFO at a daily dose of 40 mg/kg/day for 5–7 nights/week for the past several years. These patients were randomly assigned either to continue treatment with DFO alone (DFO group, n = 30) or prospectively receive additional alternating therapy with DFP at 75 mg/kg/day for 4 days/week and DFO for the other 2 days/week (alternating therapy group, n = 30). The efficacy of both groups was assessed by measurements of serum ferritin, echocardiography, and 24 h urine iron excretion (UIE) levels throughout 1 year follow-up.

Results: In the 60 evaluable patients, the mean serum ferritin (± SD) fell dramatically from 4500 (± 1250) ng/ml at the start of the study to 1250 (± 750) ng/ml (alternate therapy group; P < 0.001) at the end of the study. There was also a significant improvement in the myocardial function as assessed by the ejection fraction (P < 0.002) and fractional shortening (P < 0.01) in those patients on alternate therapy for 1 year. Their mean urinary iron excretion elevated from 0.41 ± 0.27 to 0.76 ± 0.49 mg/kg/24 h (P < 0.003). There was a significant difference between both groups as regard the studied parameters at the end of the study. Whereas, there was no statistical difference as regard the studied parameters at the start and the end of the study in the DFO group. No significant adverse effects had occurred in both groups that necessitated withdrawal from the study.

Conclusions: β-Thalassemic major patients with transfusional iron overload can be safely and effectively treated with an alternate therapy of DFO/DFP with a progressive fall in the mean serum ferritin and significant improvement of myocardial performance.     

口服与静脉铁剂治疗血液透析患者贫血的疗效观察

目的比较维持性血液透析患者口服和静脉补铁治疗肾性贫血的疗效,以及对促红细胞生成素(EPO)作用的影响。方法将30例病情稳定的血液透析患者随机分成静脉组和口服组2组各15例,观察期6个月。口服组口服福乃得(含硫酸亚铁525mg)1片/天,静脉组静脉补充铁剂。先按公式在2周内给予负荷剂量,以后每2周给予维持量100mg。若患者的血红蛋白(Hb)达到目标值120g/l,则将EPO的剂量减少25%。结果治疗后两组患者的Hb、红细胞压积(Hct)、铁蛋白(SF)和转铁蛋白饱和度(TSAT)进行性升高,治疗后3个月时口服组和静脉组患者的Hb、Hct、SF和TSAT均较治疗前显著升高,而静脉组升高的幅度明显高于口服组(P<0.01)。透析患者的贫血得到纠正,EPO用量开始减少,同时SF和TSAT保持在较高水平。6个月时EPO用量开始明显减少,减少的幅度明显高于口服组(P<0.01),明显高于治疗前静脉组(P<0.01)。结论长期静脉补铁不仅能及时有效地补充慢性肾衰竭血透患者贫血所需的铁剂,使贫血状况改善,而且能减少EPO用量。     

The differentiation of anaemia in rheumatoid arthritis: parameters of iron-deficiency in an Indian rheumatoid arthritis population

Iron deficiency anaemia (IDA) is common in Indian patients with rheumatoid arthritis (RA). We evaluated red blood cell indices, serum iron related and bone marrow iron stores measurements in diagnosing iron deficiency in patients with RA. Fifty consecutive anaemic patients with RA had their complete blood counts, red cell indices, serum iron, serum ferritin and serum total iron binding capacity (TIBC) measured and underwent posterior iliac crest bone marrow aspiration. Fixed smears were stained for iron with Perl’s Prussian blue and patients who had no (grade 0) or minimal stainable iron (grade I) were regarded as iron deficient and rest iron replete (grade II–IV) and hence as having anaemia of chronic disease (ACD). To determine diagnostic power of tests used for diagnosing iron deficiency in addition to positive likelihood ratio, sensitivity, specificity and negative predictive values; receiver operating characteristics (ROC) curves were plotted and areas under the receiver-operating curves were compared. Eighteen patients (36%) had IDA and 32 (64%) had ACD. Correlation between the bone marrow iron stores and serum ferritin was poor in the IDA group (r = −0.09, P = 0.57) and significant in the ACD group (r = 0.79, P < 0.0001). Areas under the ROC curves for mean corpuscular haemoglobin (MCV), serum iron, TIBC and mean corpuscular haemoglobin concentration (MCHC) were relatively low (0.52, 0.71, 0.75 and 0.77, respectively) and these tests had low positive likelihood ratios (1.08, 2.13, 4.62 and 1.5, respectively). Both area under ROC curve [0.98, 95% confidence interval (0.94, 0.99)] and negative predictive value (97%) were highest when cut off serum ferritin was <82 μg/l. In patients with RA serum iron, TIBC, MCV and MCHC have limited value in diagnosing iron deficiency. In this study compared to American and European studies a much higher cut off value of serum ferritin had most diagnostic power for detecting iron deficiency. Bone marrow iron stores measurements appears to be the most reliable method for diagnosing IDA however, it needs to be taken in conjunction with other laboratory findings and the clinical scenario.     

Combined therapy with desferrioxamine and deferiprone in beta thalassemia major patients with transfusional iron overload

Iron overload is the main cause of morbidity and mortality especially from heart failure in patients with beta thalassemia major (TM). Successful iron chelation is therefore essential for the optimal management of TM. Although desferrioxamine (DFX) has been the major iron-chelating treatment of transfusional iron overload, compliance is a major hindrance in achieving optimal therapeutic results. The availability of oral iron chelation with deferiprone (L₁) since 1987 is useful but showed poor efficacy when used alone as compared to DFX. We therefore decided to compare DFX alone with a prospective combined therapy with DFX and L₁ in beta thalassemia major patients with iron overload. We studied 91 patients with beta thalassemia major (mean age±SD, 15.02±5.8; range 2–30 years) attending the day care unit for regular transfusional support. They received packed red cells every 3–4 weeks to maintain pretransfusion hemoglobin concentration above 9 g/dl. They had been receiving DFX at a daily dose of 40 mg kg⁻¹ day⁻¹ by subcutaneous infusion for 8–10 h on 4–5 nights each week for the past several years. However, due to various reasons, they had developed considerable transfusional iron overload. These patients were allocated to prospectively receive additional therapy with oral iron chelator L₁ at 75 mg kg⁻¹ day⁻¹ body weight in three divided doses with food after informed consent and continued to receive treatment with DFX as per the above dosage. Of the 91 patients, six developed severe gastrointestinal (GI) upset, two agranulocytosis, two arthropathy, one persistently raised liver enzymes, two died owing to sepsis, and two received allogeneic bone marrow transplantation. Amongst the remaining 76 patients, 21 were found noncompliant (not taking DFX regularly, but taking L₁ regularly). Thus, in the 55 evaluable patients {6–48 months on combination therapy; mean [(±SD)22±12 months]}, the mean serum ferritin (±SD) fell dramatically from 3,088 (±1,299) ng/ml (DFX alone) to 2,051 (±935) ng/ml (DFX and L₁; p<0.001). It is interesting to note that there was also a significant improvement in the myocardial function as assessed by the ejection fraction (p<0.004) and fractional shortening (p<0.05) in those patients (n=42) who could be studied after being on combination therapy for a minimum of 1 year. The study emphasizes that beta thalassemia major patients with transfusional iron overload can be successfully treated with a combination of DFX and L₁. Our results also demonstrate a significant statistical improvement after as little as 6 months of combination therapy. Furthermore, these improvements lead to a progressive fall in the mean serum ferritin. Lastly, the study also demonstrates significant improvement in the echocardiographic parameters of myocardial performance in these patients receiving combination therapy.     

Long-term improvement in cardiac magnetic resonance in β-thalassemia major patients treated with deferasirox extends to patients with abnormal baseline cardiac function

The management of iron overload in thalassemia has changed dramatically since the implementation of magnetic resonance imaging, which allows detection of preclinical iron overload and prevention of clinical complications. This study evaluated the effect of deferasirox (DFX), the newest once-daily oral chelator, on cardiac function, iron overload and cardiovascular events over a longer follow up in a “real world” setting. Longitudinal changes in cardiac magnetic resonance T2*, cardiac function parameters and cardiovascular clinical events were assessed in a cohort of 98 TM patients exposed to DFX for a mean of 6.9 years (range 1.8-11.6 years). No cardiac death or incident heart failure occurred. Cardiac T2* significantly increased (+2.6 ± 11.9 msec; P = 0.035) in the whole population, with a significantly greater increase (+11.6 ± 15.5 msec, P = 0.019) in patients with cardiac iron overload (T2* <20 ms). A significant improvement in left-ventricular ejection fraction (LVEF) (from 50.6 ± 6 to 60.2 ± 5; P = 0.001) was observed in 11 (84.6%) out of 13 patients who normalized cardiac function (LVEF >56%). Arrhythmias were the most frequent cardiac adverse event noted but none led to DFX discontinuation. Our data indicate that DFX is effective in maintaining cardiac iron level in the normal range and in improving cardiac iron overload. No heart failure or cardiac death was reported over this longer observation up to 12 years. For the first time, a DFX-induced improvement in LVEF was observed in a subgroup of patients with abnormal cardiac function at baseline, a preliminary observation which deserves further evaluation.     

Assessment of liver and cardiac iron overload using MRI in patients with chronic anemias in Latin American countries: results from ASIMILA study*

ABSTRACT

Objectives: A multicenter, noninterventional, observational study was conducted in the Latin American countries including Argentina, Brazil, Colombia, Mexico, and Venezuela to assess the prevalence of liver and cardiac iron overload using magnetic resonance imaging (MRI) in patients with chronic anemias except thalassemia.

Methods: Patients aged >10 years with transfusion-dependent anemias, except thalassemia, either with <20 units of red blood cell (RBC) transfusions with serum ferritin (SF) levels >2000?ng/mL or with ≥20 units of RBC transfusions regardless of SF level in their lifetime, were enrolled. Iron overload was assessed using MRI.

Results: Among 175 patients included, the majority had sickle cell disease (SCD; 52%), followed by aplastic anemia (AA; 17.7%), myelodysplastic syndrome (MDS; 8.6%), Diamond-Blackfan anemia (DBA; 4%), pure red cell aplasia (1.1%), and others (16.6%). Liver iron overload was observed in 76.4% of patients, while cardiac iron overload was seen in 19.2% when assessed by MRI. The prevalence of iron overload was 80.2% in patients with SCD, 73.3% in MDS, 77.4% in AA, 100% in pure red cell aplasia, 71.4% in DBA, and 68.9% in other transfusion-related disorders. A moderate correlation between liver iron concentration (LIC) and SF was observed in patients with SCD and MDS (r?=?0.47 and r?=?0.61, respectively). All adverse events reported were consistent with the published data for deferasirox or underlying disease.

Conclusion: A high prevalence of iron overload in this patient population in Latin American countries indicates that a better diagnosis and management of iron overload is required in these countries.     

Biochemical expression of heterozygous hereditary hemochromatosis

Background: Hereditary hemochromatosis (HH) is a common autosomal recessive disease caused by an iron overload. Two mutations (C282Y and H63D) on the responsible HFE gene have been described. HH heterozygotes may have a slight iron overload that does not cause clinical disease. Compound heterozygosity may be associated with higher iron stores than C282Y heterozygosity. We studied biochemical iron parameters in HH C282Y and compound heterozygotes without a clinically significant iron overload. Methods: Data on hemoglobin, hematocrit, mean corpuscular volume, serum ferritin, serum iron, transferrin, and transferrin saturation were obtained from 40 C282 wild type controls (irrespective of H63D genotype), 61 C282Y heterozygotes, and 18 compound (C282Y/H63D) heterozygotes without clinical iron overload disease. Results: Serum ferritin levels were significantly higher in female HH heterozygotes, particularly in compound heterozygotes, than in normal women. In male heterozygotes, no difference in serum ferritin was found. We found higher mean serum iron and transferrin saturation levels in male and female HH heterozygotes than in normal controls, the highest in the group of compound heterozygotes. Conclusions: Mean serum ferritin (only in women), serum iron, and transferrin saturation are highest in compound heterozygotes and lowest in controls. C282Y heterozygotes seem to be an intermediate group between compound heterozygotes and the normal population.     

Safety and efficacy of early start of iron chelation therapy with deferiprone in young children newly diagnosed with transfusion‐dependent thalassemia: A randomized controlled trial

Iron overload is inevitable in patients who are transfusion dependent. In young children with transfusion‐dependent thalassemia (TDT), current practice is to delay the start of iron chelation therapy due to concerns over toxicities, which have been observed when deferoxamine was started too early. However, doing so may increase the risk of iron accumulation that will be manifested as toxicities later in life. This study investigated whether deferiprone, a chelator with a lower affinity for iron than deferoxamine, could postpone transfusional iron overload while maintaining a good safety profile. Recently diagnosed TDT infants (N = 64 their age ranged from 10 to 18 (median 12) months, 54.7% males; receiving ≤6 transfusions; serum ferittin (SF) >400 to < 1000 ng/mL were randomized to “early start deferiprone” (.ES‐DFP) at a low dose (50 mg/kg/day) or to “delay chelation” (DC), and remained in the study until their serum ferritin (SF) level reached ≥1000 μg/L. 61 patients continued the study Levels of transferrin saturation (TSAT) and labile plasma iron (LPI) were measured as well. By approximately 6 months postrandomization, 100% of the subjects in DC group had achieved SF > 1000 µg/L and TSAT > 70% compared with none in the ES‐DFP group. LPI level > 0.6 µM was observed in 97% vs. 40% of the DS and ES groups, respectively, (P < 0.001). The time to reach SF > 1000 µg/L was delayed by 6 months in the ES‐DFP group (P < 0.001) without escalating DFP dose. No unexpected, serious, or severe adverse events were seen in the ES‐DFP group.     

Serum transferrin receptor levels in patients undergoing evaluation of iron stores: correlation with other parameters and observed versus predicted results

Serum transferrin receptor (sTfR) concentrations were measured in specimens from 77 patients undergoing serum ferritin determination, and the results correlated with serum ferritin, serum iron, serum total iron-binding capacity (TIBC) saturation, erythrocyte mean corpuscular volume (MCV), and mean corpuscular haemoglobin (MCH). All parameters exhibited the expected inverse correlation with sTfR; this correlation was statistically significant for all parameters except serum iron concentration. The frequency with which iron deficiency (defined as absence of stainable marrow iron) is observed in patients with particular ferritin values in this centre was determined and used to estimate the expected number of iron deficient patients in the present study. In no setting were significantly fewer sTfR levels > 3.05 μg/ml observed than expected. However, significantly greater than expected numbers of elevated sTfR values were observed in patients with serum ferritin > 220 μg/l (P = 0.002). The results suggest that the sTfR level is probably not useful as a single test for identification of iron deficiency in unselected patients.     

Deferasirox chelation therapy in patients with transfusion‐dependent MDS: a ‘real‐world’ report from two regional Italian registries: Gruppo Romano Mielodisplasie and Registro Basilicata

Deferasirox (DFX) is an orally administered iron chelator approved for use in patients with transfusion‐dependent iron overload due to myelodysplastic syndromes (MDS). The safety and efficacy of DFX has been explored in clinical trial settings, but there is little data on unselected patients with MDS. The aim of this study was to retrospectively evaluate the safety, compliance, efficacy and effect on haematopoiesis of DFX in a large ‘real‐world’ MDS population. One hundred and eighteen patients with transfusion‐dependent MDS were treated with DFX across 11 centres in Italy. Serum ferritin levels, haematological response, dosing, adverse events and transfusion dependence were recorded at baseline, 3, 6, 12 and 24 months following initiation of treatment. DFX reduced mean serum ferritin levels from 1790 to 1140 ng/mL (P < 0.001), with 7.1% of patients achieving transfusion independence. Significant haematological improvement was seen in erythroid (17.6%), platelet (5.9%) and neutrophil counts (7.1%). Adverse events were reported in 47.5% of patients, including gastrointestinal and renal toxicity. Regression analysis showed that higher starting doses of DFX are associated with transfusion independence at 24 months. DFX is a safe, effective treatment for transfusion‐dependent MDS that can lead to transfusion independence and haematological improvement in a subset of patients.     

Hemochromatosis gene mutations may affect the survival of patients with myelodysplastic syndrome

Objectives: The recent availability of potent oral iron chelators is renewing an interest in the assessment of the possible impact of HFE genetics in MDS.

Methods: Thirty six newly diagnosed patients with MDS were studied for parameters of iron metabolism in addition to C282Y and H63D mutations of the HFE gene.

Results: Mutations were present in 11 out of 36 patients (31%), which were not different from our general population and were equally distributed among MDS subtypes. Mutated patients had higher ferritin levels (P?=?0.039) and lower TIBC (P?=?0.018). Ferritin was found to be higher for the untransfused mutated patients (P?=?0.017), but not for transfusion-dependent patients in whom ferritin levels correlated significantly with the number of blood units received (P?=?0.04). There was no difference in the number of blood units received between the mutated and wild type patients. A new observation made was that the mutated patients had a lower overall survival in addition to a poorer leukemia free survival (LFS) (P?=?0.004 and P?=?0.003, respectively).

Discussion: The HFE gene mutations are not more frequent in MDS patients. Iron overload in mutated patients was higher but there was no correlation found using supportive therapy for anemia. The effect of mutations on survival could be mediated by changes in iron metabolism.

Conclusion: The HFE genotype may predict MDS prognosis and there is a need for further studies. It remains a challenging question if HFE mutated MDS patients should be considered for potent iron chelation therapy.     

Iron status in Danes 1994

 Iron status, i.e. serum ferritin and haemoglobin (Hb) levels, was assessed in a population survey in 1994 (Dan-Monica 10) comprising 1319 Caucasian Danish women in age cohorts of 40, 50, 60 and 70 years. In the entire series, ferritin levels increased significantly from 40 years to 60 years of age. The prevalence of small iron stores (ferritin 16–32 μg/l), depleted iron stores (ferritin <16 μg/l) and of iron deficiency anaemia (ferritin <13 μg/l and Hb <121 g/l) decreased steadily with age. Blood donors (n=109) had lower ferritin levels than non-donors (P<0.0001). Ferritin levels in donors were inversely correlated with the cumulated number of lifetime phlebotomies (r _s =–0.25, P<0.01). Ferritin levels in non-donors (n=1208) were low in 40-year-old women (median 40 μg/l) and increased to a median of 95 μg/l in 60- and 70-year-old women (P<0.0001). In non-donors 40 years of age, the prevalence of small iron stores was 40.4%, the prevalence of depleted iron stores 10.8% and the prevalence of iron deficiency anaemia 2.16%. The prevalence of iron overload (ferritin >300 μg/l) was 1.54%. Ferritin levels in 60- and 70-year-old non-donors were correlated with the body mass index (r _s =0.11, P=0.01). Ferritin levels in 50- to 60-year-old non-donors were correlated with alcohol intake (r _s =0.23, P<0.0001). In the entire series, 37.5% of non-donors took supplemental ferrous iron (median 14 mg iron per day). Iron supplements had a significant positive influence on iron status in 40-year-old premenopausal non-donors but no effect in postmenopausal women or in donors. Non-donors (n=170) treated with acetylsalicylic acid had lower ferritin levels (median 55 μg/l) than non-treated (n=1038; median 75 μg/l) (P<0.0001). Compared with the Dan-Monica 1 iron status survey in 1984, the prevalence of iron deficiency and iron deficiency anaemia was unchanged, whereas the prevalence of iron overload displayed a slight increase. The 1987 abolition of the mandatory iron fortification of flour apparently had no negative effect on iron status. Received: 8 November 1999 / Accepted: 17 April 2000