Moderate Iron Overload Research Articles

Measurement of Liver Iron Concentration by MRI Is Reproducible

Purpose. The objectives were (i) construction of a phantom to reproduce the behavior of iron overload in the liver by MRI and (ii) assessment of the variability of a previously validated method to quantify liver iron concentration between different MRI devices using the phantom and patients. Materials and Methods. A phantom reproducing the liver/muscle ratios of two patients with intermediate and high iron overload. Nine patients with different levels of iron overload were studied in 4 multivendor devices and 8 of them were studied twice in the machine where the model was developed. The phantom was analysed in the same equipment and 14 times in the reference machine. Results. FeCl3 solutions containing 0.3, 0.5, 0.6, and 1.2 mg Fe/mL were chosen to generate the phantom. The average of the intramachine variability for patients was 10% and for the intermachines 8%. For the phantom the intramachine coefficient of variation was always below 0.1 and the average of intermachine variability was 10% for moderate and 5% for high iron overload. Conclusion. The phantom reproduces the behavior of patients with moderate or high iron overload. The proposed method of calculating liver iron concentration is reproducible in several different 1.5 T systems.

An assessment of iron overload in children treated for cancer and nonmalignant hematologic disorders

Our goal was to assess the natural fate of iron overload (IO) following transfusions of packed red blood cells (PRBCs) in children treated for cancer and nonmalignant disorders according to the intensity level of their treatment. Sixty-six children were followed up from February 2010 to March 2013. The transfusion burden was compared between three treatment intensity groups assigned according to the Intensity of Treatment Rating Scale 3.0 (ITR-3). IO was assessed by serial measurements of serum ferritin (SF) (n= 66) and quantification of tissue iron by magnetic resonance imaging (MRI) (n=12). Of the children studied, 36 % (24/66) received moderately intensive treatment (level 2), 21 % (14/ 66) received very intensive treatment (level 3), and 42 % (28/ 66) received the most intensive treatment (level 4). The number of PRBC (p=0.016), the total transfused volume (p= 0.026), and transfused volume adjusted to body weight (p= 0.004) were significantly higher in the level 4 group. By the median follow-up time of 35.5 months (range 8–133), 21– 29 % of patients (including level 2 and level 3 children) had SF >1,000 μg/l 1 year after cessation of transfusions. The slowest decrease of SF was observed in the level 4 group. Initial MRI examination demonstrated either mild or moderate IO in the liver and spleen. Repetitive MRI showed significant improvement in relaxation time between the initial and follow-up MRI performances in the liver (5.9 vs. 8.6 ms, p= 0.03) and the spleen (4.3 vs. 8.8 ms, p=0.03). IO diminished over time, but in the level 4 patients, it was detectable for years after cessation of transfusions.

A comparative study of deferasirox and deferiprone in the treatment of iron overload in patients with myelodysplastic syndromes

One hundred thirteen patients with myelodysplastic syndromes (MDS) with <10% of bone marrow blasts received either deferiprone in a daily dose of 40-90 mg/kg (48 patients) or deferasirox in a daily dose of 10-40 mg/kg (65 patients). Median duration of treatment was 10,9 months for deferiprone and 13,7 months for deferasirox. A substantial reduction of iron stores evaluated as a decrease in serum ferritin of more than 50% of pretreatment level was achieved in 18 patients in deferasirox group (27.7%) but not in any patient treated with deferiprone, The incidence of adverse effects (mostly gastrointestinal symptoms) was similar after administration of both the drugs. The symptoms of deferasirox toxicity were mild and mostly transient and no drug related myelosuppresive effect was observed in contrast to deferiprone where agranulocytosis occurred in 4% of patients and the treatment had to be discontinued due to side effects in 20% of patients. The results confirmed the usefulness of deferasirox as an effective and safe iron chelator in MDS patients and indication of deferiprone as an alternative treatment only in patients with mild or moderate iron overload clearly not indicated for deferasirox.

Iron overload in children undergoing cancer treatments

Iron overload is responsible for severe morbidity and mortality in polytransfused patients. Although repeated blood transfusions are needed during the treatment of most cancers, pediatric patients are not routinely screened for subsequent iron overload. Seventy-five patients were identified as candidates for cancer treatment and enrolled prospectively in a yearly protocol including a cardiac and liver magnetic resonance imaging coupled with ferritin level measurements. Patients were divided into four groups using the intensity of treatment rating (ITR-3). Fifty-nine patients reached 1-year of follow-up and liver iron overload was found in up to 66% of them. Such overload correlated with the total volume of red blood cells transfused and persisted at least 2 years after the initiation of therapy. Moderate myocardial overload was also, but less frequently (14%), observed in these patients. Our study demonstrated that severe liver iron overload as well as moderate myocardial iron overload can be found 1 year after cancer treatment and that this overload persists overtime. The patients with higher ITR and those who have received more than a liter of blood red cells per square meter, regardless of their diagnosis or ITR, are at risk of iron overload and should be screened carefully.

The use of appropriate calibration curves corrects for systematic differences in liver R2* values measured using different software packages

The use of appropriate calibration curves corrects for systematic differences in liver <scp>R</scp>2* values measured using different software packages

Peripheral intrahepatic cholangiocarcinoma occurring in patients without cirrhosis or chronic bile duct diseases

Peripheral intrahepatic cholangiocarcinoma (ICC) occurring mainly in the absence of cirrhosis represents an increasing subgroup of primary liver tumors in Western countries. Histopathologic changes in the non-neoplastic liver in this context are not well characterized. We assessed the clinical characteristics and histopathologic changes in the distant nontumoral liver of 57 consecutive White patients (34 men, mean age 59 years) referred to one medical and one surgical liver institution over a 16-year period who developed a peripheral ICC in the absence of cirrhosis or bile duct disease. High alcohol consumption was observed in 11 patients (20%), 38 patients (66%) had a BMI of 25 kg/m or more, 22 patients (40%) had diabetes, two patients had hepatitis B virus infection, two others had hepatitis C virus infection, three patients had genetic hemochromatosis, and two patients had cutaneous porphyria tarda. The distant nontumoral liver was normal in 10 patients (18%). The two main histopathologic changes observed were macrovesicular steatosis (>10% of hepatocytes) in 38 patients (66%), including 11 patients (19%) with steatohepatitis, and moderate or intense hepatocyte iron overload in 22 patients (38%). This study shows a high prevalence of macrovesicular steatosis associated or not with steatohepatitis and iron overload in patients who develop peripheral ICC in the absence of cirrhosis or bile duct disease.

Iron metabolic disorder in chronic hepatitis C: insights from recent evidence.

The liver is the major iron storage organ in the body, and therefore iron metabolic disorder is sometimes involved in chronic liver diseases. Chronic hepatitis C is one of the liver diseases that show hepatic iron accumulation. The present review highlights the current concept of hepatic iron overload status in chronic hepatitisC and discusses how iron metabolic disorder develops in this disease, and the impact of hepatic iron overload on disease progression and its relevance to hepatocarcinogenesis. The level of hepatic iron accumulation in chronic hepatitis C should be recognized to be basically mild to moderate and sometimes within the normal range. However, even mild to moderate iron overload in the liver contributes to disease progression and hepatocarcinogenesis in chronic hepatitis C, probably by reinforcing the oxidative stress induced by hepatitis C virus (HCV) protein. The mechanisms by which hepatic iron overload develops in chronic hepatitis C have not been fully elucidated. Reduction of the transcription activity of hepcidin by HCV-induced reactive oxygen species may in part account for it, but the regulation of hepcidin is very complex and may depend on many variables, including the particular stage of the systemic and/or hepatic inflammatory conditions and the circulating transferrin-bound iron and intracellular iron stores. This might explain the variations in hepatic iron concentrations reported among patients with HCV-related chronic liver disease.

Standardization of the quantification of iron concentration in the liver by magnetic resonance imaging

ObjectiveTo calibrate 1.5T magnetic resonance (MR) scanners for the quantification of the concentration of iron in the liver. Material and methodsWe analyzed twenty-eight 1.5T MR scanners using a phantom with four tubes containing different concentrations of iron (III) chloride and one tube without iron. The phantom represented two typical patients: one with moderate iron overload and one with high iron overload. We measured the signal intensity (SI) ratio between each iron-containing tube and the tube without iron; then we calculated the theoretical levels of iron concentration in each scanner according to the model for the two levels of overload. We compared the results of each scanner with those of the reference scanner in which the model and the phantom had been designed, and we calculated the percentage of difference between the two scanners. ResultsThe mean difference in the ratios compared to the reference center was 11% (0.3–39). The mean concentration of iron was 71μmolFe/g for moderate overload and 193μmolFe/g for high overload. The mean difference was 6% (1.2–7%) and 3.4% (0–16%), respectively.In two scanners, we applied a correction factor so that the difference was below 25% in all cases. ConclusionWe calibrated twenty-eight 1.5T scanners for the concentration of iron in the liver and achieved variability less than 25%.

T2* MRI in Hypertransfused Children with Thalassemia Intermedia: Serum Ferritin Does Not Reflect the Reality

Abstract 5304 Background:Non-transfused patients with thalassemia intermedia (TI) accumulate iron in their body due to increased gastrointestinal absorption of iron and release of iron from the macrophages. Earlier studies have revealed that serum ferritin does not reflect the severity of iron overload in non-transfused TI patients. The current study aims at evaluating the iron overload status in a group of young hypertransfused TI children. Materials and Methods:Eleven patients (mean age 13.18±4.094 years) with TI on regular follow-up at the Pediatric Thalassemia Day Care Centre, Sultan Qaboos University Hospital, Oman were included in the study after approval by the Medical Research and Ethics Committee. All patients had beta gene mutational analysis. They were diagnosed as intermedia because of their definitive TI mutation, late age at presentation (>5 years) and transfusion independence (mean baseline Hb 6.9 g/dl). Patients were treated conventionally with hypertransfusion, and chelation, as guided by their serum ferritin levels. Serum ferritin (2 monthly) was analyzed using the Beckman Coulter Access 2 Immunoassay System.Based on serum ferritin levels, patients were classified into 2 groups, group 1(six patients) and 2 (five patients) with serum ferritin levels below and above 1000 ng/ml respectively. All patients underwent cardiac T2* MRI assessment. Based on local reference values for T2*MRI, quantification of cardiac iron deposition was categorized as normal, mild, moderate and severe iron overload at values > 20 ms, 14–20 ms, 10–14 ms and < 10 ms respectively. Simultaneous liver iron T2* values were categorized into normal, mild, moderate and severe iron overload at values > 9.1 ms, 7.1–9.0 ms, 3.1– 7.0 ms and <3.0 ms respectively. Results:Patients in group 1 and 2 had mean serum ferritin levels of 817.300±244.690 ng/ml and 1983.80±662.862 ng/ml respectively (p = 0.003). Despite this very high variation in serum ferritin values, T2* MRI showed comparable hepatic iron overload status in both the groups with mean hepatic T2* value of 2.51±0.46 ms and 3.4±1.63 ms in group 1 and group 2 respectively. The difference in hepatic T2* between the 2 groups is −0.88 (95% confidence interval −2.44 to 0.68) which is statistically insignificant (p =0.23, t-test). None of the studied patients had myocardial iron deposition (overall mean 36.86±7.8 ms). Other confounders like initial ages at presentation, pre-transfusion hemoglobin levels, durations of transfusion and chelation therapies were statistically insignificant for the 2 groups. No specific pattern of beta gene sequence was noted in either group. Conclusions:We conclude in our patients with TI on hypertransfusion, serum ferritin does not reflect their moderate to severe hepatic iron overload status. Inspite of steady serum ferritin trends, evaluation of iron overload by T2* MRI and optimal chelation is strongly recommended in hypertransfused TI patients.Table 1:Demographic and laboratory characteristics of the 2 study groups.Group12Serum Ferritin, ng/ml<1000>1000Total number of children, n65Male: Female2:43:2Mean age of presentation, years7.17.8Mean pre-transfusion hemoglobin, g/dl7.06.8Mean duration of transfusion therapy, years5.06.6Mean duration of chelation therapy, years4.35.8Splenectomy (n)00Chelation monotherapy (DFP), n (mean dose mg/kg/day)6 (87)4 (100)Chelation combination (DFP+DFO), n (mean dose mg/kg/day)01 (100+40)n= number of patients DFP=Deferiprone DFO=DesferrioxamineTable 2Serum ferritin levels (ng/ml) T2* MRI values (ms) in the 2 groupsGroup 1Group 2Mean age ± SD, years12.16 ± 4.9114.4 ± 2.88Median age, range12.5 (4-18)15 (10-18)Mean serum ferritin ± SD, ng/ml817.300 ± 244.6901983.80 ± 662.862Median serum ferritin, range903.5 (323-990)1898 (1330-3008)Mean hepatic T2* ± SD, ms2.51 ± 0.463.4 ± 1.63Median hepatic T2*, range2.35 (2.1-3.1)3.3 (1.4-5.6)Mean cardiac T2* ± SD, ms37.41 ± 10.0836.2 ± 4.92Mean cardiac T2*, range33.9 (29-55)36 (30.3-42.6) [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Deferasirox Safety Profile in Patients with Transfusion-Dependent Anaemias:Results From the Interim Analysis of a Hellenic Study,

Abstract 3183 Background:The introduction of iron chelation treatment has led to a significant improvement in morbidity and overall survival in patients with transfusion-dependent anemias. Deferasirox is a once-daily, oral iron chelator approved for the treatment of transfusional iron overload in both adult and pediatric patients. The efficacy and safety of deferasirox in a variety of transfusion-dependent anemias has been established in numerous Phase II/III clinical trials. Since most patients with transfusion-dependent anemias require lifelong iron chelation therapy, there is a need to assess the long-term safety of deferasirox in both adult and pediatric patients. Aim:To assess the safety profile of deferasirox in patients with transfusional iron overload in a real-world clinical setting. To further investigate the safety profile of deferasirox in patients with congenital erythrocyte disorders and transfusional iron overload, with ferritin levels <4000 ng/ml and without severe cardiac siderosis. Methods:Between July 2009 and September 2010, 85 patients with transfusion-induced iron overload treated with deferasirox as per the approved product labeling were enrolled in the study. These data represent the 24-week planned interim analysis of a 12-month observational study on deferasirox safety profile in the treatment of pediatric and adult patients with transfusion-dependent anemias who were newly-treated with deferasirox. Safety was evaluated through the monitoring and recording of all adverse events and serious adverse events, as well as routine laboratory testing, including hematology, blood chemistry and hepatic function assessments. Results:The population had a median age of 37.6 years (range: 5.3–61.4) and a female to male ratio of 1.3. Beta-thalassemia (67.1%) was the most common transfusion-dependent anemia, followed by thalassemia intermedia requiring periodic transfusions (20.0%) and sickle cell anemia (12.9%). Mean baseline ferritin levels were 1502.1±870.5 (pediatric group: 1480.2±522.8 and adult group: 1503.6±891.4), while 53 out of the 85 patients (62.4%) had serum ferritin level above 1000 ng/ml. Mean baseline liver T2* value was 10.4±9.7 ms; 44.4% of patients demonstrated minimal liver iron deposition (MRI T2* > 6.3 ms), 51.4% had mild to moderate liver iron overload (T2* ≤ 6.3 ms), and 4.2% had severe liver iron overload (T2*<1.4 ms).54 (63.5%) of patients analysed had been pre-treated with iron chelators and 31 (36.5%) were chelation-naïve. The initial average daily dose of deferasirox was 25.9±4.8 mg/kg, and 70.6% of patients had no dose modification during the 24-week follow-up period. A statistical significant decrease in median serum ferritin levels was observed by Week 24 (mean absolute change from baseline:-214.5 ng/mL; p=0.009) [Figure 1]. No statistically significant changes were observed in creatitine levels, creatinine clearance and transaminases by Week 24 [Figure 1]. [Display omitted] 37 ADRs were reported by 17 patients (20%) over the 24-week period. Among the most frequently observed ADRs (>5%) were epigastralgia reported by 7.1% of patients (6/85) and loose stools/diarrhoea by 5.9% of patients (5/85). The majority of ADRs reported (nevents=25; 67.6%) were graded as mild in severity, while 21.6% (nevents=8) were graded as moderate and 10.8% (nevents=4) as severe. Most ADRs (nevents=31; 83.8%) resulted in full recovery by Week 24. The overall incidence of SADRs was as low as 1.2% (in particular one patient experienced severe epigastralgia and upper extremity pain which resulted in her withdrawal from the study after four months of treatment). The all-cause discontinuation rate was 9.4% (8/85), while only two patients (2.4%) discontinued the study therapy due to ADR; 1 patient due to increased transaminase levels and 1 patient due to the aforementioned SADR. Conclusions:These data highlight the safety profile of deferasirox in both adult and pediatric patients; the regular monitoring of serum ferritin levels as well as other iron-overload parameters and transfusion requirements play a major role in determining and optimizing the outcome of iron chelation therapy. Disclosures:Ladis:Novartis Hellas S.A.C.I.: Investigator participating in a trial sponsored by Novartis. Drossou:Novartis Pharmaceuticals: Investigator participating in a trial sponsored by Novartis. Vini:Novartis Pharmaceuticals: Investigator participating in a trial sponsored by Novartis. Athanasiou-Metaxa:Novartis Hellas S.A.C.I.: Research Funding. Oikonomou:Novartis Hellas S.A.C.I.: Investigator participating in a trial sponsored by Novartis. Vlachaki:Novartis Hellas S.A.C.I.: Investigator participating in a trial sponsored by Novartis. Tigka:Novartis Hellas S.A.C.I.: Employment. Tzavelas:Novartis Hellas S.A.C.I.: Employment. Liakopoulou:Novartis Hellas S.A.C.I.: Investigator participating in a trial sponsored by Novartis. Adamopoulos:Novartis Hellas S.A.C.I.: Investigator participating in a trial sponsored by Novartis. Kattamis:Novartis Hellas S.A.C.I.: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Monitoring Cardiac Siderosis in Patients with Beta-Thalassemia Major on Various Chelation Regimens,

Abstract 3177 Background:Patients with Beta-thalassemia major develop progressive iron overload in various organs. Cardiac siderosis is a major cause of mortality and morbidity in these patients, and also poses a significant treatment challenge. Methods:We have reviewed 101 beta-thalassemia major patients 39 Male (M) 62 Female (F) with a mean age of 27.9 (range: 2 to 60 years). All received regular transfusions to maintain pre transfusion Hb levels of 9 to10 gm/dl and all received iron chelation initially with deferoxamine (DFO) and subsequently treated with deferasirox (DFX) or deferiprone (DFP) in combination with DFO. Each patient was monitored yearly for iron excess by hepatic and cardiac magnetic resonance imaging (MRI) T2*. They were also assessed with monthly evaluations for liver and renal function (Bili, AST, ALT, BUN, Creatinine), serum ferritin, CBC (or weekly if on DFP), and urinalysis. Annual EKG, ECHO, hearing and vision testing and endocrine evaluations were also performed. The patients were grouped according to the severity of cardiac siderosis. Mild to moderate cardiac siderosis was defined as a T2* 12–20 msec and severe cardiac siderosis T2*≤ 11 msec. Annual studies were compared using paired student T test and repeated measures Analysis Of Variance (ANOVA) when necessary. Patient population:Twenty one of the 101 patients (7M and 14F) with a mean age of 30.6 yr, age range 15 to 56 yr, had abnormal cardiac T2* of <20 msec and three or more subsequent annual cardiac T2* measurements. Thirteen patients, 3 M 10 F with a mean age of 33 (range: 19 to 60), had severe cardiac siderosis and 8 patients, 3 M 5 F with mean age of 38 (range: 25 to 49), had mild-moderate cardiac siderosis. During the course of the observation their iron chelation therapy was optimized to reduce serum ferritin levels < 1500 μg/dl and to reduce or maintain liver iron concentration (LIC) ≤ 7 mg/gm dw. Data analysis:At the time of their first annual MRI study (baseline), 8 patients were on DFO of which 6 were switched to DFX, 13 patients were on DFX, 11 patients were dose escalated on DFX, and 4 patients were switched to combination chelation with DFO and DFP. At baseline, patients with severe cardiac siderosis had a mean cardiac T2* level = 7.4 ± 0.47 SEM (range: 4.6 to 11msec). Over the treatment course of 6 years annual cardiac T2* levels consistently improved and by 6 years cardiac T2* reached a mean level =14.3 ±1.5 SEM (range: 12 to 17 ms) (Fig 1). Those patients who at baseline had a mild to moderate cardiac siderosis with mean cardiac T2* of 14.6 ± 1.02 SEM (range: 12 to 19 msec) improved by 3 years of treatment when they achieved a mean cardiac T2* of 26.3 ± 3.4 SEM (range of 16 to 42 msec) (Fig 2). Liver iron concentration (LIC) was measured annually by MRI. Initially the majority, 16 out of 21 of patients, had hepatic iron overload LIC ≤ 10 mg/ gm dw of whom 56% (9 of the 16) had severe cardiac siderosis. 5 of 21 patients had a LIC > 15 mg/ gm dw of whom 80% (4 out of 5) patients had severe cardiac siderosis (Fig 3). Patients with LIC ≤10 mg/ gm dw had ferritin levels ranging from 166 to 3240 μg/ dl and patients with LIC >15 mg/ gm dw had elevated serum ferritin levels of 1180 to 17,000 μg/ dl. Patients with severe cardiac siderosis had mean MRI ejection fraction (EF)= 55.8% (range: 31 to 70%) while patients with mild to moderate cardiac siderosis had mean MRI EF= 60% (range: 53 to 66%). One patient with severe cardiac siderosis was recovering from symptomatic congestive heart failure. [Display omitted] [Display omitted] [Display omitted] Conclusion:Cardiac siderosis can be noninvasively diagnosed utilizing MRI T2* techniques and subsequently to monitor treatment. The majority of patients improve cardiac T2* over time with optimal chelation therapy. Severe cardiac siderosis occurs even with mild to moderate hepatic iron overload. Left ventricular EF may not predict severe cardiac siderosis. Therefore it is important to annually monitor cardiac siderosis with MRI T2*. Disclosures:No relevant conflicts of interest to declare.

Estandarización de la cuantificación de la concentración de hierro en el hígado por resonancia magnética

ObjectiveTo calibrate 1.5 tesla magnetic resonance scanners for the quantification of the concentration of iron in the liver. Material and methodsWe analyzed twenty-eight 1.5 tesla magnetic resonance scanners using a phantom with four tubes containing different concentrations of iron (III) chloride and one tube without iron. The phantom represented two typical patients: one with moderate iron overload and one with high iron overload. We measured the signal intensity ratio between each iron-containing tube and the tube without iron; then we calculated the theoretical levels of iron concentration in each scanner according to the model for the two levels of overload. We compared the results of each scanner with those of the reference scanner in which the model and the phantom had been designed, and we calculated the percentage of difference between the two scanners. ResultsThe mean difference in the ratios compared to the reference center was 11% (0.3-39). The mean concentration of iron was 71μmol Fe/g for moderate overload and 193μmol Fe/g for high overload. The mean difference was 6% (1.2- 7%) and 3.4% (0-16%). respectively.In two scanners, we applied a correction factor so that the difference was below 25% in all cases. ConclusionWe calibrated twenty-eight 1.5 tesla scanners for the concentration of iron in the liver and achieved variability less than 25%.

Liver iron overload is associated with elevated SHBG concentration and moderate hypogonadotrophic hypogonadism in dysmetabolic men without genetic haemochromatosis

To assess the relation between moderate iron overload on sex hormone binding globulin (SHBG) levels and gonadotroph function in men with dysmetabolic iron overload syndrome and the effects of phlebotomy. The relationship between magnetic resonance imaging assessed liver iron concentration (LIC) and plasma ferritin levels with total testosterone, bioavailable testosterone (BT), SHBG and LH levels, were studied in 50 men with moderate dysmetabolic iron excess, in the absence of genetic haemochromatosis, who were randomised to phlebotomy therapy or to normal care. Four patients (8%) had low total testosterone (<10.4 nmol/l) and 13 patients (26%) had low BT (<2.5 nmol/l). In the entire population, those with LIC above the median (90 μmol/l) had a higher mean SHBG (P=0.028), lower LH (P=0.039) than those with LIC below the median. In multivariable analysis (adjusted for age, and fasting insulin) LIC was significantly associated with SHBG (positively) and LH (negatively). Patients in the highest quartile of SHBG had higher LIC (P=0.010) and higher ferritinaemia (P=0.012) than those in the three other quartiles. Iron depletion by venesection did not significantly improve any hormonal levels. Hypogonadism is not infrequent in men with dysmetabolic iron overload syndrome. Liver iron excess is associated with increased plasma SHBG and moderate hypogonadotrophic hypogonadism. Phlebotomy therapy needs further investigation in symptomatic hypogonadal men with dysmetabolic iron excess.

Efficacy And Safety Of Administration Of Oral Iron Chelator Deferiprone In Patients With Early Myelodysplastic Syndrome

Forty-eight patients with early myelodysplastic syndrome (MDS) without excess of blasts, with average initial serum ferritin levels of 2739.5 μg/L (range 825–11287 μg/L), were treated with deferiprone (L1) in a daily dose of 40–90 mg/kg. Median duration of chelation treatment was 10.9 months (range 4–24 months). Chelation was effective (maintained or decreased iron stores) in 16 out of 22 patients (73%) with serum ferritin levels <2000 μg/L in contrast to only 12 out of 26 patients with serum ferritin levels >2000 μg/L. Combination of L1 with recombinant human erythropoietin (rHuEPO) (30–40 kU/week) resulted in effective chelation in five additional patients with serum ferritin levels >3000 μg/L. Incidence of adverse effects was comparable to that in thalassemic patients. Gastrointestinal symptoms represented the most frequent adverse effect of L1 therapy (37.5% of patients) that limited an effective escalation of the daily dose of the drug and led to discontinuation of the treatment for six patients. A decreased number of granulocytes was observed in five (13%) patients and agranulocytosis occurred in two patients (4%). Granulocyte counts were restored after cessation of L1 treatment and administration of granulocyte colony stimulating factor (G-CSF) in all but one patient. Administration of L1 in a daily dose of at least 75 mg/kg may represent an alternative approach in treatment of mild and moderate iron overload in MDS patients who cannot be treated with deferasirox (DFRA) or deferoxamine (DFO).

Iron overload in polytransfused patients without heart failure is associated with subclinical alterations of systolic left ventricular function using cardiovascular magnetic resonance tagging.

BackgroundIt remains incompletely understood whether patients with transfusion related cardiac iron overload without signs of heart failure exhibit already subclinical alterations of systolic left ventricular (LV) dysfunction. Therefore we performed a comprehensive evaluation of systolic and diastolic cardiac function in such patients using tagged and phase-contrast CMR.Methods19 patients requiring regular blood transfusions for chronic anemia and 8 healthy volunteers were investigated using cine, tagged, and phase-contrast and T2* CMR. LV ejection fraction, peak filling rate, end-systolic global midventricular systolic Eulerian radial thickening and shortening strains as well as left ventricular rotation and twist, mitral E and A wave velocity, and tissue e' wave and E/e' wave velocity ratio, as well as isovolumic relaxation time and E wave deceleration time were computed and compared to cardiac T2*.ResultsPatients without significant iron overload (T2* > 20 ms, n = 9) had similar parameters of systolic and diastolic function as normal controls, whereas patients with severe iron overload (T2* < 10 ms, n = 5), had significant reduction of LV ejection fraction (54 ± 2% vs. 62 ± 6% and 65 ± 6% respectively p < 0.05), of end-systolic radial thickening (+6 ± 4% vs. +11 ± 2 and +11 ± 4% respectively p < 0.05) and of rotational twist (1.6 ± 0.2 degrees vs. 3.0 ± 1.2 and 3.5 ± 0.7 degrees respectively, p < 0.05) than patients without iron overload (T2* > 20 ms) or normal controls. Patients with moderate iron overload (T2* 10-20 ms, n = 5), had preserved ejection fraction (59 ± 6%, p = NS vs. pts. with T2* > 20 ms and controls), but showed reduced maximal LV rotational twist (1.8 ± 0.4 degrees). The magnitude of reduction of LV twist (r = 0.64, p < 0.001), of LV ejection fraction (r = 0.44, p < 0.001), of peak radial thickening (r = 0.58, p < 0.001) and of systolic (r = 0.50, p < 0.05) and diastolic twist and untwist rate (r = -0.53, p < 0.001) in patients were directly correlated to the logarithm of cardiac T2*.ConclusionMultiple transfused patients with normal ejection fraction and without heart failure have subclinical alterations of systolic and diastolic LV function in direct relation to the severity of cardiac iron overload. Among all parameters, left ventricular twist is affected earliest, and has the highest correlation to log (T2*), suggesting that this parameter might be used to follow systolic left ventricular function in patients with iron overload.

Disorders associated with systemic or local iron overload: from pathophysiology to clinical practice

In healthy subjects, the rate of dietary iron absorption, as well as the amount and distribution of body iron are tightly controlled by hepcidin, the iron regulatory hormone. Disruption of systemic iron homeostasis leads to pathological conditions, ranging from anemias caused by iron deficiency or defective iron traffic, to iron overload (hemochromatosis). Other iron-related disorders are caused by misregulation of cellular iron metabolism, which results in local accumulation of the metal in mitochondria. Brain iron overload is observed in neurodegenerative disorders. Secondary hemochromatosis develops as a complication of another disease. For example, repeated blood transfusions, a standard treatment of various anemias characterized by ineffective erythropoiesis, promote transfusional siderosis, while chronic liver diseases are often associated with mild to moderate secondary iron overload. In this critical review, we discuss pathophysiological and clinical aspects of all types of iron metabolism disorders (265 references).

Highly Transfused MDS Patients Often Have Cardiac Iron Overload, as Shown by MRI Assessment

AbstractAbstract 2906 Background:Cardiac complications of transfusional iron overload are well documented in various inherited anemias. In regularly transfused MDS, the deleterious role of iron overload on cardiac disease is more disputed, due in particular to frequent concomitant causes of cardiac failure. Cardiac MRI T2* allows accurate and specific measurement of iron content. Methods:We prospectively evaluated in 4 centers of the GFM by standardized and transferable MRI methods both cardiac T2* according to Anderson (Eur Heart J. 2001Dec;22(23):2171-9) and liver iron content (LIC) according to Gandon (Lancet. 2004 Jan 31;363(9406):357-62), as well as cardiac function by routine echocardiography or MRI in regularly transfused MDS patients. Results:From Dec 2005 to March 2010, 73 patients (pts) were included (14 of them had more than one MRI evaluation over time): 38 M/35F, Median age 68 (24-86); WHO : RA=5, RARS=33, RMCD-RS=3, RMCD=1, RAEB1=9, RAEB2=5, RAEB-T/AML=1, 5q- syndrome=8 and unclassified=8; Karyotype: fav n=50, Int n=9, unfav n=4, failure n=10; IPSS: low n=29, Int-1 n=28, Int-2 n=5 and High n=1, unknown n=10. Median interval from MDS diagnosis and MRI T2* assessment was 49 months (range 0–324). Median serum ferritin at MRI assessment was 1750 ng/ml (range 282–7339) and 54/73 pts were on chelation therapy (CT) (median duration of CT prior to first MRI: 18 months, range 1–125). 37/73 pts had cardiac symptoms and 28 were on cardiac therapy. At first MRI T2* analysis, the median number of RBC units transfused was 68 (range 5–574). Median LIC was 330 micromoles/g/dw (range 40–908). Median Cardiac T2* was 27 ms (range 6–74). 14/73 pts had cardiac iron overload defined by MRI T2* ≤20 ms (19%) and among them 3/73 (4%) had severe cardiac iron overload (T2*≤ 10 ms). LVEF was below normal (55%) in 13/59 cases evaluated. A correlation was found between cardiac T2*and the number of RBC units transfused (Pearson correlation =-0.342, p=0.004) but not with LIC (p= 0.65) and serum ferritin (p=0.21). Cardiac overload was seen in 1/19 (5.5%) pts transfused <50 RBC units, 4/37(12.1%) pts transfused 50–150 units, 9/17 (52.9%) pts transfused >150 units (p= 0.0005). Those 3 pt subgroups also differed in median LIC (μmoles/g/dw) (<50 units= 250, 50–150 units=340, > 150 units=414) (p=0.044 Kruskall-Wallis' test), but not significantly in serum ferritin (p= 0.085).No significant correlation was found between decreased LVEF (< 55%) and cardiac T2* <20 ms (p=0.5), or T2*≤10 ms (p=0.23). In particular, 5/13 pts (38%) with LVEF <55% had T2*<20ms, vs versus 8/46 pts (17%) with LVEF >55% (p= 0.13). However, 1/14, 0/30 and 3/12 pts having received <50, 50–150 and > 150 RBC units had severe cardiac failure (ie LVEF≤35%)(p=0.012). 3/4 pts with severe cardiac failure had T2*< 20ms,compared to 8/54 pts without severe cardiac failure (p=0.023).14 pts had another cardiac MRI 6 to 34 months (median 18) after the first. All were on CT and had received a median of 60 and 214 PRBC units at first and last MRI, resp. Median Cardiac T2* was 21.6 ms (range 8.5–35.3) and. 28 ms (range 6.4–41) at last and at first assessment, respectively (p=0.3) Conclusions:Moderate and severe post transfusional cardiac iron overload was seen in 19% and 4% of regularly transfused MDS, respectively. The level of cardiac iron overload was well correlated to the number of RBC transfused. The impact of cardiac overload on LVEF was unclear except in pts with severe cardiac impairment (LVEF <35%), possibly suggesting that iron overload is only one of the factors responsible for cardiac disease in many of those elderly patients. Disclosures:No relevant conflicts of interest to declare.

Gender-related variations in iron metabolism and liver diseases

The regulation of iron metabolism involves multiple organs including the duodenum, liver and bone marrow. The recent discoveries of novel iron-regulatory proteins have brought the liver to the forefront of iron homeostasis. The iron overload disorder, genetic hemochromatosis, is one of the most prevalent genetic diseases in individuals of Caucasian origin. Furthermore, patients with non-hemochromatotic liver diseases, such as alcoholic liver disease, chronic hepatitis C or nonalcoholic steatohepatitis, often exhibit elevated serum iron indices (ferritin, transferrin saturation) and mild to moderate hepatic iron overload. Clinical data indicate significant differences between men and women regarding liver injury in patients with alcoholic liver disease, chronic hepatitis C or nonalcoholic steatohepatitis. The penetrance of genetic hemochromatosis also varies between men and women. Hepcidin has been suggested to act as a modifier gene in genetic hemochromatosis. Hepcidin is a circulatory antimicrobial peptide synthesized by the liver. It plays a pivotal role in the regulation of iron homeostasis. Hepcidin has been shown to be regulated by iron, inflammation, oxidative stress, hypoxia, alcohol, hepatitis C and obesity. Sex and genetic background have also been shown to modulate hepcidin expression in mice. The role of gender in the regulation of human hepcidin gene expression in the liver is unknown. However, hepcidin may play a role in gender-based differences in iron metabolism and liver diseases. Better understanding of the mechanisms associated with gender-related differences in iron metabolism and chronic liver diseases may enable the development of new treatment strategies.

Homozygous deletion of HFE is the common cause of hemochromatosis in Sardinia

We recently characterized an Alu-mediated recombination causing the loss of the complete HFE gene sequence. Here, we describe the case of a novel homozygous patient. We further show that HFE deletion results from a founder effect and that it represents the common cause of hemochromatosis in Sardinia. We recently reported the case of a 47-year old woman with a moderate iron overload due to an Alu-mediated recombination causing the loss of the complete HFE gene sequence.1 The same chromosomal alteration was identified by Pelucchi and co-workers in another woman. Despite a younger age at diagnosis (29 years), their patient showed a more impressive iron overload.2 A third case, a man, came to our attention. At the age of 44 he showed a transferrin saturation level of 80% and a serum ferritin level of 2080 μg/L. He was not genotyped for the p.C282Y and p.H63D variations because of an inability to amplify the HFE exons 2 and 4. We confirmed absence of the HFE gene in this patient but we were also interested in its origins. Indeed, the patient and both previously reported women were of Sardinian descent. The Sardinian population is genetically differentiated from the other Caucasian populations.3 It represents a genetic isolate where the p.C282Y mutation is considered as rare or even absent.4 This led us to assume that the HFE deleted allele was present at the population level and, related to a founder effect, was the common cause of hemochromatosis in this Mediterranean island. To characterize the contribution of the HFE deletion in the Sardinian population, we first established the frequency of this mutation in a sample set of 198 controls who originated from different districts of the island (90% of them were from South Sardinia, while the others originated from central and Northern parts of the island). Genotype analysis was performed using a rearrangement specific PCR, as previously described.1 The HFE deletion was detected at the heterozygous state in 4 subjects, giving a carrier frequency of 2.02% and an estimated homozygous frequency of 0.01% (one person in 10,000). We also looked for the p.C282Y mutation. It was identified at the heterozygous state in one of 193 subjects (0.52%). We next proceeded to analyze polymorphic microsatellite repeat markers flanking HFE. Based on results from the consanguineous family reported in our initial study,1 we selected a set of informative markers and defined a first chromosomal region of 12.049 megabases (Mb). This chromosomal region encompassed two HLA-class I loci which were added to the haplotypes analysis. Final results are summarized in Table 1 and Figure 1. A conserved haplotype of 3.150 Mb was deduced from the consideration of alleles shared by the 2 homozygous cases identified by us (P1, P2), and the 4 mutation carriers (MC 1–4). However, a recombination event could account for differences in HLA-A, HLA-B and D6S273 alleles of one of the study subjects (MC 3 in Table 1). This allowed us to consider a common haplotype of 7,359 Mb. Figure 1. Physical map of the chromosome 6 region flanking HFE. Distance between the D6S1621 and D6S2414 marker is indicated in grey; the arrow marks a possible ancestral haplotype. Distance between the D6S1621 and D6S1022 markers is indicated in black; the arrow ... Table 1. Allelic distribution of markers surrounding HFE. *The parentheses mark differences between the 6 individuals; these differences are probably related to a recombination event on chromosome 6 of the mutation carrier number 3. By their position on the same maritime routes, the histories of the West Mediterranean islands are very similar. Studies based on HLA polymorphisms have confirmed singularity of these populations, and have further revealed a close relationship between the Sardinian and Corsican populations. However, it must be pointed out that the HLA-A*2-B*58 haplotype is frequent in Sardinia (4.9%) and almost absent in the other West Mediterranean islands (Corsica and Balearic Islands). In fact, this haplotype could be of African origin.5 If so, comparing frequency of the HFE deleted allele (2%) to that of the HLA-A*2-B*58 haplotype (4.9%), one may assume that deletion of the HFE gene arose in the Sardinian population after contacts with African populations. But an African ancestry for the HFE deletion cannot be completely excluded. To conclude, we show that HFE deletion results from a founder effect rather than that of a mutational hotspot. We also demonstrate that, with an estimated homozygous frequency of one person in 10,000, HFE deletion is the common cause of hemochromatosis in Sardinia.

From Renal Siderosis Due to Perpetual Hemosiderinuria to Possible Liver Overload Due to Extravascular Hemolysis: Changes in Iron Metabolism in Paroxysmal Nocturnal Hemoglobinuria (PNH) Patients On Eculizumab.

Abstract 4031Poster Board III-967Iron metabolism in PNH patients is dominated by perpetual iron loss consequent to the chronic complement-mediated intravascular hemolysis; thus, they are prone to develop iron deficiency rather than iron overload, even in presence of large transfusional requirement. Eculizumab (Ecu) has proven effective for the treatment of intravascular hemolysis in PNH patients, resulting in reduction and even abolishment of transfusion requirement and improvement of signs and symptoms of intravascular hemolysis; however, Hb gain is heterogeneous among patients, in most cases due to residual C3-mediated extravascular hemolysis hampering Hb normalization. The goal of our study was to identify possible modifications in iron compartmentalization associated with Ecu treatment and possible clinical consequences. We evaluated iron metabolism in 5 untreated PNH patients and 23 who were receiving Ecu (of whom 4 have been also studied before treatment), combining biochemical parameters with a semiquantitative T2* MRI technology. MRI was performed using four gradient-echo sequences and one spin-echo sequence; signal intensity (SI) was measured on images obtained with each sequence by means of three regions of interest placed in the renal cortex, liver, spleen and at the level of the para-spinal muscle, resulting in a semiquantitative SI value (Grandon et al., Radiology 1994). Within the total patient cohort (regardless they were or were not on Ecu), there was a significant correlation between liver SI and serum ferritin (P<0.001), while kidney SI correlated with the presence of hemosiderinuria (HS, P<0.001). All untreated PNH patients showed similar MRI findings, with significant renal cortex siderosis and normal SI in liver and spleen. This was consistent with overt intravascular hemolysis, as confirmed by biochemical routine testing, and consequent perpetual hemosiderinuria; as expected, all these patients had abundant HS. In contrast, the 23 PNH patients on Ecu showed a distinct and heterogeneous pattern. All patients showed a normal renal SI, with the exception of 2 cases who have recently started Ecu and 2 experiencing Ecu breakthrough; these 4 patients had normal hepatic and splenic SI. All of them (but none of those with normal renal SI) had persistent HS, while only the latter 2 had increased LDH; we conclude that these 4 patients have had residual intravascular hemolysis, and that HS was more sensitive than LDH to identify recent history of intravascular hemolysis. In contrast, the majority of patients showed increased hepatic SI: we found 6 cases with moderate and 5 cases with severe iron overload; in some patients, high hepatic SI was associated with increased SI in the spleen. The 4 patients evaluated before and during treatment showed pre-treatment renal siderosis which progressively disappeared after months of Ecu therapy; in 2 of them, who had a longer exposition to Ecu, moderate hepatic iron overload was demonstrated. Hepatic SI significantly correlated with serum ferritin (P<0.05), but not with transferrin saturation nor with LDH. Iron overload was predictable as a result of persistent transfusional need only in two patients with partial response to Ecu; however, within the whole cohort, patients with suboptimal hematological response (i.e., those with persistent Hb<11) were more likely to develop severe hepatic iron overload (P=0.02). Thus, we hypothesized that iron overload in these patients may be pathophysiilogically linked to persistent extravascular hemolysis; we found a direct correlation between liver SI and both % of C3+ PNH RBCs (P=0.02) and absolute reticulocyte count (P=0.02), which were considered markers of extravascular hemolysis (Risitano et al, Blood 2009). In conclusion, we show by T2* RMI that untreated PNH patients have significant renal siderosis, which tends to disappear during Ecu treatment as a result of the blockade of intravascular hemolysis. However, such blockade of urinary iron loss may render PNH patients susceptible to liver iron overload resulting from transfusions, as well as from residual extravascular hemolysis. While is still not clear the proportion of patients developing clinically significant iron overload requiring specific treatment, we provide evidence that iron metabolism substantially changes during eculizumab treatment, and C3-mediated extravascular hemolysis may play a major role in this process. Disclosures:Risitano:Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.