Pancreatic iron loading predicts cardiac iron loading in thalassemia major

Abstract Diabetes mellitus and cardiomyopathy are common in chronically transfused thalassemia major patients, occurring in the second and third decades of life. We postulated that pancreatic iron deposition would precede cardiac iron loading, representing an environment favorable for extrahepatic iron deposition. To test this hypothesis, we examined pancreatic and cardiac iron in 131 thalassemia major patients over a 4-year period. Cardiac iron (R2* > 50 Hz) was detected in 37.7% of patients and pancreatic iron (R2* > 28 Hz) in 80.4% of patients. Pancreatic and cardiac R2* were correlated (r2 = 0.52), with significant pancreatic iron occurring nearly a decade earlier than cardiac iron. A pancreatic R2* less than 100 Hz was a powerful negative predictor of cardiac iron, and pancreatic R2* more than 100 Hz had a positive predictive value of more than 60%. In serial analysis, changes in cardiac iron were correlated with changes in pancreatic iron (r2 = 0.33, P < .001), but not liver iron (r2 = 0.025, P = .25). As a result, pancreatic R2* measurements offer important early recognition of physiologic conditions suitable for future cardiac iron deposition and complementary information to liver and cardiac iron during chelation therapy. Staging abdominal and cardiac magnetic resonance imaging examinations could significantly reduce costs, magnet time, and need for sedation in young patients.

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Pituitary Iron and Volume Predicts Hypogonadal Hypogonadism in Transfusional Iron Overload

Blood ◽

10.1182/blood.v118.21.1094.1094 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1094-1094

Author(s):

Leila Noetzli ◽

Ashok Panigrahy ◽

Steven D Mittelman ◽

Aleya Hyderi ◽

Ani Dongelyan ◽

...

Keyword(s):

Iron Overload ◽

Chelation Therapy ◽

Iron Concentration ◽

Thalassemia Major ◽

Iron Deposition ◽

Iron Loading ◽

Volume Loss ◽

Z Score ◽

Liver Iron Concentration ◽

Liver Iron

Abstract Abstract 1094 Introduction: Hypogonadotropic Hypogonadism (HH) is one of the most common morbidities in patients with transfusion-dependent anemias such as thalassemia major. Unfortunately, pituitary dysfunction is difficult to detect prior to puberty because of immaturity of the hypothalamic-pituitary-gonadal axis. We used MRI to measure pituitary R2 and volume to determine at what age these patients develop pituitary iron overload and volume loss. Additionally, we aimed to stratify the risk of clinical HH based on pituitary R2 and pituitary volume, and determine predictors of pituitary iron deposition and volume loss. Methods: We recruited 56 patients (52 with thalassemia major and 4 with Blackfan-Diamond syndrome) to have pituitary MRIs to measure pituitary R2 and volume. Diagnosis of HH was determined by either lack of secondary pubertal characteristics by age 13 for females or age 14 for males, by primary or secondary amenorrhea in females ages 16 or older, or by the need for testosterone administration in males. Patients also had pancreas R2*, heart R2*, and liver iron concentration measured by MRI. Normative pituitary R2 and volume trends were determined by a cohort of 100 control patients. Results: Patients were 20.4 ± 12.1 years old and well distributed by sex (31 males, 25 females). All subjects received blood transfusions every 2–4 weeks and were on appropriate chelation therapy as indicated by their physician. Mean pituitary R2 Z-score was 4.5 and mean anterior pituitary volume Z-score was −0.9. Figure 1 shows pituitary R2 values as a function of age, superimposed on normal trends from the control population. Patients with transfusional iron overload began to develop pituitary iron overload in the first decade of life; however, significant iron deposition were observed beginning in the second decade. Heavy pituitary iron deposition (Z-score > 5) and volume loss (Z-score < −2.5) were predictive of HH (Figure 2). Volume loss was highly specific (87%) but identified only half of HH cases. The remaining HH patients had heavy pituitary iron (Z-score > 5), but preserved pituitary volume. Pituitary R2 correlated significantly with serum ferritin as well as liver iron concentration, pancreatic R2*, and cardiac R2* by MRI. Discussion: Pituitary iron loading begins as early as the first decade of life in chronically transfused patients, meriting a pituitary MRI in children under 10 years old. Severe pituitary iron loading as well as volume loss throughout the second decade of life, and are predictive of HH, warranting more intensive screening in this age group. However, many patients with moderate-to-severe pituitary iron overload retained normal gland volume and function, representing a potential therapeutic window. This may also be explained by improvements in gland function observed following intensive chelation therapy. Serial tracking of pituitary iron and volume trends on age-appropriate nomograms should improve diagnostic accuracy and toxicity prophylaxis. Disclosures: Wood: Novartis: Research Funding; Ferrokin Biosciences: Consultancy; Cooleys Anemia Foundation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Effect of transfusional iron intake on response to chelation therapy in β-thalassemia major

Blood ◽

10.1182/blood-2007-08-109306 ◽

2008 ◽

Vol 111 (2) ◽

pp. 583-587 ◽

Cited By ~ 103

Author(s):

Alan R. Cohen ◽

Ekkehard Glimm ◽

John B. Porter

Keyword(s):

Chelation Therapy ◽

Iron Concentration ◽

Chelating Agent ◽

Thalassemia Major ◽

Phase Iii ◽

Iron Loading ◽

Iron Intake ◽

Liver Iron ◽

Iron Stores ◽

Using Data

The success of chelation therapy in controlling iron overload in patients with thalassemia major is highly variable and may partly depend on the rate of transfusional iron loading. Using data from the 1-year phase III study of deferasirox, including volumes of transfused red blood cells and changes in liver iron concentration (LIC) in 541 patients, the effect of iron loading on achieving neutral or negative iron balance was assessed in patients receiving different doses of deferasirox and the comparator deferoxamine. After dose adjustment, reductions in LIC after 1 year of deferasirox or deferoxamine therapy correlated with transfusional iron intake. At a deferasirox dose of 20 mg/kg per day, neutral or negative iron balance was achieved in 46% and 75% of patients with the highest and lowest transfusional iron intake, respectively; 30 mg/kg per day produced successful control of iron stores in 96% of patients with a low rate of transfusional iron intake. Splenectomized patients had lower transfusional iron intake and greater reductions in iron stores than patients with intact spleens. Transfusional iron intake should be monitored on an ongoing basis in thalassemia major patients, and the rate of transfusional iron loading should be considered when choosing the appropriate dose of an iron-chelating agent. This study is registered at http://clinicaltrials.gov as NCT00061750.

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Reduction of Hepatic Iron in Patients with Thalassemia Major According to Iron Chelation Regime Assessed by MRI T2*

Blood ◽

10.1182/blood.v112.11.5410.5410 ◽

2008 ◽

Vol 112 (11) ◽

pp. 5410-5410

Author(s):

Vassilios Ladis ◽

Giorgos Chouliaras ◽

Kirikos Zannikos ◽

Panagiotis Moraitis ◽

Eleni Berdoussi ◽

...

Keyword(s):

Statistical Significance ◽

Linear Regression Analysis ◽

Thalassemia Major ◽

Rate Of Change ◽

Hepatic Iron ◽

Iron Loading ◽

Liver Iron ◽

Cardiac Iron ◽

Iron Load ◽

Number Of Patients

Abstract In 212 thalassemia major patients, repeated assessments for cardiac and hepatic iron (LIC) assessed by Magnetic Resonance Imaging (MRI – T2*) have been performed. The chelation regimes were either desferrioxamine (DFO), deferiprone (DFP), combination of DFO and DFP (Comb) or deferasirox (DFX). In general over the last few years, tailoring of chelation therapy has been principally guided by the cardiac iron loading. As many patients had been found to have excess cardiac iron, the majority (48%) had been placed on Comb. Patients were grouped according to the degree of siderosis. A T2* of <1.6ms was regarded as heavy LIC, between 1.6–4.0 moderate, 4.1–9.0 mild and > 9.1 acceptable. Taking into account that the change in T2* is not necessarily linear with respect to time and as the overall time of exposure to DFO, DFP and Comb regimes was significantly greater than that with DFX it was unjustified to perform comparative analysis using the total time period of the patients who were on any of the non DFX regimes. Therefore, to compare the efficacy of the four regimes on LIC, we performed an analysis using student T test to assess the rate of change only between the first and second MRI in patients with comparable LIC according to each chelation regime with adjustment for overall time of exposure (Table 1). Using the same data and applying linear regression analysis (Table 2) we compared the effect of DFO to the other three regimes in the annual rate of increasing hepatic T2*. Only Comb is effective at all levels of hepatic iron loading in reducing the iron content. DFX is effective in the mildly iron loaded patients and for the moderately iron loaded patients, its efficacy approaches statistical significance. DFP does not seem to significantly decrease LIC at any level of hepatic iron load however the numbers of patients in that group are very small. Interestingly DFO seems the least effective at all levels of hepatic iron loading and particularly in the heavy loaded patients. This factor may be related to poor compliance to its use as the patients who have reached such levels of iron load are more often those who are not compliant. In the comparison analysis to DFO, only Comb is significantly better and DFP and DFX are equivalent to it. In addition Comb is more effective than DFX and DFP in that over 12 months it would increase the T2* by 3.8ms (p <0.001) and 3.9ms (p 0.012) respectively. DFX and DFP are similar in efficacy in that they maintain the liver iron at the same levels (DFP vDFX 0.009ms p=0.95). In patients with hepatic T2* >9ms, 4 of 11 on DFO, 5 of 6 on DFX, 7 of 11 on DFP and 3 of 22 on Comb fell below 9. It is of note that DFO only maintains LIC and that a number of patients in the normal range increased LIC. Taking this data into account the DFX and DFP results are compatible with those seen both in the clinic and in trials. It is apparent however that combination therapy is the most effective regime for reducing hepatic iron significantly. As with cardiac iron loading, by knowing the degree of hepatic iron loading by the non-invasive T2* measurement and being able to manipulate patients chelation regimes, it seems possible to be able to have patients free of excess hepatic iron and potentially reduce other iron related morbidities as well. Table 1 Annual estimated mean change in T2* according to severity of hepatic siderosis Regime Heavy Moderate Mild ΔT2* p ΔT2** p ΔT2* p *tm= mean time (in months) between MRI studies DFO n= 42 tm*= 24.6 0.05 0.5 0.57 0.37 0.1 0.7 DFP n= 11 tm= 23.8 0.56 0.25 0.88 0.31 3.5 0.19 Comb n= 101 tm=21.7 1.17 0.0064 3.6 <0.001 5.9 <0.001 DFX n=58 tm=15.2 3.1 0.11 1.25 0.06 3.8 0.014 Table 3 Mean estimated difference in T2* Standard Error p DFP v. DFO −0.7 1.6 0.7 Comb v DFO 3.1 1.05 0.03 DFX v DFO −0.7 1.2 0.5

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Renal iron deposition by magnetic resonance imaging in pediatric β-thalassemia major patients: Relation to renal biomarkers, total body iron and chelation therapy

European Journal of Radiology ◽

10.1016/j.ejrad.2018.04.007 ◽

2018 ◽

Vol 103 ◽

pp. 65-70 ◽

Cited By ~ 5

Author(s):

Mohsen Saleh ElAlfy ◽

Nayera Hazaa Khalil Elsherif ◽

Fatma Soliman Elsayed Ebeid ◽

Eman Abdel Rahman Ismail ◽

Khaled Aboulfotouh Ahmed ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Magnetic Resonance ◽

Chelation Therapy ◽

Thalassemia Major ◽

Iron Deposition ◽

Resonance Imaging ◽

Body Iron ◽

Renal Biomarkers ◽

Total Body

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Vitamin D Deficiency Is Associated with Cardiac Iron Loading in Thalassemia Major.

Blood ◽

10.1182/blood.v110.11.574.574 ◽

2007 ◽

Vol 110 (11) ◽

pp. 574-574

Author(s):

John C. Wood ◽

Susan Claster ◽

Susan Carson ◽

Khanna Rachna ◽

Thomas Hofstra ◽

...

Keyword(s):

Vitamin D ◽

Multivariate Analysis ◽

Vitamin D Deficiency ◽

Transferrin Saturation ◽

Thalassemia Major ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Iron Loading ◽

Liver Iron ◽

Cardiac Iron

Abstract Vitamin D deficiency is epidemic in the United States and is associated with decreased calcium absorption and metabolism, leading to bone loss, muscle weakness, and impaired pancreatic function. Many thalassemia major patients, as a result of decreases sunlight exposure and increased metabolic demand, are vitamin D deficient. We hypothesized that vitamin D deficiency might be associated with cardiac siderosis and impaired cardiac function through its modulation of calcium signaling in these patients. Methods: Permission for review of medical records was obtained from the Committee on Clinical Investigation at Children’s Hospital Los Angeles. We compared vitamin D25-0H and D1-25 levels in our thalassemia major patients with cardiac R2* (1/T2*) and left ventricular ejection fraction (LVEF) from the patient’s most recent cardiac MRI. Time difference between the exams was 2.8 ± 3.3 months with a range of 0.2 to 9.4 months. Other parameters recorded included age, gender, ferritin, liver iron (by MRI) and transferrin saturation. Univariate and multivariate regression was performed using JMP 5.1 (SAS, Cary, NC). Results: Twenty four patients had records suitable for review. There were 11 women and 13 men with a mean age of 14.7 ± 7.6 years [1.4 – 25.8]. Population was moderately iron overloaded with ferritin values of 2089 ± 1920 ng/ml [246 – 8230], liver iron 13.7 ± 11.4 mg/g dry wt [2–39.5], cardiac R2* 65 ± 61 Hz [19.8 – 229], and transferrin saturation 84 ± 18% [36%–106%]. Vitamin D25-OH levels were markedly depressed, 17.1 ± 8.5 pg/ml [1–33], with 13/24 values below the lower limit of 20 ng/ml. Surprisingly, vitamin D1-25OH levels were normal or elevated in all patients, 59.9 ± 19.5 pg/ml [32–103] with four patients exceeding the upper limit of normal of 71 pg/ml. There was no correlation between D25-0H and D1-25OH levels. D25-OH levels (but not D1-25OH levels) fell sharply with age (r2 = 0.48) and were negatively associated with liver iron (r2 = 0.20). Figures 1 and 2 demonstrated cardiac R2* and LVEF as functions of D25-OH levels. Cardiac R2* was log-linearly correlated with D25-OH level (r2 = 0.44, p=0.0001; levels below 13 ng/ml were associated with severe cardiac iron loading. Multivariate analysis of D25-OH, D1-25, HIC, ferritin, age, and transferrin saturation demonstrated that D25-0H and ferritin are the sole predictors of abnormal cardiac R2*, accounting for 38% and 5% of the variability respectively. LVEF was also negatively related to D25-OH levels (r2 = 0.35, p = 0.002). In multivariate analysis, vitamin D250H and vitamin D1-25OH levels accounted for 50% of the LVEF variability, independent of cardiac R2*. Conclusion Vitamin D deficiency is common in thalassemia major patients and strongly associated with cardiac iron uptake and ventricular dysfunction. Figure Figure Figure Figure

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Update in Combined Chelation Therapy with Deferoxamine and Deferiprone in Brazilian Patients with Thalassemia Major: Assessment of Three Years

Blood ◽

10.1182/blood.v112.11.5415.5415 ◽

2008 ◽

Vol 112 (11) ◽

pp. 5415-5415

Author(s):

Sandra Regina Loggetto ◽

Mônica Veríssimo ◽

Antônio Fabron Júnior ◽

Giorgio Roberto Baldanzi ◽

Nelson Hamerschlak ◽

...

Keyword(s):

Adverse Events ◽

Iron Overload ◽

Serum Ferritin ◽

Chelation Therapy ◽

Combined Therapy ◽

Thalassemia Major ◽

Liver Iron ◽

Cardiac Iron ◽

Cardiac Iron Overload

Abstract Introduction: Cardiac failure is a main cause of morbidity and mortality in patients with thalassemia major (TM) who are receiving regular blood transfusion due to iron overload. So, effective and adequate iron chelation is extremely important. Deferoxamine (DFO), the most widely used iron chelator, has poor compliance. Combined therapy with Deferiprone (DFP) increases chelation efficacy, decreases iron-induced complications, improves compliance increasing survival in thalassemia. Objectives: Assessment of efficacy and safety in combined chelation with DFP and DFO in thalassemic patients with iron overload. Methods and results: We have 50 thalassemia major patients in 4 Brazilian Centers (Boldrini Hospital, Sao Paulo Hematology Center, HEMEPAR and FAMEMA) receiving combined chelation therapy with follow up to three years. DFP (75–100 mg/kg/daily) and DFO (30–60 mg/kg, 4–7 days/week) are being administered during one to three years. Median age of this group is 21,5 y/o (range 8–35), with 48% female. Median age to start regular transfusions was 12 months (range 2–140) and to begin chelation therapy was 57 months (range 17–216). All patients were screened for Hepatitis C and 26% had positive sorology and/or PCR. Statistical analysis were made with Spearman test and Fisher test. All patients, except two, did cardiac and liver MRI in the initial phase of the study, resulting in 60,5% with cardiac iron overload (T2*<20ms), being severe in 31,2%. Assessment of liver iron concentration (LIC) showed 95,7% with liver iron overload (>3ug/g dry weight), being severe in 17,4%. During follow up, only 43 patients (86%) was screened with MRI. From these, 67,4% had cardiac iron overload (severe in 32,5%) and 78,6% had liver iron overload (severe in 11,9%). Mean serum ferritin before and after three years were 3095,7 ±1934,5 ng/ml and 2373,9±1987,6 ng/ml, respectively. Our data showed positive correlation between serum ferritin, LIC and ALT, even in initial data and after combined chelation therapy (p<0,001), but there is no correlation between cardiac T2* and LIC and between cardiac T2* and ferritin. DFP adverse events included 8% agranulocytosis, 22% neutropenia, 20% arthralgia and 38% gastric intolerance. DFO adverse events were 2,6% deafness, 2,0% cataract and 12% growth deficit. Hepatic toxicity was found in 6%, but without necessity to stop treatment. Compliance in this group was excellent in 48%, good in 22% and poor in 30%. Conclusions: This is the first multicenter study to evaluate combined chelation therapy in Brazil based on cardiac MRI and LIC. Most patients had cardiac and hepatic iron overload probably because they began iron chelation lately, due to difficult access to iron chelators in the past. Cardiac iron overload didn’t have correlation with ferritin and LIC and these data need more understanding. Age of initial regular blood transfusion, increased transfusional requirement, inadequate chelation or delayed chelation may play a role in this question. Combined therapy with DFO and DFP is effective to decrease serum ferritin and LIC. Follow up and improving compliance may decrease cardiac iron overload. Adverse events are similar to literature. Combined therapy is safety in TM patients with transfusional iron overload.

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A Decade Follow-up of a Thalassemia Major (TM) Cohort Monitored by Cardiac Magnetic Resonance Imaging (CMR): Significant Reduction In Patients with Cardiac Iron and In Total Mortality

Blood ◽

10.1182/blood.v116.21.1011.1011 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1011-1011 ◽

Cited By ~ 7

Author(s):

Alison S Thomas ◽

Maciej Garbowski ◽

Ai Leen Ang ◽

Farrukh T Shah ◽

J. Malcolm Walker ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Chelation Therapy ◽

Thalassemia Major ◽

Iron Loading ◽

Myocardial Iron ◽

Advisory Committees ◽

Cardiac Iron

Abstract Abstract 1011 Background. CMR was introduced in London to assess myocardial iron loading in 1999 and some of these patients now have 10 years of follow-up, most with contemporary CMR determinations. The impact of long-term monitoring of myocardial iron loading in thalassemia major (TM) on the proportion of patients with increased myocardial iron (cT2* <20ms) and on patterns of mortality has not been previously described in a longitudinal cohort over this duration. Patients and Methods. All patients regularly attending two London thalassemia centres, who received their first CMR Jan 1999 - Dec 2000 were analyzed as a cohort. Patients underwent initial CMR at the Royal Brompton Hospital and received CMR follow up (FU) either there or at the Heart Hospital (UCLH). 132 patients were identified as having received a CMR in 1999–2000. A minimum 7 years CMR FU was required for inclusion in the long-term CMR analysis. 109 patients had at least 7 years of CMR follow up (range 7.0–10.6 years, median 9.2). The median age at 1st CMR was 27.9 years (range 7.7 – 49.5 years). At baseline, patients were receiving chelation with deferoxamine (DFO) monotherapy (70%), deferiprone (DFP) monotherapy (21%), or a combination of these agents (9%). At latest FU, patients were receiving DFO (32%), deferasirox (DFX) (28%), DFP (22%), or combined DFP and DFO therapy (18%). Results: Improvement in cardiac iron: In 1999–2000, 60% of TM patients had cT2* values ≤20ms and 17% had cT2* values <10ms. By contrast, at long term FU, only 23% now have cT2* ≤20ms, 7% have cT2* values <10ms (p<0.001). Changes to chelation therapy: 31% of patients stayed on the same chelator; 33% had 1 chelator switch, 26% 2 switches and 11% 3 or more switches. 18 switches in chelation therapy were due to side-effects (12 DFP, 5 DFX, 1 DFO). There were 9 breaks in chelation therapy during pregnancy in 8 different women. The proportions of patients with T2* < 20ms fell significantly for those who remained on DFO or DFP monotherapies throughout, or who changed chelation modalities on only one (p=0.002) or two (p=0.02) occasions. Patients who received had 3 or more switches did not show a improvement in this respect. The latter group was also the only subset that showed significant deterioration in myocardial iron (p<0.001). Mortality rates: the overall mortality rate for the initial cohort was 1.65 per 1000 patient years (95% CI 0.71 – 3.24); median age at death 35.6 years (range 27.3–48.4). This is a substantial improvement in the mortality index compared with the UK thalassemia registry data, of 4.3 per 1000 patient years during the period 2000–2003 (Modell et al, JCMR, 2008). The incidence rate ratio is 0.387 (95% CI 0.11–0.961), p<0.05, with patients in our cohort 61% less likely to die than those in the 2000–2003 cohort. Causes of death: there were 8 deaths during the FU period: 3 with complications of hepatitis C (all with cT2* > 20ms), 3 with sepsis (2 with cT2* <10ms and impaired ejection fraction, 1 with cT2* of 18ms), 1 with breast cancer, 1 with sudden unexplained death (cT2* > 20ms). Thus in only 2 patients could excessive cardiac iron loading be considered a causal/contributory factor. There was no significant difference in the baseline cT2* between those who died and those currently still alive (p= 0.2), meaning that death as a drop-out cause does not explain iron loading trends over FU. Chelators at death: DFO (4), DFP (2), DFX (1), combination (1). Conclusions: Over a decade we have seen an almost 3 fold fall in the proportion of patients with myocardial iron overload. Mortality has become substantially lower and cardiac iron overload is no longer the leading cause of mortality. In addition to CMR, this decade has seen the advent of two new oral iron chelators and many patients switched chelation regimen, sometimes several times, during the follow up period. Whilst the contribution of the individual components of this practice to the improved outcome cannot be concluded without randomized studies, it is clear that this modern management of TM is associated with reduced TM mortality. Disclosures: Off Label Use: Deferiprone is off label in the USA but licensed in Europe. Shah:Novartis: Honoraria, Speakers Bureau; Apotex/ Swedish Orphan: Honoraria. Pennell:Siemens: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Apotex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Cardiovascular Imaging Solutions: Director of CVIS, Equity Ownership. Porter:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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ICL670 Removes Cardiac Iron in a Gerbil Model of Iron Overload.

Blood ◽

10.1182/blood.v106.11.2695.2695 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2695-2695 ◽

Cited By ~ 3

Author(s):

John C. Wood ◽

Maya Otto-Duessel ◽

Ignacio Gonzales ◽

Michelle Aguilar ◽

Hanspeter Nick ◽

...

Keyword(s):

Iron Content ◽

Chelation Therapy ◽

Iron Concentration ◽

Iron Loading ◽

Liver Iron Concentration ◽

Liver Iron ◽

Myocyte Hypertrophy ◽

Cardiac Iron ◽

Liver Iron Content ◽

Wet Weight

Abstract Introduction: Deferasirox (ICL670) is a novel tridentate oral iron chelator currently being evaluated for the treatment of transfusional iron overload. Phase III clinical trials have demonstrated that once-daily ICL670 (20 mg/kg) is equally effective at controlling liver iron concentration as standard deferoxamine therapy (40 mg/kg/day, 5 days per week). While ICL670’s long serum half-life should offer good protection against cardiac iron accumulation, little is known regarding its ability to remove stored cardiac iron. Therefore, we compared the relative efficacy of ICL670, deferiprone (L1), and deferoxamine (DFO) in removing cardiac iron from iron-loaded gerbils. Methods: 37 8–10 week old female gerbils underwent ten weekly iron dextran injections of 200 mg/kg/D, followed by a 13 day equilibration period. Five animals were then sacrificed to determine pre-chelation iron burdens. Chelation was initiated in 3 groups of 8 animals (ICL670 100 mg/kg/D po QD, L1 375 mg/kg/D po divided TID, DFO 200 mg/kg/D sub Q divided BID) five days per week and maintained for 12 weeks. The remaining 8 animals received sham chelation. All animals underwent ECG and treadmill assessment at baseline, following iron loading, and after completing chelation therapy. Animals were sacrificed for liver and heart iron measurement (Mayo Medical Laboratory) and semiquantitative histology. Hearts were evaluated for iron loading/distribution, tissue fibrosis, and myocyte hypertrophy, while livers were scored for iron loading/distribution and fibrosis. Results: Chelator-independent iron excretion and redistribution was evident, unlike in humans. Cardiac and liver iron contents fell 30.4% and 23.2%, respectively, with sham chelation; all subsequent chelator comparisons are reported with respect to the sham-chelated animals. ICL670 reduced cardiac iron content 20.5%. There were no changes in cardiac weight, myocyte hypertrophy, fibrosis, or wet-to-dry weight ratio. ICL670 treatment reduced liver iron content 51%. Iron elimination was greatest in hepatocytes with no detectable Kupfer-cell iron clearance. L1 produced comparable reductions in cardiac iron content (18.6%). Wet weight cardiac iron concentration fell nearly 30% but this was offset by greater cardiac mass (16.5% increase). Histologic analysis demonstrated decreased iron staining but increased myocyte hypertrophy. L1 decreased liver iron content 24.9%. Wet weight liver iron concentration fell 43.8% but was offset by a 30% increase in liver weight and water content. Iron elimination was balanced between Kupfer cells and hepatocytes. DFO did not reduce biochemically-assayed cardiac or liver iron content, although it improved histologic iron scores in both organs. Hearts from DFO treated animals were enlarged and had greater fibrosis. Cardiac and liver iron contents were closely correlated (r = 0.66), but ICL670 animals had lower hepatic iron contents for any given cardiac iron content. Iron loading broadened QRS duration by 10.6%; this effect was antagonized by both L1 and ICL670 therapy. PR, QRS, and QTc interval were weakly correlated with cardiac and liver iron contents. Treadmill exercise time was independent of chelation therapy. Conclusion: ICL670 and L1 were equally effective in removing stored cardiac iron in a gerbil animal model but ICL670 removed more hepatic iron for a given cardiac iron burden.

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Impact of Iron Assessment by MRI

Hematology ◽

10.1182/asheducation-2011.1.443 ◽

2011 ◽

Vol 2011 (1) ◽

pp. 443-450 ◽

Cited By ~ 69

Author(s):

John C. Wood

Keyword(s):

Chelation Therapy ◽

Hypogonadotropic Hypogonadism ◽

Iron Concentration ◽

Elevated Serum ◽

Iron Chelation ◽

Thalassemia Major ◽

The Body ◽

Liver Iron ◽

Cardiac Iron ◽

Kinetics Of Uptake

Abstract The use of magnetic resonance imaging (MRI) to estimate tissue iron was conceived in the 1980s, but has only become a practical reality in the last decade. The technique is most often used to estimate hepatic and cardiac iron in patients with transfusional siderosis and has largely replaced liver biopsy for liver iron quantification. However, the ability of MRI to quantify extrahepatic iron has had a greater impact on patient care and on our understanding of iron overload pathophysiology. Iron cardiomyopathy used to be the leading cause of death in thalassemia major, but is now relatively rare in centers with regular MRI screening of cardiac iron, through earlier recognition of cardiac iron loading. Longitudinal MRI studies have demonstrated differential kinetics of uptake and clearance among the difference organs of the body. Although elevated serum ferritin and liver iron concentration (LIC) increase the risk of cardiac and endocrine toxicities, some patients unequivocally develop extrahepatic iron deposition and toxicity despite having low total body iron stores. These observations, coupled with the advent of increasing options for iron chelation therapy, are allowing clinicians to more appropriately tailor chelation therapy to individual patient needs, producing greater efficacy with fewer toxicities. Future frontiers in MRI monitoring include improved prevention of endocrine toxicities, particularly hypogonadotropic hypogonadism and diabetes.

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Liver and Cardiac Iron Measurements in Very Young Chronically Transfused Patients Show Dangerous Levels of Iron Loading

Blood ◽

10.1182/blood.v118.21.1086.1086 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1086-1086

Author(s):

Vasilios Berdoukas ◽

Mammen Puliyel ◽

Adam Bush ◽

Thomas Hofstra ◽

Bhakti P. Mehta ◽

...

Keyword(s):

Iron Overload ◽

Research Funding ◽

Iron Status ◽

Iron Concentration ◽

Thalassemia Major ◽

Iron Loading ◽

Liver Iron ◽

Body Iron ◽

Cardiac Iron ◽

Total Body

Abstract Abstract 1086 Recurrent blood transfusion results in significant iron overload that can cause serious organ damage and death if not properly treated. Liver iron concentration (LIC) is the best indicator of total body iron status and can be measured non-invasively by magnetic resonance imaging (MRI). In the past, it was recommended that LIC assessments by liver biopsy begin after about 6 years of age (yo). MRI is also an excellent way to monitor iron cardiomyopathy, which remains a major cause of death in chronically transfused patients. To understand how rapidly iron overload develops, we reviewed the 1316 MRI iron studies we have performed since 2002 and summarized the LIC and cardiac R2* in a subset of 127 subjects who had their first MRI studies before 10 yo. Because of the known serious pitfalls in the assessment of total body iron by measurement of ferritin, LIC is measured by MRI in our center as standard of care in all patients on chronic transfusion soon after the start of iron chelation therapy. Most children less than 6 years of age require general anesthesia for this procedure. In some older children cooperation can be achieved by distraction techniques. Thirty three percent had sickle cell disease (SCD), 33% thalassemia major (TM), 11% Blackfan Diamond anemia (DBA), 3% congenital dyserythropoietic anemia (CDA), and 8.6% had other transfusion dependent anemias (OTRAN) and 11.4% had studies done not related to transfusion. This paper will focus on the 114 subjects whose MRI was done to evaluate transfusion related iron overload. The median age at first MRI was 6 years with 25% having their first study before 3.7and 10% before 2.1 yo. The median LIC was 9.8 mg/g dry weight (dw) and 10% of subjects had a first LIC > 22 mg/g dw. Only 2.5% had evidence of cardiac iron (T2* < 20ms). The median LICs (mg/g dw) were 8.9 for SCD, 11.8 for TM, 13 for DBA, 6.1 for CDA, and 8.7 OTRAN and were not statistically different. The minima ranged from 0.6 in OTRAN to 4.2 for CDA and the maxima ranged from 25 in CDA to 39.7 for SCD. There was significant iron loading even when we restricted the analysis to 27 subjects with a first MRI at < 3.5 yo; SCD (2.3 median (med), 2.8 maximum (max)), TM (14.6 med, 35 max), DBA (13 med, 15 max),CDA (6.6 med, 25 max) and OTRAN (5.8 med, 11 max). There were 4 subjects who had evidence of cardiac iron loading. Two had DBA with T2* of 18 ms and 16 ms at 2.5 and 3.7 years of age respectively. A third DBA subject had a T2* of 20 ms at only 4.6 yo. Two TM subjects had a T2* of 15 ms at 6.6 and 9.1 yo respectively. These data indicate that there is significant elevation in LIC by the age of 3.5 years with a median LIC of 11 mg/g dw and 25% of subjects having a LIC > 15 mg/g dw. These are very high levels of iron loading. Furthermore, 2.5% of subjects in this age already have evidence of cardiac iron loading. On the basis of such findings, direct measurement of liver iron by MRI is essential as soon as possible after the start of regular transfusions and cardiac iron should be measured early in high risk children with Diamond Blackfan anemia and thalassemia major. Disclosures: Berdoukas: ApoPharma Inc.: Consultancy. Carson:ApoPharma Inc.: Honoraria; Novartis Inc: Speakers Bureau. Wood:Novartis: Research Funding; Ferrokin Biosciences: Consultancy; Cooleys Anemia Foundation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Coates:Novartis Inc: Speakers Bureau.

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