Brain iron content in systemic iron overload: A beta-thalassemia quantitative MRI study

Abstract Background Sickle cell disease (SCD) is considered the most prevalent monogenic diseases worldwide. Iron overload is one of the major complications in those patients, especially who in need for frequent transfusion, affecting many organs including the brain. MRI is a valuable, reliable and non-invasive method for quantifying iron concentration in many organs as the liver and heart and it is now used for monitoring of the chelation therapy in SCD patients. Several studies began reporting differences in global cognitive function, particularly for children with SCD, they are at a high risk for neurocognitive impairment they often scored lower on general IQ measures than healthy children which is due to iron overload in brain tissue from the chronic transfusions which can lead to strokes and may be a silent stroke. Objective The current study assessed brain iron content (using R2* values) in the caudate and thalamic regions through quantitative brain MRI study in SCD patients in comparison to age and sex-matched healthy controls. Methods A case-control study recruited 32 patients with SCD and 11 healthy controls. Brain MRI study using multi-echo fast gradient echo sequence was done for all the patients and controls. Brain R2* values of both caudate and thalamic regions (right and left sides) were calculated for only 15 SCD patients and the 11 controls. All recruited SCD patients and controls were examined for the neurocognitive functions by these tests: Wechsler IV Intelligence Scale for Adult shows (Verbal, Perceptual, Memory, Processing and Total IQ), their all normal values between 90 – 110. Benton Visual Retention Test have cut of point at (> 4 or = 4). Those values are the same for the difference between the obtained correct and the expected correct, and the difference between the obtained error and expected error. Results The fifteen patient with SCD who underwent brain MRI were age and sex matched with the eleven healthy control (15 SCD patients: mean-age: 16.93 ± 3.41 years, 40.6% females and 11healthy controls: mean age: 18.73 ± 4.84 years, 54.5% females) were enrolled in the study. As regards the brain MRI, there was no statistically significant differences between SCD and control group in all regions of interests (p > 0.05). Our study showed that 72.7% of our SCD patients had under threshold TIQ scores. Also18% of the patients showed moderate anxiety, 9% mild anxiety and 9% showed severe anxiety. Conclusion The results of our study showed that even in cases of iron overload which affects vital organs as the liver, cardiac and brain iron overload don't occur.

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Hidden Brain iron content in Sickle cell disease: Impact on Neurocognitive Functions

10.21203/rs.3.rs-399346/v1 ◽

2021 ◽

Author(s):

Mohsen Saleh ElAlfy ◽

Ahmed Samir Ibrahim ◽

Ghada Samir Ibrahim ◽

Hanaa Midhat Abdel Gader Hussein ◽

Hend Galal Eldeen Mohammed ◽

...

Keyword(s):

Sickle Cell Disease ◽

Iron Overload ◽

Sickle Cell ◽

Brain Mri ◽

Thalassemia Major ◽

Beta Thalassemia ◽

Brain Iron ◽

Cell Disease ◽

Neurocognitive Dysfunction ◽

Neurocognitive Functions

Abstract Children with sickle cell disease (SCD) are at a high risk for neurocognitive impairment. We aim to quantitatively measure cerebral tissue R2* to investigate the brain iron deposition in children and young adults with SCD in comparison to beta thalassemia major (BTM) and healthy controls and evaluate its impact on neurocognitive functions in patients with SCD. Thirty-two SCD, fifteen BTM and eleven controls were recruited. Multi-echo fast-gradient echo sequence brain MRI was performed and brain R2* values of both caudate and thalamic regions were calculated. SCD patients were examined for the neurocognitive functions. SCD had high iron overload 0.30±0.12 mg/kg/day. 68.9% of SCD had under- threshold IQ, 12.5% had moderate to severe anxiety and 60.8% had depression. There was no differences between SCD, BTM and controls in brain MRI except that left thalamus R2* higher in BTM than both SCD and controls (p=0.032). Mean right caudate R2* was higher in female than male (p=0.044). No significant association between brain R2* and LIC or heart R2* values in SCD. Left caudate R2* directly correlate with age and HbS%, negative correlate with HbA% while right thalamus R2* negatively correlate with transfusion index and among SCD patients. Conclusion: Neurocognitive dysfunction in SCD could not be explained solely by brain iron overload.

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Non-invasive Quantitative MRI assessment of brain iron overload in patients with BThalassemia and Sickle cell disease

QJM ◽

10.1093/qjmed/hcab106.023 ◽

2021 ◽

Vol 114 (Supplement_1) ◽

Author(s):

Ghada Samir Ibrahim ◽

Fatma Soliman Elsayed Ebeid ◽

Hend Galal Eldeen Mohammed Ahmed Samir Ibrahim

Keyword(s):

Sickle Cell Disease ◽

Iron Overload ◽

Chelation Therapy ◽

Brain Mri ◽

Control Group ◽

Healthy Controls ◽

Brain Iron ◽

Cell Disease ◽

Mri Study ◽

Age And Sex

Abstract Background B-Thalassemia, sickle cell disease (SCD) and other inherited hemoglobin disorders are considered the most prevalent monogenic diseases worldwide. Secondary iron overload is one of the major complications in such groups of patients affecting many organs (e.g. liver, heart and endocrinal glands). Objective The current study will assess brain iron content ( using R2* values ) in the caudate and thalamic regions through quantitative brain MRI study in B-Thalassemia and SCD patients in comparison to age and sex-matched healthy controls. Also evaluation of the association with LIC (liver iron concentrations) and MIC (myocardial iron concentrations) was done. Methods A case control study on 30 patients (15 with B-thalassemia major and 15 with SCD) and 11 age and sex-matched healthy controls was carried out in the period between August 2018 till August 2019. Brain MRI study using multiecho fast gradient echo sequence was done for all the patients and controls. Brain R2* values of both caudate and thalamic regions (right and left sides) were calculated. Also brain R2* values were correlated with the LIC and HIC in B-thalassemia and SCD groups. Results 15 transfusion dependent B-thalassemia (mean-age: 19.40 ± 4.31 years, 53.3% females), 15 SCD patients (SCD; mean-age: 16.93 ± 3.41 years, 40.6% females) and 11 age and sex matched healthy controls (HC; mean age: 18.73 ± 4.84 years, 54.5% females) were enrolled in the study. No statistically significant differences were found between SCD and control group in all regions of interests No statistically significant differences were found between the three subgroups (p > 0.05) in right thalamus, left and right caudate regions. However, in B-thalassemia subgroup, patients had moderately significantly higher R2* values compared to the controls and SCD patients as regards the left thalamic region with mean R2* values (16.69 ± 1.34) Hz compared to (15.65 ± 1.10) Hz in the control group (p = 0.021) and (15.79 ± 0.77) Hz in the SCD group (p = 0.029). There were no significant correlations between LIC and HIC with brain R2* values of all regions of interests in both B-thalassemia and SCD subgroups. Conclusion MRI is a valuable, reliable, safe and noninvasive method for quantifying iron concentration (in cases of iron overload) in many organs as the liver and heart and it is now used internationally for regular follow up of LIC and HIC for monitoring of the chelation therapy in B-thalassemia and SCD patients. The results of our study showed that even in cases of iron overload which affects vital organs as the liver, cardiac and brain iron overload don't occur. This may be explained by heavy chelation therapy regimens given to our patients due to their poor compliance so as to keep the pre-transfusion hemoglobin level above 10mg/dl to prevent detrimental cardiac affection as cardiac siderosis, arrhythmias including heart block, or even heart failure.

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Kinetic of Iron Absorption and Expression of Iron Related Genes in Beta-Thalassemia.

Blood ◽

10.1182/blood.v106.11.3846.3846 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3846-3846

Author(s):

Laura Breda ◽

Sara Gardenghi ◽

Ella Guy ◽

Ninette Amariglio ◽

Konstantin Adamsky ◽

...

Keyword(s):

Iron Overload ◽

Iron Content ◽

Iron Absorption ◽

Globin Gene ◽

Active Form ◽

Beta Thalassemia ◽

Post Transplantation ◽

Divalent Metal Transporter 1 ◽

Hematopoietic Stem ◽

Divalent Metal Transporter

Abstract We generated the first transplantable adult mouse models of beta-thalassemia intermedia and major by infusing mouse hematopoietic-fetal-liver cells (HFLC) heterozygous or homozygous for a deletion of the beta-globin gene (respectively with th3/+ and th3/th3 cells) into lethally irradiated congenic C57BL/6 mice. Six to 8 weeks post transplantation, mice transplanted with th3/+ HFLCs show 7 to 9 g/dL of hemoglobin levels, splenomegaly, abnormal red cells and increased iron overload. Mice transplanted with th3/th3 HFLCs, unless blood transfused, die 8 to 10 weeks after engraftment showing profound anemia, massive splenomegaly and very rapid and dramatic iron overload. For this reason, we began a systematic study to compare iron content and the expression level of iron related genes in normal and thalassemic mice of varying ages and sex in different organs (liver, duodenum, spleen, kidney and heart). In liver, we observed that iron content increases proportionally with the level of anemia, age and if the blood transfusion is included. We are currently analyzing the other organs. The expression of hepcidin, ferroportin, Hfe, ferritin, transferrin, transferrin-receptor 1 and 2, ceruloplasmin, divalent metal transporter 1 and hemojuvelin are being tested also in all these organs. In particular, we observed that hepcidin is dramatically downregulated in liver of beta-thalassemic animals. Our hypothesis is that low expression of this gene leads to high iron content in these animals. We intend to demonstrate that administration or increasing hepcidin levels of this peptide can prevent iron absorption in beta-thalassemia. We developed two alternative strategies to test our hypothesis. In the first one, we synthesized the active form of the mouse hepcidin peptide that will be administered intraperitoneally to mice affected by beta-thalassemia. In the second, lentiviral vectors have been generated in order to constitutively secrete hepcidin in the bloodstream of animals affected by beta-thalassemia. These vectors were introduced into hematopoietic stem cells derived from mouse embryos of normal and mice affected by beta-thalassemia and engrafted in myeolablated normal mice. The engrafted mice express hepcidin 6 weeks post transplantation by RT PCR. These animals, along with the animals in which hepcidin will be administrated intraperitoneally, will be analyzed at the endpoint of the experiment (> 4 months) for their hematological values and iron content to see if the use of hepcidin can be used to prevent excessive iron absorption in beta-thalassemia.

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Brain Iron Content in Egyptian Patients with Sickle Cell Disease: Impact on Neurocognitive Functions

Blood ◽

10.1182/blood-2020-139168 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 37-37

Author(s):

Mohsen Saleh Elalfy ◽

Ahmed Smair ◽

Ghada Samir ◽

Hanaa Hussein ◽

Hend Mohammed ◽

...

Keyword(s):

Young Adults ◽

Sickle Cell Disease ◽

Iron Overload ◽

Negative Correlation ◽

Iron Content ◽

Brain Mri ◽

Brain Iron ◽

Cell Disease ◽

Neurocognitive Functions ◽

Left Caudate

Background:Children with sickle cell disease (SCD) are at a high risk for neurocognitive impairment which may be due to iron overload in brain tissue or hemoglobin polymerization and endothelial dysfunction.Primary objectivewas measuring brain iron content (using R2* values) in the caudate and thalamic regions through quantitative brain MRI in Egyptian adolescents and young adults with multi-transfused SCD in comparison to beta thalassemia major (BTM) and age- and sex-matched healthy controls.Secondary objectiveswere evaluating the impact of brain iron content on neurocognitive functions of SCD patients and its association with MRI assessment of liver iron concentration (LIC) and cardiac iron (myocardial T2*).Methods: 32 children and young adults with SCD (mean age: 15.3 ± 3.7, 19 males and 13 females), 15 BTM (mean age: 19.4 ± 4.3, 7 males and 8 females) and 11 healthy control age- and gender-matched were recruited. Thorough clinical assessment, hematological and serum ferritin were performed. Brain MRI study using multi-echo fast gradient echo sequence was performed only for 15 patients with SCD, 15 patients with BTM and 11 controls and brain R2* values of both caudate and thalamic regions (right and left sides) were calculated. LIC and myocardial T2 were performed for; 15 with SCD and 15 with BTM. 32 SCD patients were examined for the neurocognitive functions; Wechsler IV Intelligence scale (verbal, perceptual, memory, processing and total IQ), Benton Visual Retention Test and Brief Psychiatric Rating Scale (BPRS).Results:For SCD patients their mean transfusion index was 174.70±63.98ml/kg/year and mean iron overload/day 0.30±0.12 mg/kg. 30 (93.8%) all SCD patients were on regular chelation therapy; 16 were on deferiprone and 16 were on combined chelation over last 5 years. Of those 32 SCD patients; 20 received concomitantly hydroxyurea therapy. Mean total IQ for SCD patients was 86.9±10.7; 68.9% had under- threshold <90 IQ and 27.5% had average (90-109) IQ. 12.5% of SCD patients had moderate to severe anxiety and 60.8% had of SCD patients had depression. No significant differences were found between SCD, BTM as regards LIC (p=0.102) No significant differences were found between SCD, BTM and control group in all regions of interests in brain MRI except that left thalamus R2* higher in BTM patients than both SCD and controls (p=0.032). R2* values of different regions of brain in relation with the studied parameters of SCD patients was not significant except that mean right caudate R2* was higher in female 17.4±0.8 than male 15.6±1.7 (p=0.044). The correlation coefficients showed no significant association between brain R2* and LIC or heart R2* values of SCD patients. There were positive correlation between left caudate R2* and both age and HbS%, negative correlation between transfusion index and right thalamus R2*, negative correlation between HbA% and left caudate R2* among SCD patients.Conclusion:Brain iron content in adolescents and young adults with SCD was not significantly different from either controls or BTM; SCD had high prevalence of neurocognitive dysfunction, which could not be explained by brain iron content or distribution. Figure 1 Disclosures No relevant conflicts of interest to declare.

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R* Magnetic Resonance Imaging (MRI) of the Liver for Patients with Iron Overload.

Blood ◽

10.1182/blood.v110.11.2670.2670 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2670-2670

Author(s):

Jane S. Hankins ◽

M. Beth McCarville ◽

Ralph Loeffler ◽

Ruitian Song ◽

Russell E. Ware ◽

...

Keyword(s):

Liver Biopsy ◽

Iron Overload ◽

Correlation Coefficient ◽

Serum Ferritin ◽

Iron Content ◽

Bone Marrow Failure ◽

Correlation Coefficients ◽

Beta Thalassemia ◽

Liver Iron ◽

Hematological Diseases

Abstract Iron overload is an inevitable consequence of multiple transfusions and occurs in many hematological diseases including sickle cell anemia (SCA) and beta thalassemia (β-thal). Liver biopsy provides quantification of iron content in the liver, but is not without risks such as bleeding, pain, and infection. MRI R2* has the advantage of quantifying liver iron without the risks of invasive procedures, however, this technique has not been fully investigated or validated. Furthermore, the variability introduced by multiple MRI readers has not been investigated to date. Patients with hematological diseases were selected to participate in this prospective IRB-approved study if they received ≥ 18 transfusions or had a serum ferritin ≥ 1000 ng/mL. All study participants completed 1.5 Tesla MRI R2* testing (Siemens Symphony), serum ferritin, and liver biopsy with quantification of liver iron content (LIC) within 30 days. Regions of interest (ROI) were drawn on R2* maps in a homogeneous area of the right hepatic lobe, avoiding blood vessels and obvious bile ducts. Three independent reviewers, blinded to the patients’ clinical status and the other 2 reviewers’ results, performed the ROI analysis. The correlation between LIC and liver R2* was calculated using the Spearman’s Rank-Order Correlation Coefficient. Due to possible outliers in the data, robust simple linear regression methods were used to fit a regression line to scatter plots. All liver biopsy samples were sent to Mayo Laboratories for LIC quantification. The agreement among the 3 raters was assessed using the interclass correlation coefficient (ICC). Forty-seven patients, median age 14 years (range 7 – 37) participated; 24 were female. Thirty-five of them had SCA, 8 had β-thal (major or intermedia), and 4 had bone marrow failure syndromes. Total table time for R2* MRI testing was between 20 to 30 minutes. All patients tolerated the liver biopsy without complications. The mean (±1SD) ferritin was 2917ng/mL (±2239), mean LIC was 12.139 mg/ 100g of dry weight liver (±8.269), and mean liver R2* ranged from 425 to 432 Hz (±257 to 249 Hz). All 3 raters produced R2* values strongly associated with LIC, with correlation coefficients from 0.93 to 0.95 (p<0.00005). There was a significant positive association between serum ferritin and R2* liver values (correlation among the 3 reviewers ranged from 0.39 to 0.50 with all p<0.009). The agreement among the 3 raters was 0.98. To summarize: 1) 1.5 T MRI R2* liver values are highly associated with LIC in patients with iron overload. This is the largest sample of MRI R2* liver measurements correlated with LIC obtained by liver biopsy; 2) The three raters had excellent agreement which suggests that, in our study, R2* liver values do not differ greatly among qualified readers; 3) R2* measurements of the liver were significantly associated with serum ferritin, however, the correlation coefficients were relatively low (0.39 to 0.50), documenting a weak relationship; and 4) MRI R2* of the liver is a feasible and valid technique to assess LIC non-invasively, and appears to be reproducible when performed by qualified reviewers. We conclude that liver MRI R2* can be incorporated into clinical research protocols for safe, painless, and accurate liver iron quantitation.

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Pharmacokinetic and Toxicological Results of a 28-Day Multiple Dose Study of Starch-Conjugated Deferoxamine (S-DFO, 40SD02) in Iron-Loaded Dogs.

Blood ◽

10.1182/blood.v110.11.2780.2780 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2780-2780

Author(s):

Robert W. Grady ◽

James Bakke ◽

Karen Steinmetz ◽

Terry R. Bishop ◽

Bo E. Hedlund

Keyword(s):

Iron Overload ◽

Iron Content ◽

Multiple Dose ◽

Clinical Chemistry ◽

Iron Status ◽

Beta Thalassemia ◽

Iron Loading ◽

Single Dose Study ◽

Cardiovascular Side Effects ◽

Dose Study

Abstract Starch-conjugated deferoxamine (S-DFO) is a long-acting, polymeric iron chelator designed to achieve iron balance in patients requiring frequent transfusions. Results from an ascending single dose study in 16 patients with beta-thalassemia showed that S-DFO is capable of achieving up to 7 days of iron balance (Br. J. Haematol. 138, 374–381, 2007). The multiple dose toxicology study described here was conducted to support extended clinical studies in patients with thalassemia and other iron overload disorders. The study was designed to evaluate physiological effects of S-DFO in iron-loaded animals;to seek evidence of cardiovascular side-effects;to find evidence of drug accumulation in plasma and other tissues; andto determine the No Observable Adverse Effect Level (NOAEL) following biweekly intravenous infusion for 4 weeks. Iron loading was achieved by multiple biweekly infusions of iron-dextran so as to give a cumulative dose of 500 mg of iron/kg body weight. Equilibration of iron was then allowed to proceed for 10 weeks before initiation of treatment. The study included four groups of 10 iron-loaded animals (5M/5F): saline controls; 210 and 420 mg/kg of deferoxamine (DFO) equivalents as S-DFO; 105 mg/kg of non-conjugated DFO; and two groups of 10 normoferremic animals (5M/5F): saline controls; and 210 mg/kg of DFO equivalents as S-DFO. All animals received 8 doses of either S-DFO, DFO or saline over 28 days. Six animals in each group (3M/3F) were euthanized on Day 29 for histological examination, the remaining 4 animals in each group on Day 43. Safety parameters for cardiovascular pharmacology, hematology and clinical chemistry showed no changes attributable to S-DFO treatment. The polymeric chelator is cleaved/metabolized by serum amylase(s). While trough concentrations of S-DFO fragments prior to the final drug infusion on Day 25 showed some accumulation, there was no evidence of resulting pathological changes. Thus, the NOAEL is at least 420 mg/kg of DFO equivalents. The hepatic iron content of the iron-loaded animals was approximately 20 times greater than that of the normoferremic controls. Treatment with 420 mg/kg of DFO equivalents led to a 13% reduction in the liver iron content. Neither iron loading nor treatment with S-DFO had a significant effect upon the cardiac iron status. The lack of toxicity in normoferremic animals suggests that S-DFO may have applications in clinical situations where increased iron stores are not characteristic of the disease. Furthermore, the ability to safely infuse up to 420 mg/kg of DFO equivalents without concern for hypotension indicates that S-DFO may also be well suited for treatment of acute iron poisoning. Finally, these results support initiation of multidose studies of S-DFO in patients with thalassemia and other iron overload disorders. Supported by NIDDK Contract Number N01-DK-32624.

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