Magnetic Ressonance Image T2* for the Evaluation of Iron Overload in Patients with Hereditary Hemochromatosis. A New Guide for the Indication of Therapeutic Phlebotomies.

Abstract Hereditary hemochromatosis is highly prevalent in those with northern European ancestry (1 in 8 individuals are heterozygous and 1 in 100 – 200 are homozygous). It is characterized by laboratory tests as ferritin > 150 ng/mL, transferrine saturation > 40% and HFE mutations (C282Y and H63D). Presently the indications for treatment (therapeutic phlebotomies, TP) are based solely on the ferritin levels. It is possible that patients with moderate or even high levels of ferritin do not have iron overload. Performing liver biopsies would be an option for the actual evaluation, though invasive and risky. A non-invasive method to evaluate this deposition would be helpful in order to determine which patients actually demand TP. To evaluate if the use of Magnetic Ressonance Image (MRI) is a method for measuring tissue iron and could be a new guide for the indication of therapeutic phlebotomies, nineteen patients (mean age 43,47 y.o, +/− 9,85, gender = 16 male, 3 female) with hereditary hemochromatosis were scanned with T2- star (T2*) (GE equipment, Milwaukee, USA). The median of ferritin level was 594 (21–9300) The MRI method was previously validated to chemical estimation of iron in thalassemic major patients undergoing liver biopsies. The evaluated organs were liver and heart. All patients were in normal range of myocardial T2*. The images of four patients (25%), showed liver iron deposition. Eleven patients who presented serum ferritin levels below 600 ng/ml showed no liver iron deposition. Just one among five patients (20%), who presented ferritin levels between 601 and 1000 ng/ml showed hepatic iron overload. The three patients with ferritin levels higher than 1000 ng/ml had liver iron deposition quantified using liver T2* MRI techique. MRI T2* showed that some patients who would have an indication for TP based on laboratory tests, might avoid these procedures based on image results of internal organs. These patients can have an image follow up in order to decide when would be the appropriate time to start TP. This method can also be used to evaluate the efficacy of TP in patients who have already received this treatment. A larger group of patients would have to be evaluated in order to validate these results.

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Discrepancy between Serum Ferritin and Liver Iron Concentration in a Patient with Hereditary Hemochromatosis – The Value of T2* MRI

Case Reports in Oncology ◽

10.1159/000507756 ◽

2020 ◽

Vol 13 (2) ◽

pp. 712-715

Author(s):

Mustafa A. Al-Tikrity ◽

Mohamed A. Yassin

Keyword(s):

Iron Overload ◽

Serum Ferritin ◽

Ferritin Level ◽

Hereditary Hemochromatosis ◽

Iron Concentration ◽

Hfe Gene ◽

Liver Iron Concentration ◽

C282y Mutation ◽

Liver Iron ◽

T2 Mri

Primary hemochromatosis is an inherited disorder, and the homeostatic iron regulator (HFE) gene C282Y mutation is a common cause of hemochromatosis in Europe. We are reporting a case of a 56-year-old female known to have hemochromatosis with the HFE gene C282Y mutation with a serum ferritin level of 482 μg/L who underwent heart and liver T2* MRI which showed no evidence of iron overload – neither in the heart nor in the liver. This indicates that there is a discrepancy between serum ferritin and liver iron concentration by MRI and the superiority of T2* MRI in diagnosis and follow-up of iron overload in patients with hereditary hemochromatosis.

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The Effect of Combination Iron Chelating Agents on Reducing the Severity Grading of Heart and Liver Iron Overload in β-Thalassemia Patients

Iranian Journal of Pediatric Hematology & Oncology ◽

10.18502/ijpho.v9i4.1573 ◽

2019 ◽

Author(s):

Majid Ghanavat ◽

Alireza Fazeli Varzaneh ◽

Nahid Reisi

Keyword(s):

Iron Overload ◽

Serum Ferritin ◽

Serum Ferritin Level ◽

Ferritin Level ◽

Iron Deposition ◽

Liver Iron ◽

Liver Iron Overload ◽

Severity Grading ◽

Group A ◽

Group B

Background: Deferasirox (DFX), Deferoxamine (DFO), and Deferiprone (DFP) are iron chelators that can be used in thalassemic patients with iron overload. Materials and Methods: This clinical trial was performed on 108 thalassemic patients who were randomly divided into group A (n=54) and B (n=54). Group A received combination of DFX and DFP, and group B received DFO and DFP for six months. Serum ferritin level was measured at the beginning of the study, 3, and 6 months after the treatment; The heart and liver iron deposition rates were also measured at the beginning of the study, and 6 months after the treatment in both groups and compared using Magnetic Resonance Imaging T2 plus (MRI T2*). Results: The mean age of patients in group A and B was 17.29±4.3 and 17.89±5.61 years old, respectively. Serum ferritin level significantly reduced after the treatment (Serum ferritin level at baseline, 3, and 6 months after the treatment in Group A: 2476.25±1289.32, 2089.62±1051.64 and 1290.22±724.78 ng/ml, respectively; in Group B: 2044.63±989.82, 1341.30±887.62 and 1229.41±701.22 ng/ml, respectively) (p<0.01, for both groups). MRI T2* heart and liver was also improved at the end of the study in both groups (p<0.01, for both groups). However, the combination of DFO/DFP significantly decreased severity grades of liver iron deposition in comparison to DFX/DFP regimen after six months (p<0.01). Conclusion: The results of the present study indicated that both combination therapies of DFO/DFP and DFX/DFP could improve heart and liver MRI T2*. However, DFO/DFP combination therapy was more effective in reducing the severity grades of liver iron deposition.

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A T2* MRI Prospective Survey on Heart and Liver Iron In Thalassemia Major Patients Treated with Sequential Deferipron–Desferrioxamine versus Deferasirox

Blood ◽

10.1182/blood.v116.21.5165.5165 ◽

2010 ◽

Vol 116 (21) ◽

pp. 5165-5165

Author(s):

Alessia Pepe ◽

Giuseppe Rossi ◽

Antonella Meloni ◽

Dell'Amico Maria Chiara ◽

D'Ascola Domenico Giuseppe ◽

...

Keyword(s):

Iron Overload ◽

Conflicts Of Interest ◽

Ferritin Level ◽

Thalassemia Major ◽

Mean Difference ◽

Quantitative Mri ◽

Cardiac Complications ◽

Myocardial Iron ◽

Liver Iron ◽

Multi Centre Study

Abstract Abstract 5165 Introduction: Most deaths in thalassemia major (TM) result from cardiac complications due to iron overload. No data are available in literature about possible different changes in cardiac and liver iron in TM patients treated with sequential deferiprone–deferoxamine (DFP-DFO) versus deferasirox (DFX). Magnetic Resonance (MR) is the unique non invasive suitable technique to evaluated quantitatively this issue. The aim of this multi-centre study was to assess prospectively in the clinical practice the efficacy of the DFP-DFO vs DFX in a cohort of TM patients by quantitative MR. Methods: Among the first 739 TM patients enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network, 253 patients performed a MR follow up study at 18 ± 3 months according to the protocol. We evaluated prospectively the 25 patients treated with DFP-DFO versus the 44 patients treated with DFX between the 2 MR scans. Myocardial and liver iron concentrations were measured by T2* multislice multiecho technique. Results: The doses of the sequential treatment were DFP 70±14 mg/kg/d for 4 d/w and DFO 42±8 mg/kg/d for 3 d/w, the dose of DFX was 26±6 mg/kg/d. Excellent/good levels of compliance were similar in the 2 groups (DFP-DFO 96% vs DFX 100%; P = 0.36). At baseline the 2 groups were homogeneous for cardiac and liver iron. Among the patients with no significant myocardial iron overload at baseline (global heart T2* 3 20 ms), there were no significant differences between groups to maintain the patients without myocardial iron overload (DFP-DFO 95% vs DFX 96%; P = 1.0). Among the patients with myocardial iron overload at baseline (global heart T2* < 20 ms), only in the DFX group there was a significant improvement in the global heart T2* value (11 ± 5 ms at baseline versus 16 ± 8 at 18 ± 3 months, P = 0.0001) and in the number of segment with a normal T2* value (P = 0.003). The improvement in the global heart T2* was not significantly difference in the DFP-DFO versus the DFX group (mean difference global heart T2* 2.2 ± 4.1 ms versus 4.6 ± 4.8 P = 0.2). The changes in the mean serum ferritin level were not significantly different between groups. In patients with liver iron overload at baseline (liver T2* < 5.1 ms), the change in the liver T2* was not significant between groups (mean difference liver T2* 0.9 ± 2.1 ms vs 2.4 ± 5.2; P = 0.3). Conclusions: Prospectively in the clinical setting over 15 months we did not find significant differences on cardiac and liver iron by quantitative MRI in TM patients treated with sequential DFP–DFO versus the TM patients treated with DFX. Disclosures: No relevant conflicts of interest to declare.

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Target TMPRSS6 Using Antisense Technology for the Treatment of Hereditary Hemochromatosis and β-Thalassemia

Blood ◽

10.1182/blood.v120.21.481.481 ◽

2012 ◽

Vol 120 (21) ◽

pp. 481-481 ◽

Cited By ~ 1

Author(s):

Shuling Guo ◽

Carla Casu ◽

Sara Gardenghi ◽

Sheri Booten ◽

Andy Watt ◽

...

Keyword(s):

Treatment Group ◽

Iron Overload ◽

Hereditary Hemochromatosis ◽

Iron Concentration ◽

Transferrin Saturation ◽

Control Group ◽

Mrna Levels ◽

Liver Iron ◽

Hepcidin Expression ◽

Antisense Technology

Abstract Abstract 481 Hepcidin, the master regulator of iron homeostasis, is a peptide that is mainly expressed and secreted by the liver. Low levels of hepcidin are associated with increased iron absorption. In conditions in which hepcidin is chronically repressed, such as hereditary hemochromatosis and b-thalassemia, patients suffer from iron overload and very severe pathophysiological sequelae associated with this condition. Hepcidin expression is regulated predominantly at the transcriptional level by multiple factors. TMPRSS6, a transmembrane serine protease mutated in iron-refractory, iron-deficient anemia, is a major suppressor of hepcidin expression. It has been demonstrated that hepcidin expression is significantly elevated in Tmprss6−/− mice and reduction of Tmprss6 expression in hereditary hemochromatosis (Hfe−/−) mice ameliorates the iron overload phenotype (Finberg et al. Nature Genetics, 2008; Du et al. Science 2008; Folgueras et al. Blood 2008; Finberg et al., Blood, 2011). It has also been demonstrated that hepcidin up-regulation using either a hepcidin transgene or Tmprss6−/− significantly improves iron overload and anemia in a mouse model of β-thalassemia intermedia (th3/+ mice) (Gardenghi et al. JCI, 120:4466, 2010; Nai et al. Blood, 119: 5021, 2012). In this report, we have examined whether reduction of Tmprss6 expression using antisense technology is an effective approach for the treatment of hereditary hemochromatosis and β-thalassemia. Second generation antisense oligonucleotides (ASOs) targeting mouse Tmprss6 were identified. When normal male C57BL/6 mice were treated with 25, 50 and 100mg/kg/week ASO for four weeks, we achieved up to >90% reduction of liver Tmprss6 mRNA levels and up to 5-fold induction of hepcidin mRNA levels in a dose-dependent manner. Dose-dependent reductions of serum iron and transferrin saturation were also observed. ASOs were well tolerated in these animals. In Hfe−/− mice (both males and females), ASOs were administrated at 100 mg/kg for six weeks. This treatment normalized transferrin saturation (from 92% in control animals to 26% in treatment group) and significantly reduced serum iron (from >300ug/dl in control group to <150ug/dl in treatment group), as well as liver iron accumulation. Histopathological evaluation and Prussian's Perl Blue staining indicated that iron was sequestered by macrophages, which led to an increase in spleen iron concentration. The mouse model of thalassemia intermedia that we utilized mimics a condition defined as non-transfusion dependent thalassemia (NTDT) in humans. These patients exhibit increased iron absorption and iron overload due to ineffective erythropoiesis and suppression of hepcidin; iron overload is the most frequent cause of morbidity and mortality. Th3/+ animals exhibit ineffective erythropoiesis, characterized by increased proliferation and decreased differentiation of the erythroid progenitors, apoptosis of erythroblasts due to the presence of toxic hemichromes, reticulocytosis and shorter lifespan of red cells in circulation, leading to splenomegaly, extramedullary hematopoiesis and anemia (∼ 8 g/dL; Libani et al, Blood 112(3):875–85, 2008). Five month old th3/+ mice (both males and females) were treated with Tmprss6 ASO for six weeks. In th3/+ mice, ∼85% Tmprss6 reduction led to dramatic reductions of serum transferrin saturation (from 55–63% in control group down to 20–26% in treatment group). Liver iron concentration (LIC) was also greatly reduced (40–50%). Moreover, anemia endpoints were significantly improved with ASO treatment, including increases in red blood cells (∼30–40%), hemoglobin (∼2 g/dl), and hematocrit (∼20%); reduction of splenomegaly (∼50%); decrease of serum erythropoietin levels (∼50%); improved erythroid maturation as indicated by a strong reduction in reticulocyte number (50–70%) and in a normalized proportion between the pool of erythroblasts and enucleated erythroid cells. Hemichrome analysis showed a significant decrease in the formation of toxic alpha-globin/heme aggregates associated with the red cell membrane. This was consistent with a remarkable improvement of the red cell distribution width (RDW) as well as morphology of the erythrocytes. In conclusion, these data demonstrate that targeting TMPRSS6 using antisense technology is a promising novel therapy for the treatment of hereditary hemochromatosis and β-thalassemia. Disclosures: Guo: Isis Pharmaceuticals: Employment. Booten:Isis Pharmaceuticals: Employment. Watt:Isis Pharmaceuticals: Employment. Freier:Isis Pharmaceuticals: Employment. Rivella:Novartis Pharmaceuticals: Consultancy; Biomarin: Consultancy; Merganser Biotech: Consultancy, Equity Ownership, Research Funding; Isis Pharma: Consultancy, Research Funding. Monia:Isis Pharmaceuticals: Employment.

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Hereditary Hemochromatosis in an Adult Due to H63D Mutation: The Value of Estimating Iron Deposition By MRI T2* and Dissociation Between Serum Ferritin Concentration and Hepatic Iron Overload

Blood ◽

10.1182/blood.v124.21.4891.4891 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4891-4891

Author(s):

Mohamed A. Yassin ◽

Ashraf T Soliman ◽

Vincenzo Desanctis ◽

Sandara Abusamaan ◽

Ahmed Elsotouhy ◽

...

Keyword(s):

Iron Overload ◽

Basal Ganglion ◽

Serum Ferritin ◽

Normal Values ◽

Hereditary Hemochromatosis ◽

Transferrin Saturation ◽

Iron Deposition ◽

Ferritin Concentration ◽

H63d Mutation ◽

Serum Ferritin Concentration

Abstract Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by excessive intestinal absorption of dietary iron, causing iron overload in different organs, especially the liver. Hemochromatosis may not be recognized until later in life. Patients are usually asymptomatic but may present with a variety of signs and symptoms. These include: hyper-pigmented skin, hepatomegaly, arthralgia, diabetes mellitusand/or heart failure/arrhythmia. The risk of HH related morbidity in HFE compound homozygotes patients (H63D /H63D) is considered rare, we report a male patient with H63D mutation who developed impaired glucose tolerance, and high hepatic enzymes due to significant iron accumulation in the liver as well as Parkinsonian-like syndrome due to iron deposition in the basal ganglia. A 40 year old Qatari male was referred for evaluation of a rise in hemoglobin and hematocrit values with normal MCV, total leucocyte and platelet counts. The patient was asymptomatic with normal vital signs, no depigmentation or hepato-splenomegaly. Hematologic findings included a hemoglobin concentration of Hb 16.5 g/dL, hematocrit 53%, mean corpuscular volume (MCV) 93 fL/red cell, leucocyte count of 7200/ μL and a platelet count of 199000/μL. His serum ferritin was 359 μg/l ( normal values: < 336 μg/l), serum iron: 37 μmol/l ( normal values <28.6μmol/l), fasting transferrin saturation: 64% (normal < 50%). A random glucose 6.5 and 6.4 mmol/L (normal values 5.5mmol/L ), A1C of 5,4 %, normal creatinine and electrolytes, alanine aminotransferase (ALT) of 66 U/l (normal < 40U/l), mild elevation of bilirubin 39 umol/l (normal <24umol/l), normal U&E Hepatitis B and C antibodies were negative. OGTT revealed impaired glucose tolerance. Thyroid function, morning serum cortisol, LH and FSH and serum total testosterone concentrations were in the normal range. A diagnosis of polycythemia vera was excluded on the basis of WHO Criteria 2008. The polymerase chain restriction assay was negative for the common mutation (C282Y) but positive for H63 D mutation. Family screening confirmed HH in his brother (homozygous), whereas his mother, two brothers and the sister were carriers (heterozygous). His four offspring were carriers. This suggested an autosomal recessive mode of inheritance. Conventional MRI study showed a normal liver size with diffuse fatty changes and focal areas of fatty sparing with some evidence of iron deposition. Whereas, T2-star (T2*) sequences showed a diffuse and significant decrease in liver signal intensity. A LIC liver concentration of 27 mg Fe/g dry wt was found (normalvalues:< 2 mg Fe/g dry wt; severe iron overload: ≥15 mg Fe/g dry wt). No significant iron deposition in the spleen, heart or pancreas was observed. At the age of 41 years the patient complained of tremors in both hands and arms while sitting or standing still (resting tremor) that improved with hands movements. A brain MRI revealed iron deposition in the basal ganglion. It was concluded that basal ganglionicn iron deposition mediated the neurological decline. Currently, the transferrin saturation and serum ferritin levels are within normal. Discussion: This is the first case of HH secondary to H63 D among an Arab family and the first reported case of Parkinsonism tremors secondary to this mutation. The H63D HFE variant is less frequently associated with HH, but its role in the neurodegenerative diseases has received a great attention. An accurate evaluation of iron overload is necessary to establish the diagnosis of HH and to guide iron chelation in HH by determination of liver iron concentration (LIC) by means of T2* MRI. Although serum ferritin concentration was only mildly increased a significant siderosis in the liver was detected by MRI T2* technique occurred. Liver siderosis was associated with mild impairment of liver function (increased serum ALT and bilirubin ). Conclusion: Our data further confirm that serum ferritin levels are not an accurate measure of total body iron stores in HH. Iron deposition in the liver and basal ganglion occurred despite mild elevation of ferritin. changes in basal ganglion may present by parkinsonian like tremors in these patients Use,T2* MRI should be encouraged in patients with HH for better evaluation of Iron overload and avoidance of Complications since serum ferritin can be misleading in these conditions. Disclosures Yassin: Qatar National research fund: Patents & Royalties, Research Funding. Aldewik:Qatar Ntional Research Fund: Patents & Royalties, Research Funding.

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Asymptomatic hemochromatosis subjects: genotypic and phenotypic profiles

Blood ◽

10.1182/blood.v96.12.3707.h8003707_3707_3711 ◽

2000 ◽

Vol 96 (12) ◽

pp. 3707-3711 ◽

Cited By ~ 1

Author(s):

Ronald L. Sham ◽

Richard F. Raubertas ◽

Caroline Braggins ◽

Joseph Cappuccio ◽

Margaret Gallagher ◽

...

Keyword(s):

Iron Overload ◽

Hereditary Hemochromatosis ◽

Transferrin Saturation ◽

Entire Group ◽

Iron Loading ◽

Asymptomatic Patients ◽

Liver Biopsies ◽

The Relationship ◽

Genotypic Profile ◽

Compound Heterozygotes

Screening for hereditary hemochromatosis (HHC) by means of transferrin saturation (TS) levels has been advocated and will identify many patients who are asymptomatic. The purposes of this study were (1) to determine HFE genotypes among asymptomatic HHC patients and correlate this profile with the degree of iron overload and (2) to evaluate the relationship between mobilized iron (mob Fe), age, serum ferritin (SF), and quantitative hepatic iron (QHI) in this population. One hundred twenty-three asymptomatic HHC patients were evaluated; all had quantitative phlebotomy to determine mob Fe and genotyping for C282Y and H63D mutations. Liver biopsies with QHI determinations were performed on 72 of the 123 patients. Of the entire group, 60% were homozygous for C282Y, and 13% were compound heterozygotes (C282Y/H63D). Among asymptomatic patients, the prevalence of homozygous C282Y is lower compared with previous studies that include clinically affected patients. Of those patients with more than 4 g mob Fe, 77% were homozygous C282Y. Asymptomatic patients with lower iron burdens frequently had genotypes other than homozygous C282Y. There was no correlation between age and mob Fe in these patients; however, there was a correlation between mob Fe and both SF (r = 0.68) and QHI (r = 0.75). In conclusion, asymptomatic patients with moderate iron overload had a different genotypic profile than was seen in advanced iron overload. The significance of identifying patients with modest degrees of iron loading, who may not be homozygous for C282Y, must be addressed if routine TS screening is to be implemented.

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Evaluation of Liver Iron Deposition in Transfusion-Dependent Patients By Dual-Energy CT

Blood ◽

10.1182/blood.v128.22.3619.3619 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3619-3619

Author(s):

Hironori Kobayashi ◽

Norihiko Yoshimura ◽

Takayuki Katagiri ◽

Takashi Ushiki ◽

Kyoko Fuse ◽

...

Keyword(s):

Blood Transfusion ◽

Iron Overload ◽

Unit Group ◽

Left Lobe ◽

Iron Deposition ◽

Dual Energy Ct ◽

Liver Iron ◽

Iron Chelate ◽

Ct Attenuation ◽

Chelate Therapy

Abstract [Introduction] The launch of the oral iron chelator "Deferasirox" has improved the outcomes of blood transfusion-dependent patients with iron overload in the last decade. Although serum ferritin (SF) remains the mostly commonly used metric to monitor body iron stores for decisions regarding the indication of iron chelate therapy, it is known to be affected by many factors. The liver iron concentration (LIC) is considered to be an indicator of total body iron stores, and the MR imaging-based R2 technique is the standard non-invasive technique used to evaluate LIC. However, this technique is not used in every institution due to some limitations such as its high cost and the requirement for special software. Although the application of CT, which is easy to use and inexpensive, needs to be considered for the evaluation of LIC, the use of conventional single energy CT (SECT) to measure LIC is also limited by normal variations in CT attenuation, predominantly in patients with mild iron overload. Moreover, SECT fails to detect iron in fatty livers, which has an inverse effect on attenuation by lowering CT numbers. Dual-energy CT (DECT) is a technique that is employed to obtain precise information on tissue composition and may be useful for monitoring LIC. It is based on substances showing different densities with two different energies, with each substance displaying its own energy-dependent change in CT attenuation. The role of DECT in monitoring LIC has not yet been clarified in blood transfusion-dependent patients with iron overload. We herein evaluated iron deposition in the livers of blood transfusion-dependent patients using DECT. [Patients and Methods] Seventeen blood transfusion-dependent patients underwent liver DECT using a dual-source 128-slice CT system, and SF levels were measured at same time. DECT images were acquired using a tube voltage pair of 140 kV and 80 kV or 140 kV and 100 kV, and the three-material decomposition of fat, soft tissue, and iron. [Results] The median age of patients was 52 years (range, 25 to 66), and 8 patients were male. Eight patients with AML, 3 with MDS, and 1 each with ALL, lymphoma, aplastic anemia, Evans syndrome, congenital dyserythropoietic anemia, and chronic renal failure underwent DECT. Nine patients had undergone stem cell transplantation before DECT, and 3 were receiving iron chelate therapy. The total number of units of blood transfused was available in 11 out of 17 patients. The median number of units given was 66 (range, 36 to 150). The median SF level was 2346 ng/ml (range, 569 to 7875). We divided patients into three groups based on SF levels: high >3000 ng/ml, intermediate 1000~3000 ng/ml, low <1000 ng/ml. Five patients were classified into the high SF group (range, 3765-7875 ng/ml), 8 into the intermediate SF group (1645-2916), and 4 into the low SF group (569-1240). Four patients in high, 4 in the intermediate, and 2 in the low SF groups showed diffuse iron deposition in the liver on DECT images. One patient in the high, 2 in the intermediate, and 2 patients in the low SF groups showed focal iron deposition in the left lobe of the liver. On the other hand, two patients in the intermediate SF group did not show iron deposition on DECT images. We then divided patients into two groups based on the number of units of blood transfused: 6 patients were classified into the high unit group (range, 66-150 units), and 5 into the low unit group (36-60). Four patients in the high unit and 3 in the low unit groups showed diffuse iron deposition in the liver on DECT images. Two patients in the high unit and 1 in the low unit groups showed focal iron deposition in the left lobe of the liver. One patient in the low unit group did not show iron deposition. [Conclusion] Discrepancies between SF levels and DECT images indicate that DECT is a useful technique for the accurate evaluation of LIC, and the detection of focal iron deposition in the liver may be useful for optimizing iron chelation therapy. Disclosures No relevant conflicts of interest to declare.

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Whole Liver Iron Overload Measurement by Magnetic Iron Detector (MID). A Non Cryogenic Bio-Susceptometer.

Blood ◽

10.1182/blood.v108.11.1547.1547 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1547-1547

Author(s):

Mauro Marinelli ◽

Piergiorgio Beruto ◽

Barbara Gianesin ◽

Antonella Lavagetto ◽

Martina Lamagna ◽

...

Keyword(s):

Iron Overload ◽

Iron Reduction ◽

Hereditary Hemochromatosis ◽

Iron Concentration ◽

Large Error ◽

Liver Iron ◽

Heterogeneous Distribution ◽

Ferritin Concentration ◽

Liver Iron Overload ◽

Liver Needle Biopsy

Abstract Accurate assessment of body-iron accumulation is essential for diagnosis and therapy of iron-overload in diseases such as thalassemia, hereditary hemochromatosis and other forms of severe congenital or acquired anemias. At present, the gold standard to determine liver-iron concentration (LIC) is the invasive liver needle biopsy. This technique might lead to large error, in assessing iron burden, due to the heterogeneous distribution of iron deposition in the liver. SQUID bio-susceptometer and MRI are currently the only non-invasive validated methods for LIC measurements. The susceptometer presented herein, named Magnetic Iron Detector (MID), measures directly the iron overload in the whole liver. All of its components operate at room temperature. Since February 2005 about 150 patients and 90 healthy volunteers have been measured and the measures were obtained in blind. The local Ethics Committee approved the study and all subjects gave informed consent. The result of correlations with the LIC measurements by SQUID susceptometry (Dr. A. Piga, Turin) in 43 patients showed a R 0.86 (Fig 1). In 2 patients, affected by Congenital Hemocromatosis, we correlated the LIC measurement by MID with the assessment of the expected iron depletion obtained with the phlebotomy therapy R 0.94 (Fig 2). All the measurements were correlated with the serum-ferritin concentration values R 0.72. We obtained correlation with the LIC measurement by liver biopsy in 7 patients R 0.89, further measures are in progress. The reproducibility of the iron overload of the same patients, measured after a relatively short lapse of time, is better than 0.5g. In conclusion the data obtained shows that MID is a reliable instrument for the diagnosis of the liver iron overload and for the follow-up of the chelation therapy. It is simpler to operate being manageable directly in the Clinical Center and more affordable than competing techniques. Fig. 1 LIC measured by MID vs LIC measured by SQUID Fig. 1. LIC measured by MID vs LIC measured by SQUID Fig. 2 The iron reduction of two hemochromatosis patients, under phebotomy therapy, compare with the reduction measured by the MID. Fig. 2. The iron reduction of two hemochromatosis patients, under phebotomy therapy, compare with the reduction measured by the MID.

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A High Through-Put Screen Identifies MCP-1 (CCL2) As a Novel Regulator of Iron Homeostasis and a Modifier of Hereditary Hemochromatosis Disease Severity

Blood ◽

10.1182/blood.v118.21.685.685 ◽

2011 ◽

Vol 118 (21) ◽

pp. 685-685

Author(s):

Martina U. Muckenthaler ◽

Maja Vujic Spasic ◽

Katarzyna Mleczko-Sanecka ◽

Mingang Zhu ◽

Rainer Pepperkok ◽

...

Keyword(s):

Iron Overload ◽

Mrna Expression ◽

Disease Severity ◽

Iron Homeostasis ◽

Expression Profiles ◽

Hereditary Hemochromatosis ◽

Transferrin Saturation ◽

Human Cells ◽

Liver Iron ◽

Deficient Mice

Abstract Abstract 685 To identify genes that modify the severity of human iron disorders we pre-selected 74 genes from gene expression profiles of cells and tissues with altered iron levels and assessed whether siRNA-mediated knock-down of these genes affects uptake of transferrin, a key cellular process to acquire iron. This screen identifies the monocyte chemoattractant protein-1 (MCP-1), also known as CCL2, as a critical suppressor of transferrin receptor mRNA expression in human cells. We next analyzed CCL2-deficient mice and demonstrate profound alterations of parameters of systemic iron homeostasis. Specifically, CCL2 knock-out mice show decreased serum iron levels and transferrin saturation, strong iron-overload in the spleen and duodenum as well as mild iron accumulation in the liver. Iron imbalance in CCL2−/− mice is unlikely explained by an impairment of the major control system of systemic iron homeostasis, the hepcidin/ferroportin regulatory system: hepcidin mRNA expression is unaltered and splenic ferroportin protein expression is strongly increased in CCL2−/− mice, as would be expected as a consequence of splenic iron overload. We speculate that increased iron absorption from the plasma, possibly mediated by inappropriately high levels of TfR1 in the spleen, duodenum and liver, may be responsible for tissue iron overload. It is of note that CCL2 levels are strongly decreased in Hfe-deficient mice and patients with Hfe-associated Hereditary Hemochromatosis (HH). We therefore asked whether CCL2 levels could modify disease severity of HH. Analysis of 51 HH patients, all homozygous for the C282Y HFE mutation, confirms significantly lower MCP-1 levels in the serum compared to a group of 23 sex- and age-matched normal controls. Importantly, CCL2 levels in HH patients show a significant negative correlation with liver iron overload at the time point of diagnosis. Furthermore, low CCL2 concentrations are significantly associated with the HLA-A3 genotype and the CD8+ T lymphocyte phenotype, both traits previously shown to correlate with iron overload in HH patients. These patient data and the data from CCL2-deficient mice suggest that appropriate CCL2 expression is required to prevent iron overload. Taken together our data demonstrate the power of siRNA screens to identify novel regulators of iron metabolism in human cells that are critically involved in maintaining systemic iron homeostasis in the mouse and that play a role in modifying hepatic iron overload in the frequent iron overload disorder Hereditary Hemochromatosis. Disclosures: No relevant conflicts of interest to declare.

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An RNAi-Therapeutic Targeting Tmprss6, in Conjunction With Oral Chelator Therapy, Ameliorates Anemia and Additively Diminishes Secondary Iron Overload In a Mouse Model Of β-Thalassemia Intermedia

Blood ◽

10.1182/blood.v122.21.1019.1019 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1019-1019

Author(s):

Paul J Schmidt ◽

Tim Racie ◽

Jim S Butler ◽

Kevin Fitzgerald ◽

Mark D Fleming

Keyword(s):

Mouse Model ◽

Iron Overload ◽

Iron Deposition ◽

Iron Loading ◽

Thalassemia Intermedia ◽

Ineffective Erythropoiesis ◽

Liver Iron ◽

Therapeutic Targeting ◽

Hepcidin Expression ◽

Secondary Iron Overload

Abstract β-Thalassemias are a group of inherited blood disorders caused by loss of β-globin synthesis and are characterized by anemia, extramedullary hematopoiesis and ineffective erythropoiesis leading to secondary iron overload. Increased iron absorption is due to inappropriately low levels of the liver hormone, hepcidin (HAMP). The membrane serine protease Matriptase-2 (TMPRSS6) attenuates BMP-mediated HAMP induction by cleaving the BMP co-receptor, hemojuvelin (HJV). Previously, we demonstrated that an RNAi-therapeutic targeting Tmprss6 elevates hepcidin expression and reduces disease severity in the Hbbth3/+ mouse model of β-Thalassemia intermedia (Blood. 2013; 14;121(7):1200-8). To further interrogate the efficacy of this therapeutic approach, Hbbth3/+ animals were treated with a siRNA directed against Tmprss6 on a replete 50ppm iron diet, a low iron diet (3-5ppm iron) or a 50ppm iron diet containing deferiprone. Systemic administration of an siRNA directed against Tmprss6 in the three diet conditions leads to significant inhibition of Tmprss6 mRNA in the livers of Hbbth3/+ mice with concomitant elevation in hepcidin expression. In correspondence with earlier studies, we demonstrate here that Tmprss6 silencing in animals under each of the three diet regimens leads to a significant improvement in the anemia of Hbbth3/+ mice as evidenced by increased total hemoglobin. Furthermore, hallmarks of ineffective erythropoiesis, including splenomegaly and reticulocytosis, were decreased in all Tmprss6 silenced Hbbth3/+ animals. If untreated, excessive iron loading in humans with β-Thalassemia leads to tissue iron deposition and eventual organ damage and failure. Importantly, here we demonstrate that the total body iron burden of Hbbth3/+ mice, as assessed by non-heme liver iron, is decreased by almost 30% in animals chelated with oral deferiprone and treated with Tmprss6 siRNA. A similar diminution of iron deposition is not evident in animals on a low iron diet or in mice fed deferiprone alone. Taken together, this data suggest that siRNA suppression of Tmprss6, in conjunction with chelation therapy, may provide an improved modality for treatment of the anemia and secondary iron loading seen in hemoglobinopathies such as β-Thalassemia. Disclosures: Racie: Alnylam Pharmaceutical, Inc: Employment. Butler:Alnylam Pharmaceutical, Inc: Employment. Fitzgerald:Alnylam: Employment. Fleming:Alnylam Pharmaceutical, Inc: Research Funding.

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