Iron Deficiency in Distance Runners A Reinvestigation Using 59Fe-Labelling and Non-Invasive Liver Iron Quantification

Abstract The liver orchestrates systemic iron balance by producing and secreting hepcidin. Known as the iron hormone, hepcidin induces degradation of the iron exporter ferroportin to control iron entry into the bloodstream from dietary sources, iron recycling macrophages, and body stores. Under physiologic conditions, hepcidin production is reduced by iron deficiency and erythropoietic drive to increase the iron supply when needed to support red blood cell production and other essential functions. Conversely, hepcidin production is induced by iron loading and inflammation to prevent the toxicity of iron excess and limit its availability to pathogens. The inability to appropriately regulate hepcidin production in response to these physiologic cues underlies genetic disorders of iron overload and deficiency, including hereditary hemochromatosis and iron-refractory iron deficiency anemia. Moreover, excess hepcidin suppression in the setting of ineffective erythropoiesis contributes to iron-loading anemias such as β-thalassemia, whereas excess hepcidin induction contributes to iron-restricted erythropoiesis and anemia in chronic inflammatory diseases. These diseases have provided key insights into understanding the mechanisms by which the liver senses plasma and tissue iron levels, the iron demand of erythrocyte precursors, and the presence of potential pathogens and, importantly, how these various signals are integrated to appropriately regulate hepcidin production. This review will focus on recent insights into how the liver senses body iron levels and coordinates this with other signals to regulate hepcidin production and systemic iron homeostasis.

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Curcumin, a cancer chemopreventive and chemotherapeutic agent, is a biologically active iron chelator

Blood ◽

10.1182/blood-2008-05-155952 ◽

2009 ◽

Vol 113 (2) ◽

pp. 462-469 ◽

Cited By ~ 140

Author(s):

Yan Jiao ◽

John Wilkinson ◽

Xiumin Di ◽

Wei Wang ◽

Heather Hatcher ◽

...

Keyword(s):

Iron Deficiency ◽

Cultured Cells ◽

Transferrin Saturation ◽

Iron Chelator ◽

Biologically Active ◽

Liver Iron ◽

Liver Iron Content ◽

Inflammatory Conditions ◽

Dose Dependent

Abstract Curcumin is a natural product currently in human clinical trials for a variety of neoplastic, preneoplastic, and inflammatory conditions. We previously observed that, in cultured cells, curcumin exhibits properties of an iron chelator. To test whether the chelator activity of curcumin is sufficient to induce iron deficiency in vivo, mice were placed on diets containing graded concentrations of both iron and curcumin for 26 weeks. Mice receiving the lowest level of dietary iron exhibited borderline iron deficiency, with reductions in spleen and liver iron, but little effect on hemoglobin, hematocrit, transferrin saturation, or plasma iron. Against this backdrop of subclinical iron deficiency, curcumin exerted profound 2 effects on systemic iron, inducing a dose-dependent decline in hematocrit, hemoglobin, serum iron, and transferrin saturation, the appearance of microcytic anisocytotic red blood cells, and decreases in spleen and liver iron content. Curcumin repressed synthesis of hepcidin, a peptide that plays a central role in regulation of systemic iron balance. These results demonstrate that curcumin has the potential to affect systemic iron metabolism, particularly in a setting of subclinical iron deficiency. This may affect the use of curcumin in patients with marginal iron stores or those exhibiting the anemia of cancer and chronic disease.

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Liver Iron Quantification with MR Imaging: A Primer for Radiologists

Radiographics ◽

10.1148/rg.2018170079 ◽

2018 ◽

Vol 38 (2) ◽

pp. 392-412 ◽

Cited By ~ 33

Author(s):

Roxanne Labranche ◽

Guillaume Gilbert ◽

Milena Cerny ◽

Kim-Nhien Vu ◽

Denis Soulières ◽

...

Keyword(s):

Mr Imaging ◽

Liver Iron ◽

Iron Quantification

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Agreement of liver iron quantification measurements with low Tc-SQUID biosusceptometers in Oakland, Torino and Hamburg

International Congress Series ◽

10.1016/j.ics.2007.01.048 ◽

2007 ◽

Vol 1300 ◽

pp. 279-282

Author(s):

Rainer Engelhardt ◽

Ellen B. Fung ◽

Filomena Longo ◽

Marco Borri ◽

Zahra Pakbaz ◽

...

Keyword(s):

Liver Iron ◽

Iron Quantification

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Non Invasive Assessment of Hepatic Fibrosis by Measurement of Liver Stiffness in Post Transfusional Iron Overload: Preliminary Results in 15 Patients.

Blood ◽

10.1182/blood.v108.11.3740.3740 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3740-3740

Author(s):

T. Mirault ◽

D. Lucidarme ◽

B. Turlin ◽

Y. Deugnier ◽

P. Brissot ◽

...

Keyword(s):

At Risk ◽

Liver Fibrosis ◽

Iron Overload ◽

Predictive Value ◽

Liver Stiffness ◽

Liver Iron ◽

Preliminary Results ◽

Non Invasive ◽

Patients At Risk ◽

Severe Fibrosis

Abstract Background: The prognosis of liver iron overload is highly dependent on liver iron content (LIC) and the extent of liver fibrosis. Liver biopsy is the invasive reference method for fibrosis evaluation but with several limitations. Non-invasive biological methods (FibroTest, APRI) are not applicable in blood diseases. Transient elastography (TE) is a new non-invasive and rapid bedside method used to measure liver stiffness.This technique has been extensively studied with success in evaluation of liver fibrosis in HCV infection (Ziol, Hepatology 2005; Castera, Gastroenterology 2005). Until now, no data are available on evaluation of liver fibrosis by TE in highly transfused patients with iron overload. Methods: We assessed liver stiffness (kPa) by elastography measurement (Fibroscan; Echosens, Paris, France). Ishak’s and Metavir’s scales were used to stage fibrosis and hepatitis activity; LIC was measured by atomic absorption spectometry in a central laboratory (Rennes, France) and by MRI procedure according to Gandon (Lancet 2004). Cardiac MRI T2* (indirect estimation of iron heart content) was also measured by MRI according to Anderson (Eur Heart J 2001). Serum ferritin level and HCV serology were assayed in all cases. Correlation statistical analysis used Spearman’s Rho and Pearson tests and mean comparisons were done by a non-parametric Mann-Whitney test. Results: 15 liver samples (weight >1mg except 1) from monthly transfused patients (13 major beta Thalassemia, 1 sickle cell disease, 1 myelodysplastic syndrome) were analyzed. Median age was 37 years (7–75). Histological results were: 3 cirrhosis (METAVIR F=4 (F4), or Ishak’s Staging =6 (IS6)) among 5 patients with severe fibrosis (F3,F4) or (IS4-6) and 10 patients with no or mild fibrosis (F0-2) or (IS0-3). Mean ferritin was 2579 ng/ml CI 95% [1372–3786]. 2 patients were HCV positive. Correlation between LIC and ferritin was 0.82 (p<0,05); between LIC and MRI LIC: 0.88 (p<0,05); LIC and MRI Heart T2*: 0.72(p<0,05); METAVIR F score and Ishak’s grading score: 0.86 (p<0,05). A correlation was also observed between METAVIR F and elastography: 0.60(p<0,05); and mean values of elastography were significally different in patients with severe fibrosis: 9.1kPa CI95% [4.5–13.7] vs 5.9kPa CI95% [4.6–7.2] in those without sever fibrosis (p<0,05) (fig). A value of elastography above 6.25kPa (Se=80%; Sp=70%; AUROC=0.820) identified patients at risk for severe fibrosis (F3,F4 or IS 4–6) (Negative Predictive Value = 88%; Positive Predictive Value = 57%). Conclusion: A significant correlation between Metavir Fibrosis scale and elastography values was found. This new non-invasive method would be helpful to evaluate liver fibrosis and to determine patients who could avoid invasive procedures in particular in regularly transfused low risk myelodysplastic patients at risk of bleeding due to abnormal platelet function. These preliminary results will have to be confirmed in a larger population. Figure Figure

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Liver Fibrosis in Adult Thalassemia Patients Assessed by Transient Elastography.

Blood ◽

10.1182/blood.v110.11.3820.3820 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3820-3820

Author(s):

Elena Cassinerio ◽

Mirella Fraquelli ◽

Elisabetta Volpato ◽

Cristina Rigamonti ◽

Massimo Colombo ◽

...

Keyword(s):

Iron Overload ◽

Transient Elastography ◽

Thalassemia Major ◽

Hcv Rna ◽

Liver Iron ◽

Non Invasive ◽

Group I ◽

Group Ii ◽

T2 Mri ◽

Severe Fibrosis

Abstract Background and aim. Transient elastography (TE) is a new, non-invasive and reproducible technique that measures liver stiffness (LSM). It has been demonstrated to be a reliable tool for assessing hepatic fibrosis and cirrhosis in patients with chronic liver disease (CLD). However, its role in patients with b- thalassemia has not been extensively investigated. The aim of the present study was to assess LSM and its possible correlation with iron overload in HCV positive patients with b- thalassemia major and intermedia. Methods. During a six-month period (from January to June 2007) 46 consecutive adults patients with b- thalassemia afferring to a single Italian Thalassemia Care Center in Milan, Italy, were enrolled in the study. Twenty-nine patients (Group I: 7 M and 23 F; mean age 31±SD 7.1 yrs; mean BMI 23.4±SD 3 Kg/m2) had b- thalassemia major and 17 intermedia (Group II: 10 M and 7 F; mean age 43±SD12.4 yrs; BMI 22 ±SD 3 Kg/m2). Sixteen patients (55%) in group I and two (12%) in group II were HCV RNA positive. All patients were examined by TE (FibroScan®; Echosens, Paris, France) and only the examinations with at least 10 validated measurements and a success rate of at least 60% were considered adequate. According to a previous study in CLD patients the considered TE cut off to diagnosing different stages of hepatic fibrosis were: >7.9 kPa for F≥2; >10.3 for ≥F3 and >11.9 for F=4. Twelve patients (all in group I) also had undergone liver biopsy. Necroinflammation and fibrosis were scored by METAVIR classification; liver iron concentration (LIC, mg/gr of liver dry weight) was measured on fresh tissue cores by atomic absorption spectrometry. Twenty-five patients underwent liver iron determination by T2* Magnetic Resonance Imaging (MRI) assessment. Results. In patients who underwent liver biopsy, LSM increased proportionally to the METAVIR stage and a significant positive correlation was observed between LSM and fibrosis stage (r=0.57, p= 0.039). Patients in group I had significantly higher values of mean LSM values (10.6± SD 9.3 kPa) and serum ferritin (SF) (1367±SD 1169 ng/mL) than those in group II (6.0± SD 3.3 kPa and 716±SD 472 ng/mL, respectively) (p<0.05). In both groups LSM did not significantly correlate with age, BMI, platelets count, serum iron and iron overload measured by T2* MRI. In group I a significant positive correlation was observed betweeen LSM and SF (r=0.47, p=0.008), ALT (r=0.87, p=0.0001) and GGT levels (r=0.80, p=0.0001). Among patients with b- thalassemia major LSM values did not differ significantly between HCV RNA positive (13.0±SD 12.5 kPa) and negative patients (7.7±SD 3.3 kPa) (p=NS) as well as the proportion of patients with significant (F>=2) or severe fibrosis (F>=3) did not differ significantly according to HCV viremic status. Conclusion TE is a reliable non invasive technique to stage liver fibrosis in patients with b- thalassemia major. In these patients with concomitant HCV infection a significant or severe fibrosis was observed in about one third of the cases. Apart from fibrosis also serum necroinflammatory activity, GGT levels and SF levels may influence LSM values. The reliability of liver iron overload by T2* MRI evaluation remains still to be validated.

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Hepatic Iron Quantification on 3 Tesla (3 T) Magnetic Resonance (MR): Technical Challenges and Solutions

Radiology Research and Practice ◽

10.1155/2013/628150 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 4

Author(s):

Muhammad Anwar ◽

John Wood ◽

Deepa Manwani ◽

Benjamin Taragin ◽

Suzette O. Oyeku ◽

...

Keyword(s):

Sickle Cell ◽

Iron Concentration ◽

Hepatic Iron ◽

Test Results ◽

Cell Disease ◽

Liver Iron ◽

Iron Quantification ◽

Fast Gradient ◽

Technical Challenges ◽

Hepatic Iron Concentration

MR has become a reliable and noninvasive method of hepatic iron quantification. Currently, most of the hepatic iron quantification is performed on 1.5 T MR, and the biopsy measurements have been paired withR2andR2*values for 1.5 T MR. As the use of 3 T MR scanners is steadily increasing in clinical practice, it has become important to evaluate the practicality of calculating iron burden at 3 T MR. Hepatic iron quantification on 3 T MR requires a better understanding of the process and more stringent technical considerations. The purpose of this work is to focus on the technical challenges in establishing a relationship betweenT2*values at 1.5 T MR and 3 T MR for hepatic iron concentration (HIC) and to develop an appropriately optimized MR protocol for the evaluation ofT2*values in the liver at 3 T magnetic field strength. We studied 22 sickle cell patients using multiecho fast gradient-echo sequence (MFGRE) 3 T MR and compared the results with serum ferritin and liver biopsy results. Our study showed that the quantification of hepatic iron on 3 T MRI in sickle cell disease patients correlates well with clinical blood test results and biopsy results. 3 T MR liver iron quantification based on MFGRE can be used for hepatic iron quantification in transfused patients.

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