Amount Of Iron Deposition Research Articles

Noninvasive Assessment of Fat and Iron Deposition in the Liver by PDFF and T2* Measurement Using the 6-Point DIXON Method

Background: The gold standard procedure for the diagnosis of hepatic steatosis and iron deposition in the liver is histopathological examination of tissue biopsy, but the procedure is invasive and other non-invasive techniques are desirable. The aim of this study was to evaluate the diagnostic values of magnetic resonance imaging (MRI)-based proton density fat fraction (PDFF) and T2* value in the assessment of hepatic steatosis and iron deposition, respectively, in various chronic liver diseases. Methods: This was a cross-sectional study of 196 patients between October 2015 and October 2018. PDFF and T2* value were estimated by the 6-point DIXON method. Each patient underwent MRI and histopathological examination of liver biopsy. Brunt classification used in histopathological examination classified steatosis into four stages; from S0-3 while Berlin blue staining classified iron deposition into four grades. MRIs were processed for measurement of PDFF and T2* value. Finding: The amount of iron deposition had no effect on PDFF (1.9% for S0, 6.5% for S1, 13.9% for S2 and 22.3% for S3). However, T2* value decreased with increased severity of steatosis even in the absence of iron deposition. T2* values were 24.3 ms for grade 0, 17.6 ms for grade 1, 11.9 ms for grade 2 and 5.2 ms for grade 3 in cases with PDFF of <10.6%. Liver fibrosis had no effect on PDFF and T2* values. In cases with severe iron deposition, steatosis had little effect on the T2* value. Interpretation: MRI-based PDFF and T2* value correlated with histopathologically-determined steatosis and iron grades in various chronic liver diseases. In mild iron deposition, steatosis may influence the T2* value, and thus careful evaluation is required using the 6-point DIXON method. Funding: This research was completed without any government or non-government financial support. Declaration of Interest: Hiromitsu Kumada has received honoraria from MSD K.K., Bristol-Myers Squibb, Gilead Sciences, AbbVie Inc., and Dainippon Sumitomo Pharma. Kenji Ikeda received honorarium from Dainippon Sumitomo Pharma, Eisai Co., Ltd. Yoshiyuki Suzuki received honoraria from Bristol-Myers Squibb and Abb Vie Inc. Fumitaka Suzuki received honorarium from Bristol-Myers Squibb. Norio Akuta received honoraria from Bristol-Myers Squibb and Abb Vie Inc. All other authors declare no conflict of interest. Ethical Approval: The protocol was approved by the certified clinical research review board of Toranomon Hospital (approval number #641-H/B).

Diagnosis of patients with Parkinson's disease using quantitative susceptibility mapping

Introduction: Parkinson'sdisease isassociated withirondeposition in the brain. The T2-weighted imaging, T2* mapping, R2 mapping and Quantitative Susceptibility Mapping (QSM) are three common methods to evaluating the iron deposition in brain. Among three methods the QSM is more sensitive than others. Few studies have been used QSM for evaluating the iron deposition in the basal ganglia of patients with Parkinson's Disease (PD). Therefore, our aim was to evaluate the amount of iron deposition in the basal ganglia using QSM and determination the diagnostic value of this method; Also we evaluated the relationship between the QSM with age and stage of the disease. Materials and Methods: Thirty patients categorized in three different stages using Hoehn and Yahr tests. The number of 8, 11 and 11 patients were considered for stage 1, stage 2 and stage 3, respectively. Fifteen healthy subjects were considered as control group. MRI sequences were performed using SIEMENS 3T scanner. The SPIN (Signal Processing in NMR) software was used to processing and analyzing the images. The QSM was measured in all basal ganglia (Red Nucleus, Substantia Nigra, Caudate, Globus Pallidus, Putamen, and Thalamus) separately. The SPSS 18 (SPSS Inc., Chicago, IL) used for analyzing the data. Results: There was a significant difference (P-value<0.001) for QSM in the Red Nucleus, Substantia Nigra and Globus Pallidus nuclei between two patient and control group. The relationship between disease stage with QSM was significant in Red Nucleus (RN), Substantia Nigra (SN) and Globus Pallidus (GP) nuclei (P-value<0.001). Correlation of QSM with age was not significant in any of the nuclei. The accuracy of QSM was 98.0, 86.7 and 88.9 percent for SN, RN and GP. The specificity of QSM was 93.3, 100.0 and 86.7% for SN, RN and GP; Also the sensitivity was 100.0, 80.0 and 90.0 for SN, RN and GP, respectively. Conclusion: Using QSM in RN, SN, and GP nuclei can help diagnosis and staging of patients with Parkinson's disease. Future studies with emphasis on the disease stage using larger sample size can be helpful in evaluation the different sub-parts of these nuclei.

Do Left- and Right-Handed People Have Similar Iron Deposition in the Basal Ganglia?

This study aimed to investigate whether right-, left-, or mixed-handed people differ in terms of iron deposition using susceptibility weighted imaging in healthy subjects. A total of 87 people (right-handed, 51 subjects; left-handed, 19 subjects; mixed-handed, 17 subjects) aged 20 to 40 years participated. All underwent magnetic resonance examination, including conventional and susceptibility weighted imaging sequences. Phase images were used to quantify iron deposition in the head of the caudate nucleus and lenticular nucleus. The radian angle value was calculated and compared between the 3 (right-, left-, or mixed-handed) groups. There was no significant difference in the radian angle values between left-, right-, or mixed-handed people for either the right or left side of the caudate nucleus head. However, the amount of iron deposition in the left lenticular nucleus was significantly higher for right-handed than for the left-handed subjects (P < 0.001) and significantly higher for mixed-handed than for left-handed subjects (P = 0.006). In addition, the amount of iron deposition in the right lenticular nucleus was significantly lower for left-handed than for right-handed subjects (P < 0.001). The results revealed no significant differences in iron deposition in the head of the caudate nucleus. However, there was a significant difference in iron deposition in the lenticular nucleus between left- and right-handed subjects and between left- and mixed-handed subjects.

Histopathologic Study of Livers From Chronic Iron Loaded C282Y Mice: Model of Hereditary Hemochromatosis?

Abstract 5288 Introduction:The C282Y mouse model of hemochromatosis was developed to facilitate study of hereditary hemochromatosis in humans. We studied the liver histologic findings in mice that were iron loaded over at least 10 weeks to determine if the pathological changes in the mouse liver mirror the chronic iron overload condition observed in humans with genetic hemochromatosis. Methods:C282Y and wild-type mice (C57BL) were iron loaded over a minimum of 10 weeks using weekly intraperitoneal injections of 400 mg/kg of iron dextran. Animals were sacrificed at least 2 weeks after receiving their last iron injection. Hematoxylin and eosin, Masson’s trichrome, and Perl’s Prussian blue stains were used to assess the amount and distribution of liver iron and the presence or absence of inflammation and fibrosis. The slides were evaluated by a veterinary pathologist (MAS) without knowledge of genetic or iron load status. Specific histopathologic characteristics were evaluated and graded as the mean of 10 40x high power fields. These included: Hepatocyte iron distribution graded as either periportal or diffuse, amount of iron deposition in cells was graded for hepatocytes and Kupffer cells (graded 0–5), iron deposition in endothelial cells (graded 0–4), amount of fibrosis (graded 0–4), presence or absence of inflammation, periportal lymphocyte infiltration (graded 0–3), and hematopoiesis (present, present but mild, or absent). Livers from 24 mice (3 +/+, 9 +/Y and 12 Y/Y) were studied. Results:When compared with animals that were not iron loaded, animals iron loaded with at least 4 g/kg of iron had increased cellular deposition of iron. Of the two mice that were not iron loaded, the +/Y mouse had no increase in tissue iron and the Y/Y mouse had 2+ iron in hepatocytes, Kupffer cells, and endothelial cells. The highest two categories of cellular iron were observed in the four animals loaded with the highest doses of iron (5.6–6.8 g/kg): grade 4–5 for hepatocytes and Kupffer cells, and grade 3–4 for endothelial cells. Mice loaded with 4 g/kg of iron (7 Y/Y, 8 +/Y and 3 +/+) had similar but generally lower levels of iron deposition: grade 3–5 in hepatocytes, grade 3–4 in Kupffer cells, and grade 3 in endothelial cells. The three genotypes could not be differentiated based on the amount of iron deposition. However, the distribution of iron in hepatocytes of the 3 wild type animals (+/+) was clearly periportal which differed from the diffuse distribution pattern observed in the Y/Y and +/Y mice. One +/Y mouse had a mild periportal distribution of hepatocyte iron. Iron-loaded animals in all 3 genetic groups had grade 1 or 2 fibrosis in the periportal area and around the iron laden Kupffer cell aggregates. None of animals had bridging fibrosis or cirrhosis. In the iron-loaded Y/Y and +/Y mice, hematopoiesis was present in close association with intrasinusoidal iron laden Kupffer cell aggregates. In the non-iron loaded mice hematopoiesis was rare in the Y/Y animal, absent in the +/Y mouse. Hematopoiesis was present but mild in all 3 of the +/+ mice as well as in 1 mouse of each other genotype, and was present in the remaining 17 iron-loaded mice. No hepatocyte necrosis or regenerative nodules were detected in any mouse. Discussion:Histologic evaluation of the C282Y mice showed that the deposition of iron in the liver increased with increased iron loads. The distribution of iron between Kupffer cells and hepatocytes was similar in all 3 genetic groups. The periportal iron distribution observed in humans with genetic hemochromatosis was not seen in either the Y/Y or +/Y genotypes, but was observed in the iron-loaded wild type +/+ mice. Liver histology with chronic intraperitoneal iron loading in the C282Y C57BL mice is comparable to that observed in humans with secondary iron overload and not those observed in humans with hereditary hemochromatosis. Why the liver histology in the iron loaded C282Y knock-in mouse does not mirror the changes observed in human livers from patients with genetic hemochromatosis is not clear. It may be the dosing regimen or the strain of the mouse or that additional genetic or environmental factors are required. Disclosures:No relevant conflicts of interest to declare.

Detection of Iron Deposition in Dermal Fibrocytes Is a Useful Tool for Histologic Diagnosis of Nephrogenic Systemic Fibrosis

Nephrogenic systemic fibrosis (NSF) is a fibrotic disease that presents with a history of renal dysfunction. The differential diagnosis generally includes scleromyxedema, systemic sclerosis, and morphea. Especially, scleromyxedema can be extremely difficult to distinguish microscopically. Although the fibrocytes in NSF are often positive for CD34 and procollagen-I, this is not specific for NSF. We identified positive iron staining in the skin of a patient with NSF and investigated whether this was a specific feature among 9 patients with NSF reported in Japan. We found that 6 of 9 patients showed positive iron staining in the dermal fibrocytes. The amount of iron deposition seemed to have no correlation with the degree of fibrosis or duration of the skin lesions but correlated with apparent history of the use of gadolinium-based contrast agents. As controls, skin biopsies from patients with scleromyxedema, morphea, and systemic sclerosis were evaluated by iron staining. None of these control patients showed iron deposition, indicating that positive iron staining may be specific to NSF and can be a useful tool for NSF diagnosis.

Characterizing iron deposition in multiple sclerosis lesions using susceptibility weighted imaging

To investigate whether the variable forms of putative iron deposition seen with susceptibility weighted imaging (SWI) will lead to a set of multiple sclerosis (MS) lesion characteristics different than that seen in conventional MR imaging. Twenty-seven clinically definite MS patients underwent brain scans using magnetic resonance imaging including: pre- and postcontrast T1-weighted imaging, T2-weighted imaging, FLAIR, and SWI at 1.5 T, 3 T, and 4 T. MS lesions were identified separately in each imaging sequence. Lesions identified in SWI were reevaluated for their iron content using the SWI filtered phase images. There were a variety of new lesion characteristics identified by SWI, and these were classified into six types. A total of 75 lesions were seen only with conventional imaging, 143 only with SWI, and 204 by both. From the iron quantification measurements, a moderate linear correlation between signal intensity and iron content (phase) was established. The amount of iron deposition in the brain may serve as a surrogate biomarker for different MS lesion characteristics. SWI showed many lesions missed by conventional methods and six different lesion characteristics. SWI was particularly effective at recognizing the presence of iron in MS lesions and in the basal ganglia and pulvinar thalamus.

Early detection of cardiac iron deposition in patients with thallassemia, what is the best strategy?

b-Thallassemia is an inherited disorder of haemoglobin synthesis, resulting in chronic haemolytic anemia. Adequate blood transfusions and continuous chelation therapy are the milestones of treatment. In adults, the major haemoglobin is haemoglobin A, a tetramer consisting of one pair of a chains and one pair of b chains. Normally the ratio of a to b chains is one. In patients with thallassemia production of b chains is diminished. The excess a chains are unstable and incapable of forming soluble teramers. These chains precipitate in the cell, leading to a variety of clinical manifestations [1]. Thallassemias arise from over 100 mutations, that affect every step for production of normal haemoglobin. The frequency for genetic abnormalities associated with b-thallassemia approaches 0.1 in South Mediterranean areas in Europe. Both sexes are equally affected [2]. The bthallassemia syndromes are remarkable for their heterogeneity and clinical expression of the genetic abnormality [3]. Patients with a b-thallassemia mutation on each chromosome usually exhibit some degree of a-globin inclusion body formation, with consequent anemia, hemolysis and varying degrees of ineffective erythropoiesis [1]. The clinical syndrome associated with this genetic disorder is called thallassemia major. Patients, who are heterozygotes for b-thallassemia are mostly asymptomatic. This, because the erythrocyte is able to catabolize some of the excess unpaired a-globulin chains [1]. The syndrome is usually described as thallassemia minor or thallassemia intermediate. In patients with b-thallassemia major cardiac abnormalities occur frequently next to disorders of the liver and spleen, skeletal abnormalities and kidney and endocrine abnormalities [4]. Heart failure and rhythm disturbances are the main cause of death in adults with thallassemia major. In a recently published multicenter study 5% of patients aged 16–24 years and 23% of patients older than 25 years had heart disease requiring medication [5]. In another study congestive heart failure was observed in 5.4% of patients with thallassemia intermedia. Eight percent of these patients had a history of acute pericarditis [4]. The most prominent finding in patients with thallassemia major is left ventricular dysfunction, which is mainly due to severe anemia and iron overload because of the regular blood transfusions required to avoid hypoxia [6]. The estimation of iron stores in the heart would be very helpful in order to evaluate the efficacy of chelation therapy and determine the cardiac risk. Although the iron storage proteins like hemosiderin and ferritin are mostly intracellular, serum ferritin is highly correlated with the amount of iron deposition L. H. B. Baur (&) Department of Cardiology, Atrium Medical Centre Parkstad, University of Maastricht, Maastricht, The Netherlands e-mail: lbr01@atriummc.nl

Iron deposition in renal biopsy specimens from patients with kidney diseases

This study was performed to investigate the correlation between clinical parameters and grading of iron deposition in renal biopsy specimens from 102 patients with various kidney diseases. Iron deposition in renal tissues was detected by Berlin blue staining. The extent of iron staining was semiquantitatively graded as negative (Fe−), grade 0, or positive (Fe+), including faint, grade 1; moderate, grade 2; or severe, grade 3, by light microscopy. Thirty-four of 102 patients (33%) showed positive iron staining. Fe+ patients had various renal diseases, mainly consisting of 12 patients with immunoglobulin A nephropathy and 5 patients with benign nephrosclerosis. Mean arterial pressure (MAP), serum creatinine (sCr) levels, incidence of hematuria, and urinary N-acetylβ-d-glucosaminidase (u-NAG) levels in Fe+ patients were significantly greater than those in Fe− patients, and u-NAG levels correlated positively with the extent of iron deposition. Study patients were tentatively divided into two groups according to the extent of iron deposition: group A, patients with grades 2 and 3 staining, and group B, patients with grades 0 and 1 staining. In group A, MAP, sCr level, urinary protein excretion, and the incidence of hematuria were significantly greater than in group B. Our results suggest that the amount of iron deposition in renal tissue may contribute to the progression of chronic renal disease and may be an early and sensitive indicator of renal damage in certain renal diseases. © 2001 by the National Kidney Foundation, Inc.

Topographic Relation Between Iron-Deposition and Cytotoxic Changes in Iron Lactate-Overloaded Rats.

In oder to evaluete the chronic toxicity of iron lactate, a food additive, rats consisting of ten male and ten female per group, were fed a powdered commercial diet containing 0%, 0.625%, 1.25%, 2.50% or 5.00% of iron lactate for 3 months. Main histopathologic changes were an accumulation of excess iron in the hepatocytes, renal tubular epithelial cells, macrophages in the reticuloendothelial system of liver, spleen, bone marrow, and lymph nodes. Hemosiderin-laden macrophages aggregated in the mucosal lamina propria of the stomach and the whole length of the intestinal tract, and formed small nodules without any degenerative changes in other mucosal tissue. The number of hemosiderin-laden macrophages also increased in the interstitial tissue of the testes, epididymis, and thyroid glands, but no degenerative changes were detected in cell components of these organs. A slight elevation of AST, ALT, creatinine, and blood urea nitrogen (BUN) levels in the higher dosage group suggested the toxic effect of iron overload on the function of liver and kidneys which accumulated iron deposits in their parenchymal cells. However, apparent histopathologic changes suggesting tissue damage were not clear even in the liver and kidneys, as well as in many organs infiltrated with hemosiderin-laden macrophages in the interstitium. From these results, of damage is not dependent on the amount of iron deposition.

Noninvasive analysis of skin iron and zinc levels in beta-thalassemia major and intermedia.

Diagnostic x-ray spectrometry, a method based on x-ray fluorescence analysis, was used for noninvasive determination of iron and zinc in two distinct skin areas, representing predominantly dermal and epidermal tissues, in 56 patients with beta-thalassemia major and intermedia. The mean iron levels in the skin of patients with beta-thalassemia major and intermedia were elevated by greater than 200% and greater than 50%, respectively, compared with control values. The zinc levels of both skin areas examined were within the normal range. The data indicate that the rate and number of blood transfusions, which correlated well with serum ferritin levels (r = 0.8), are not the only factors that determine the amount of iron deposition in the skin (r less than 0.6). Other sources of iron intake contribute to the total iron load in the tissues, particularly in patients who are not given multiple transfusions. The noninvasive quantitation of skin levels may reflect the extent of iron deposition in major parenchymal organs. Repeated DXS examinations of the skin could monitor the clearance of iron from the tissues of patients with iron overload in the course of therapy with chelating agents.