scholarly journals Mild Iron Overload as Seen in Individuals Homozygous for the Alpha-1 Antitrypsin Pi*Z Variant Does Not Promote Liver Fibrogenesis in HFE Knockout Mice

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1415 ◽  
Author(s):  
Nurdan Guldiken ◽  
Karim Hamesch ◽  
Shari Malan Schuller ◽  
Mahmoud Aly ◽  
Cecilia Lindhauer ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Iron Overload ◽  
Iron Metabolism ◽  
Serum Iron ◽  
Transferrin Saturation ◽  
Elevated Serum ◽  
Hfe Mutations ◽  
Alpha 1 Antitrypsin ◽  
The Impact ◽  
Significant Liver Fibrosis

The presence of the homozygous ‘Pi*Z’ variant of alpha-1 antitrypsin (AAT) (‘Pi*ZZ’ genotype) predisposes to liver fibrosis development, but the role of iron metabolism in this process remains unknown. Therefore, we assessed iron metabolism and variants in the Homeostatic Iron Regulator gene (HFE) as the major cause of hereditary iron overload in a large cohort of Pi*ZZ subjects without liver comorbidities. The human cohort comprised of 409 Pi*ZZ individuals and 254 subjects without evidence of an AAT mutation who were recruited from ten European countries. All underwent a comprehensive work-up and transient elastography to determine liver stiffness measurements (LSM). The corresponding mouse models (Pi*Z overexpressors, HFE knockouts, and double transgenic [DTg] mice) were used to evaluate the impact of mild iron overload on Pi*Z-induced liver injury. Compared to Pi*Z non-carriers, Pi*ZZ individuals had elevated serum iron, transferrin saturation, and ferritin levels, but relevant iron overload was rare. All these parameters were higher in individuals with signs of significant liver fibrosis (LSM ≥ 7.1 kPa) compared to those without signs of significant liver fibrosis. HFE knockout and DTg mice displayed similar extent of iron overload and of fibrosis. Loss of HFE did not alter the extent of AAT accumulation. In Pi*ZZ individuals, presence of HFE mutations was not associated with more severe liver fibrosis. Taken together, Pi*ZZ individuals display minor alterations in serum iron parameters. Neither mild iron overload seen in these individuals nor the presence of HFE mutations (C282Y and H63D) constitute a major contributor to liver fibrosis development.

RNAi-Mediated Inhibition of Tmprss6 Elevates Hamp1 Expression and Reduces Serum Iron Levels in Mice

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1045-1045 ◽  
Author(s):  
Ivanka Toudjarska ◽  
Zuhua Cai ◽  
Tim Racie ◽  
Stuart Milstein ◽  
Brian R Bettencourt ◽  
...  
Keyword(s):  
Iron Overload ◽  
Serum Iron ◽  
Iron Concentration ◽  
Transferrin Saturation ◽  
Elevated Serum ◽  
High Serum ◽  
Therapeutic Modality ◽  
Deficiency Anemia ◽  
Loss Of Function ◽  
Hepcidin Expression

Abstract Abstract 1045 The liver hormone Hepcidin (encoded by Hamp1) regulates serum iron levels by controlling the efflux of iron from intestinal enterocytes and macrophages. Maintaining sufficient iron levels to support erythropoiesis while preventing iron overload requires tight control of Hepcidin expression. Transcription of Hamp1 in hepatocytes is stimulated by high serum iron levels, via Transferrin Receptor signaling, as well as by activation of the BMP/SMAD pathway. The membrane serine protease Matriptase-2 (encoded by Tmprss6) inhibits BMP induced Hamp1 induction through the regulation of the BMP co-receptor, Hemojuvelin. In humans, loss of function mutations in TMPRSS6 lead to elevated Hepcidin levels resulting in iron-resistant iron-deficiency anemia (IRIDA). In diseases associated with iron overload, such as Thalassemia intermedia (TI) and Familial Hemochromatosis (FH), Hepcidin levels are low despite elevated serum iron concentrations. Studies in murine models of TI and FH have shown that elevating Hepcidin levels by genetic inactivation of Tmprss6 can prevent iron overload and correct aspects of the disease phenotype. Therefore, therapeutic strategies aimed at specifically inhibiting Tmprss6 expression could prove efficacious in these, and other, iron overloading diseases. Here we show that systemic administration of a potent lipid nanoparticle (LNP) formulated siRNA directed against Tmprss6 leads to durable inhibition of Tmprss6 mRNA in the mouse liver, with concomitant elevation of Hamp1 expression. This leads to significant decreases in serum iron concentration and Transferrin saturation, along with changes in hematologic parameters consistent with iron restriction. Further testing in mouse genetic models of TI and FH will support the rationale for developing LNP formulated Tmprss6 siRNA as a novel therapeutic modality. Disclosures: Toudjarska: Alnylam Pharmaceuticals, Inc.: Employment. Cai:Alnylam Pharmaceuticals, Inc.: Employment. Racie:Alnylam Pharmaceuticals, Inc.: Employment. Milstein:Alnylam Pharmaceuticals, Inc.: Employment. Bettencourt:Alnylam Pharmaceuticals, Inc.: Employment. Hettinger:Alnylam Pharmaceuticals, Inc.: Employment. Sah:Alnylam Pharmaceuticals, Inc.: Employment. Vaishnaw:Alnylam Pharmaceuticals, Inc.: Employment. Bumcrot:Alnylam Pharmaceuticals, Inc.: Employment.

Unexplained Serum Ferritin Elevations in Primary Care Patients with Elevated Serum Ferritin Concentrations and High Normal Transferrin Saturations.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3729-3729
Author(s):  
Onyinye C. Onyekwere ◽  
Tiffany N. Johnson ◽  
Margaret Fadojutimi-Akinsiku ◽  
Fitzroy Dawkins ◽  
Victor Gordeuk
Keyword(s):  
Primary Care ◽  
African Americans ◽  
Iron Overload ◽  
Serum Ferritin ◽  
Transferrin Saturation ◽  
Elevated Serum ◽  
Ferritin Concentration ◽  
Serum Ferritin Concentration ◽  
Primary Care Patients ◽  
Hfe Mutations

Abstract Non-HFE primary iron overload exists in African Americans and other ethnic groups, but the prevalence and spectrum of clinical manifestations are not known. In the HEIRS (Hereditary Hemochromatosis and Iron Overload Screening) Study, participants were considered for further evaluation if the serum ferritin concentration was elevated and the transferrin saturation was more than 45% for women or 50% for men. We hypothesized that these screening criteria would miss a substantial number of African Americans and members of other ethnic groups with increased iron stores. In the process of screening 21,231 predominantly African-American and Hispanic primary care patients at the Howard University field center of the HEIRS Study, we identified 161 non-HFE-C282Y homozygotes ≥ 25 years of age with serum ferritin concentrations above the 97.5 percentile for the population (>700 ng/ml for men and >500 ng/ml for women) but transferrin saturations in the upper part of the normal range (35–50% for men and 30–45% for women). Of the 123 participants we were able to contact, 68 (55%) participated in a clinical evaluation, including 64 African Americans, three Hispanics and one Asian American with a mean ± SD age of 57 ± 13 years. Thirty-eight (56%) were females, 6 (9%) were HFE H63D heterozygotes and 2 (3%) were C282Y heterozygotes. Seven patients (10%) had normal serum ferritin concentration on repeat testing while 42 (62%) had potential reasons for elevated serum ferritin concentration other than a primary increase in body iron including (sequentially) multiple blood transfusions (>10 lifetime; n = 4), abnormal liver function tests (hepatitis C positive or AST >60 IU/L and AST>ALT; n = 17), hemoglobin < 10 g/dL men or 9 g/dL women (n = 1), elevated C-reactive protein with transferrin saturation not elevated (n = 17), and excessive alcohol use (n = 3). Nineteen patients did not have these explanations for increased serum ferritin concentration and were considered to have a possible primary iron-loading process (see Table). One of the patients with unexplained elevated serum ferritin concentration (an African American) had a diagnostic liver biopsy showing 2-3+ hepatocellular iron and heavy iron deposition in Kupffer cells and is on phlebotomy therapy; the others have been advised to have diagnostic liver biopsy or quantitative phlebotomy. We conclude that there are substantial numbers of African Americans with elevated serum ferritin concentration and normal transferrin saturation who have transfusional iron overload or a probable primary increase in body iron stores. Characteristics of 19 Patients with Unexplained Serum Ferritin Elevations No. (%) of Women 8 (42) Age inyears (mean ± SD) 63 ± 14 Race (African American:Hispanic:Asian) 16:2:1 Hemoglobin in g.dL (mean ± SD) Men 13.8 ±1.5 Hemoglobin in g.dL (mean ± SD) Women 12.9 ± 0.8 HFE mutations in no. (%) C282Y heterozygotes 0 (0) HFE mutations in no. (%) H63D heterozygotes 2 (11) Ferritin category in no. (%) < 500 ng/ml 7 (37) Ferritin category in no. (%) 500–1000 ng/ml 9(57) Ferritin category in no. (%) 1000 ng/ml> 3 (16)

scholarly journals Associations of Human Colorectal Adenoma with Serum Biomarkers of Body Iron Stores, Inflammation and Antioxidant Protein Thiols

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1195
Author(s):  
Ben Schöttker ◽  
Xīn Gào ◽  
Eugène HJM Jansen ◽  
Hermann Brenner
Keyword(s):  
Iron Overload ◽  
Colorectal Adenoma ◽  
Serum Iron ◽  
Transferrin Saturation ◽  
Meat Consumption ◽  
Total Serum ◽  
Processed Meat ◽  
Hs Crp ◽  
Underlying Mechanisms ◽  
Processed Meat Consumption

Red and processed meat consumption and obesity are established risk factors for colorectal adenoma (CRA). Adverse changes in biomarkers of body iron stores (total serum iron, ferritin, transferrin and transferrin saturation), inflammation (high-sensitivity C-reactive protein [hs-CRP]) and anti-oxidative capacity (total of thiol groups (-S-H) of proteins [SHP]) might reflect underlying mechanisms that could explain the association of red/processed meat consumption and obesity with CRA. Overall, 100 CRA cases (including 71 advanced cases) and 100 CRA-free controls were frequency-matched on age and sex and were selected from a colonoscopy screening cohort. Odds ratios (OR) and 95% confidence intervals (95%CI) for comparisons of top and bottom biomarker tertiles were derived from multivariable logistic regression models. Ferritin levels were significantly positively associated with red/processed meat consumption and hs-CRP levels with obesity. SHP levels were significantly inversely associated with obesity. Transferrin saturation was strongly positively associated with overall and advanced CRA (ORs [95%CIs]: 3.05 [1.30–7.19] and 2.71 [1.03–7.13], respectively). Due to the high correlation with transferrin saturation, results for total serum iron concentration were similar (but not statistically significant). Furthermore, SHP concentration was significantly inversely associated with advanced CRA (OR [95%CI]: 0.29 [0.10–0.84]) but not with overall CRA (OR [95%CI]: 0.65 [0.27–1.56]). Ferritin, transferrin, and hs-CRP levels were not associated with CRA. Conclusions: High transferrin saturation as a sign of iron overload and a low SHP concentration as a sign of redox imbalance in obese patients might reflect underlying mechanisms that could in part explain the associations of iron overload and obesity with CRA.

Correlation of Iron Profile with Different Stages of Chronic Kidney Disease in Children Presenting at a Tertiary Care Hospital

2021 ◽  
Vol 15 (8) ◽  
pp. 2013-2016
Author(s):  
Shahid Ishaq ◽  
Muhammad Imran ◽  
Hashim Raza ◽  
Khuram Rashid ◽  
Muhammad Imran Ashraf ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Iron Overload ◽  
Serum Ferritin ◽  
Serum Iron ◽  
Tertiary Care ◽  
Transferrin Saturation ◽  
Maintenance Hemodialysis ◽  
Care Hospital ◽  
Iron Profile

Aim: To determine correlation of iron profile in children with different stages of chronic kidney disease (CKD) presenting to tertiary care hospital. Methodology: A total of 81 children with chronic kidney disease stage having glomerular filtration rate (GFR) less than 90 (ml/min/m2) aged 1 – 14 years of either sex were included. Three ml serum sample was taken in vial by hospital duty doctor for serum ferritin level, serum iron, transferrin saturation and total iron binding capacity. The sample was sent to hospital laboratory for reporting. Iron profiling was done evaluating hemoglobin (g/dl), serum iron (ug/dl), serum ferritin (ng/ml), transferrin saturation (%) and total iron binding capacity (ug/dl) while iron load was defined as serum ferritin levels above 300 ng/ml. Correlation of iron profile with different stages of CKD was determined applying one-way analysis of variance (ANOVA). Results: In a total 81 children, 46 (56.8%) were boys while overall mean age was 7.79±2.30 years. Mean duration on hemodialysis was 11.52 ± 9.97 months. Iron overload was observed in 26 (32.1%) children. Significant association of age above 7 years (p=0.031) and residential status as rural (p=0.017) was noted with iron overload whereas iron overload was increasing with increase in stages of CKD (p=0.002). Hemoglobin levels decreased significantly with increase in stages of CKD (p<0.001). Serum iron levels increased significantly with increase in the CKD stages (p=0.039). Serum ferritin levels were increasing significantly with the increase in CKD stages (p=0.031). Transferrin saturation also increased significant with increase in CKD stages (p=0.027). Conclusion: High frequency of iron overload was noted in children with CKD on maintenance hemodialysis and there was linear relationship with stages of CKD and iron overload. Significant correlation of hemoglobin, serum iron, serum ferritin and transferrin saturation was observed with different stages of CKD. Keywords: Iron overload, maintenance hemodialysis, ferritin level.

CNS Inflammation Induced by Lipopolysaccharide Up-Regulates Hepatic Hepcidin Expression by Activating IL-6/JAK2/STAT3 Pathway in Mice

2020 ◽  
Author(s):  
fali zhang ◽  
peng zhao ◽  
zhongming Qian ◽  
mingkang zhong
Keyword(s):  
Protein Expression ◽  
Iron Metabolism ◽  
Serum Iron ◽  
Transferrin Saturation ◽  
Cns Inflammation ◽  
Inflammation Response ◽  
Stat3 Pathway ◽  
Hepcidin Expression ◽  
Mrna And Protein Expression ◽  
The Brain

Abstract BackgroundLPS triggers inflammation response in periphery, whether the infection in CNS induced by LPS ICV injection affected the peripheral iron metabolism was unknown , The current study was to find out whether LPS injected to the brain could regulate hepcidin expression in liver and peripheral iron metabolism. MethodsWide type mice (IL-6+/+) and IL-6-/- mice of 8-week-old were performed on ICV injection with LPS. After 6h, hepcidin expression in liver, as well as serum iron and transferrin saturation was detected and calculated, we also tested the IL-6/JAK2/STAT3 pathway in hepcidin regulation in liver of IL-6 knockout (IL-6-/- mice) and IL-6+/+ mice, AG490 as an inhibitor of JAK2 was used to confirm the effect of IL-6/JAK2/STAT3 pathway on hepcidin expression in liver. ResultsHepcidin mRNA, IL-6 mRNA and protein expression in the liver of IL-6-/- mice was significantly lower than IL-6+/+ mice after LPS administration. IL-6 deficiency abolished the decrease of serum iron, transferrin saturation induced by LPS injection. IL-6 deficiency also abolished the decrease of Fpn1, increase of pSTAT3 and Ft-L protein in liver. AG490 significantly reduced the pSTAT3 protein and abolished the changes of Fpn1 and Ft-L expression induced by LPS in liver. ConclusionThese finding provided further evidence that the effect of central inflammation on the hepatic hepcidin expression and peripheral iron metabolism.

Molecular Diagnosis of the First Ferroportin Mutation (C326Y) in the Far East Causing a Dominant Form of Inherited Iron Overload.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3204-3204 ◽  
Author(s):  
Vip Viprakasit ◽  
Alison T. Merryweather-Clarke ◽  
Yingyong Chinthammitr ◽  
Lisa Schimanski ◽  
Hal Drakesmith ◽  
...  
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Transferrin Saturation ◽  
Far East ◽  
Rflp Analysis ◽  
Causative Mutation ◽  
The Far East ◽  
Hfe Mutations ◽  
Genetic Hemochromatosis

Abstract Genetic hemochromatosis (HH) is a common inherited disorder in populations of European origin in which different types of genetic hemochromatosis (type 1–4) have been characterized. Most hemochromatosis-type 1 patients are homozygotes or compound heterozygotes for two HFE mutations C282Y and H63D. Studies of several non-HFE iron overload families led to identification of mutations in hemojuvelin and hepcidin (juvenile form-HFE2A and B), transferrin receptor 2 (HFE3) and ferroportin (HFE4) as a cause of different forms of hemochromatosis. In the Far East, inherited hemochromatosis has rarely been reported and may have been misdiagnosed due to the high prevalence of secondary iron loading from hemoglobin disorders. This report describes, for the first time, non-HFE iron overload in patients from Southeast Asia. The affected Thai family presented with a distinctive clinical phenotype including macrocytosis and elevated transferrin saturation (>95%), increased non-transferrin bound iron (NTBI) as well as raised serum ferritin and marked hepatic hemochromatosis. Our patients tolerated therapeutic phlebotomy well. DNAs from peripheral blood leukocytes were firstly analyzed for three common HFE mutations (C282Y, H63D and IVS5+1 G→A). Subsequently, we screened all coding sequences, promoters and exon/intron boundaries of the HFE, HAMP, TfR2, HJV and SLC40A1 genes using denaturing high performance liquid chromatography (DHPLC). The entire coding region and splice sites of these genes were amplified and directly sequenced. We identified a novel mutation (C326Y) in ferroportin (SLC40A1, IREG-1, MTP-1), a membrane iron transport protein due to a G→A substitution at nucleotide 1281 in exon 7. This mutation was confirmed by restriction fragment length polymorphism (RFLP) analysis using Sfa NI. Six hundred Thai and two hundred Vietnamese chromosomes were analyzed for the C326Y mutation by RFLP analysis and it was not detected in any of the healthy controls studied. This result suggested that the G→A substitution is not a common polymorphism and is likely to be the causative mutation for the phenotype in this family. Previous reported mutations of ferroportin, including A77D and V162del, which lead to type IV hemochromatosis, were characterized by increased serum ferritin despite normal transferrin saturation, in contrast to our patients’ phenotype. These autosomal dominant mutants are postulated to lead to disease due to loss of iron exporting function. Preliminary in vivo assay using transient transfection of wild-type and ferroportin mutants in HeLa or 293T cells revealed, as expected, a loss of function and diminished surface membrane localisation in A77D and V162del mutants. Surprisingly, the C326Y mutant was indistinguishable from wt ferroportin in both iron status of the cell and protein localization suggesting different pathophysiology leading to iron overload in our patients.

Expression of Genes Regulating Iron Metabolism in Hepatocyte Cell-Line HepG2 Induced by Sera from MDS Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4612-4612 ◽  
Author(s):  
Laura Breda ◽  
Hussam Ghoti ◽  
Stefano Rivella ◽  
Gideon Rechavi ◽  
Ioav Cabantchik ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Metabolism ◽  
Hepg2 Cells ◽  
Serum Iron ◽  
Refractory Anemia ◽  
Serum Samples ◽  
Group I ◽  
Plasma Factor ◽  
Normal Expression ◽  
Plasma Factors

Abstract Liver expression of hepcidin, a key factor in the regulation of iron absorption and recycling, responds commensurately to plasma iron levels. However, in thalassemic humans and mouse models, despite the overt iron overload found, there is a low expression of liver hepcidin and low levels in urine. We have recently shown that hepcidin expression induced by plasma factors in hemochromatosis is overriden in thalassemic patients (Weiser-Stern et al, Brit. J. Haemat.135:129,2006). As low urinary hepcidin levels were also found in patients with Myelodysplastic Syndrome (MDS), mainly in those with refractory anemia (RA) with or without ring sideroblasts (RARS) and iron overload, we set out to examine whether plasma factor(s) in MDS might also affect the expression of liver genes of iron metabolism. Patients and methods. Serum samples were collected from 19 MDS patients, average age: 75.7 y, Hb 6.5–12.0 gm/dl; type and #: RA 11, RARS 5 and 3 RA with excess of blasts (RAEB). The international prognostic score (IPSS) was low in 13/19 and intermediate 1 (Int 1) in 6/19. Only 7/19 patients received less that 5 blood units, while 12/19 received 20–140 units and in 11/19 serum ferritin was >1000 ng/ml. The serum samples were incubated with human hepatoma HepG2 cells, which were harvested and their RNA isolated and analyzed by quantitative RT-PCR for: hepcidin (Hamp), the lipocalin Ngal, HFE, transferrin receptors (TfR) 1 and 2, and DMT1-IRE(−). Values were normalized against those obtained from 3 healthy individuals. Results and discussion. An apparently normal expression of all the above genes was found in 13/19 patients (group I), whereas in the remaning 6/19 (group II) there was: A. a significant increase in expression relative to normal controls (1.0±0.20) of Ngal (4.64±2.15) p<0.01, TfR1 (5.24±0.59) p<0.01, HFE (1.76±0.12) p<0.05 and DMT1-IRE(−) (1.64±0.24) p<0.05; B. a significant decrease in TfR2 (0.19±0.11) p <0.01 and C. an increased Hamp expression in only 3/6 (7.2±5.0) p<0.05 patients and normal expression in 2/6 (1.03±0.3). No clear correlation could be established between expression of the above mentioned genes and iron overload parameters (serum iron and/or ferritin) or the number of transfusions. This study shows a heterogeneous behavior of MDS sera in eliciting gene expression and highlights that increased Hamp expression of HepG2 cells in response to plasma factors is found only in a small fraction of this class of iron overloaded patients. Thus as in thalassemia (1), most of the MDS sera with ferritin levels >1000 ng/ml failed to induce Hamp, suggesting that also in MDS patients there might be circulating factors overriding the serum iron effect on Hamp expression. It remains to be established whether the putative factors modulating expression of key genes of liver iron metabolism in MDS are of the same origin or biochemical character as in thalassemia.

scholarly journals Iron Overload in Patients with Paroxysmal Nocturnal Hemoglobinuria

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1051-1051
Author(s):  
Kira Lukina ◽  
Nina Tsvetaeva ◽  
Olga Nikoulina ◽  
Elena Sysoeva ◽  
Valentin Sinitsyn ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Metabolism ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Serum Iron ◽  
Study Group ◽  
Clone Size ◽  
Laboratory Parameters ◽  
Advisory Boards ◽  
T2 Mri ◽  
Pnh Clone

Abstract Background: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal bone marrow disorder caused by a somatic mutation in PIGA that leads to a marked deficiency or absence of the complement regulatory proteins CD55 and CD59. The disease manifests with intravascular hemolysis, anemia and thrombosis. PNH is characterized by diverse changes in iron metabolism. Chronic hemolysis leads to the massive iron loss due to hemoglobinuria and hemosiderinuria, whereas frequent transfusions in severely anemic, transfusion-dependent patients might cause the development of iron overload. A im: to assess iron metabolism in PNH patients based on both laboratory parameters and MRI data. Methods: the study group included 28 PNH patients (pts) followed up in our Center between 2015 and 2017. Laboratory parameters including hemoglobin (Hb), reticulocytes (RET), erythrocyte and granulocyte PNH clone sizes and LDH levels were analyzed. Iron metabolism was characterized by measurement of serum ferritin (SF), transferrin, iron concentration, total iron binding capacity (TIBC), transferrin saturation (TS). Multiecho gradient-echo T2* magnetic resonance imaging (T2* MRI) was performed to assess both liver and kidney iron load. All pts were divided into 3 cohorts: №1 - pts on treatment with eculizumab, №2 - pts who received eculizumab in the past and №3 - eculizumab naïve pts. Results: Сohort №1 included 2 pts (2 women) aged 39 and 64 yrs. Hb level was 9,3 and 9,9 g/dl, RET count - 9,6 and 10%, LDH level - 570 and 650 U/l. Erythrocyte PNH clone size was 99 and 72%, and granulocyte PNH clone size was 99 and 87%. Cohort №2 consisted of 6 pts (2 men and 4 women, median age 39 yrs (31 - 53)) which had a history of eculizumab treatment. The median duration of eculizumab treatment in these pts was 23 months, the median time of treatment cessation (due to administrative reasons) was 6 months before study assessments. The medians of laboratory parameters were as follows: Hb = 7,7 g/dl, RET count = 6,6%, LDH level = 3296 U/l (1580 - 7444), erythrocyte PNH clone size = 36%, granulocyte PNH clone size = 98%. Cohort №3 consisted of 20 untreated pts (15 men and 5 women, median age 35 yrs (29 - 58)). The medians of laboratory parameters: Hb = 8,4 g/dl, RET count = 8,5%, LDH level = 4130 U/l (670 - 8322), erythrocyte PNH clone size = 52%, granulocyte PNH clone size = 93%. Serum iron metabolism indices in all patient cohorts are reported in Table 1. Based on the analysis of the measured serum iron metabolism indices, 3 types of iron metabolism disturbances were identified in pts of the study group (n=28): iron deficiency (14% of pts), iron overload (21% of pts) and divergent changes (65% of pts). T2* MRI was performed in 23 pts. Signs of liver iron overload were revealed in 35% pts whereas signs of kidney iron overload were detected in 91% pts. T2* MRI data was analyzed within each of the patient cohorts, results are reported in Table 1. Conclusion: the results of our pilot study demonstrate that in PNH patients laboratory parameters are not sufficient to assess iron metabolism. T2* MRI is a noninvasive and accurate technique which should be considered as a method of choice to quantify tissue iron overload. Kidney iron overload was detected in all PNH patients who did not receive eculizumab at the moment of the analysis and was absent in 2 patients on eculizumab. Thus, hemosiderin deposition in the renal cortex might play an important role in the development of renal involvement including the formation of interstitial fibrosis and chronic kidney disease. Disclosures Lukina: Sanofi Genzyme: Honoraria, Other: Principal investigator in the eliglustat Phase 2, ENGAGE, ENCORE, and EDGE trials; receives travel reimbursement; member of advisory boards, Research Funding.

scholarly journals Inflammatory and oxidative status in European captive black rhinoceroses: a link with Iron Overload Disorder?

2020 ◽  
Author(s):  
Hanae Pouillevet ◽  
Nicolas Soetart ◽  
Delphine Boucher ◽  
Rudy Wedlarski ◽  
Laetitia Jaillardon
Keyword(s):  
Oxidative Stress ◽  
Iron Overload ◽  
Serum Iron ◽  
Iron Status ◽  
The Body ◽  
Stress Markers ◽  
Oxidative Markers ◽  
Inflammatory Status ◽  
The Impact ◽  
And Oxidative Stress

AbstractIron Overload Disorder (IOD) is a syndrome developed by captive browsing rhinoceroses like black rhinoceroses (Diceros bicornis) in which hemosiderosis settles in vital organs while free iron accumulates in the body, potentially predisposing to various secondary diseases. Captive grazing species like white rhinoceroses (Ceratotherium simum) do not seem to be affected. The pro-oxidant and pro-inflammatory properties of iron, associated with the poor antioxidant capacities of black rhinoceroses, could enhance high levels of inflammation and oxidative stress leading to rapid ageing and promoting diseases. In this prospective study, 15 black (BR) and 29 white rhinoceroses (WR) originating from 22 European zoos were blood-sampled and compared for their iron status (serum iron), liver/muscle biochemical parameters (AST, GGT, cholesterol), inflammatory status (total proteins, protein electrophoresis) and oxidative stress markers (SOD, GPX, dROMs). Results showed higher serum iron and liver enzyme levels in black rhinoceroses (P<0.01), as well as higher GPX (P<0.05) and dROM (P<0.01) levels. The albumin/globulin ratio was lower in black rhinoceroses (P<0.05) due to higher α2-globulin levels (P<0.001). The present study suggests a higher inflammatory and oxidative profile in captive BR than in WR, possibly in relation to iron status. This could be either a consequence or a cause of iron accumulation, potentially explaining rapid ageing and various diseases. Further investigations are needed to assess the prognostic value of the inflammatory and oxidative markers in captive black rhinoceroses, particularly for evaluating the impact of reduced-iron and antioxidant-supplemented diets.

scholarly journals Linkage of alterations in systemic iron homeostasis to patients’ outcome in sepsis: a prospective study

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Anna Brandtner ◽  
Piotr Tymoszuk ◽  
Manfred Nairz ◽  
Georg F. Lehner ◽  
Gernot Fritsche ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Prospective Study ◽  
Iron Metabolism ◽  
Sofa Score ◽  
Serum Iron ◽  
Transferrin Saturation ◽  
Icu Admission ◽  
Iron Parameters ◽  
A Prospective Study ◽  
Prospective Study Design

Abstract Background Sepsis, a dysregulated host response following infection, is associated with massive immune activation and high mortality rates. There is still a need to define further risk factors and laboratory parameters predicting the clinical course. Iron metabolism is regulated by both, the body’s iron status and the immune response. Iron itself is required for erythropoiesis but also for many cellular and metabolic functions. Moreover, iron availability is a critical determinant in infections because it is an essential nutrient for most microbes but also impacts on immune function and intravascular oxidative stress. Herein, we used a prospective study design to investigate the putative impact of serum iron parameters on the outcome of sepsis. Methods Serum markers of iron metabolism were measured in a prospective cohort of 61 patients (37 males, 24 females) with sepsis defined by Sepsis-3 criteria in a medical intensive care unit (ICU) and compared between survivors and non-survivors. Regulation of iron parameters in patients stratified by focus of infection and co-medication as well as association of the markers with sepsis severity scores and survival were investigated with linear and logistic regression corrected for sex and age effects. Results Positive correlations of increased serum iron and ferritin concentrations upon ICU admission with the severity of organ failure (SOFA score) and with mortality were observed. Moreover, high TF-Sat, elevated ferritin and serum iron levels and low transferrin concentrations were associated with reduced survival. A logistic regression model consisting of SOFA and transferrin saturation (SOFA–TF-Sat) had the best predictive power for survival in septic ICU patients. Of note, administration of blood transfusions prior to ICU admission resulted in increased TF-Sat and reduced survival of septic patients. Conclusions Our study could show an important impact of serum iron parameters on the outcome of sepsis. Furthermore, we identified transferrin saturation as a stand-alone predictor of sepsis survival and as a parameter of iron metabolism which may in a combined model improve the prediction power of the SOFA score. Trial registration The study was carried out in accordance with the recommendations of the Declaration of Helsinki on biomedical research. The study was approved by the institutional ethics review board of the Medical University Innsbruck (study AN2013-0006).

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