FERRITIN RESEARCH

Serum ferritin levels are associated with vascular damage in patients with nonalcoholic fatty liver disease

noreply@blogger.com (Unknown) — Mon, 20 Sep 2010 20:39:00 +0000

Abstract
Background and aims
Increased ferritin and body iron stores are frequently observed in nonalcoholic fatty liver disease (NAFLD), associated with heightened susceptibility to vascular damage. Conflicting data have been reported on the role of iron in atherosclerosis, with recent data suggesting that excess iron induces vascular damage by increasing levels of the hormone hepcidin, which would determine iron trapping into macrophages, oxidative stress, and promotion of transformation into foam cells. Aim of this study was to investigate the relationship between iron status and cardiovascular damage in NAFLD.

Methods and results
Vascular damage was evaluated by common carotid arteries intima-media thickness (CC-IMT) measurement and plaque detection by ecocolor-doppler ultrasonography in 506 patients with clinical and ultrasonographic diagnosis of NAFLD, hemochromatosis gene (HFE) mutations by restriction analysis in 342 patients. Serum hepcidin-25 was measured by time-of-flight mass spectrometry in 143 patients. At multivariate analysis CC-IMT was associated with systolic blood pressure, glucose, LDL cholesterol, abdominal circumference, age, and ferritin (p = 0.048). Carotid plaques were independently associated with age, ferritin, glucose, and hypertension. Ferritin reflected iron stores and metabolic syndrome components, but not inflammation or liver damage. Hyperferritinemia was associated with increased vascular damage only in patients with HFE genotypes associated with hepcidin upregulation by iron stores (p < 0.0001), and serum hepcidin-25 was independently associated with carotid plaques (p = 0.05).

Conclusion
Ferritin levels, reflecting iron stores, are independent predictors of vascular damage in NAFLD. The mechanism may involve upregulation of hepcidin by increased iron stores in patients not carrying HFE mutations, and iron compartmentalization into macrophages.

Ramettaa, , S. Fargiona, , and A.L. Fracanzania,

a Center for the Study of Metabolic and Liver Diseases, Department of Internal Medicine, Università degli Studi Milano, Internal Medicine 1B, Hospital Fondazione Policlinico MaRE IRCCS, Granelli pavilion, via F Sforza 35, 20122 Milano, Italy

b Department of Clinical Chemistry, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands

Serum ferritin as risk factor for sinusoidal obstruction syndrome of the liver in patients undergoing hematopoietic stem cell transplantation

noreply@blogger.com (Unknown) — Wed, 19 Aug 2009 19:42:00 +0000

Hepatic sinusoidal obstruction syndrome (SOS) is a serious complication in hematopoietic stem cell transplant (HSCT) recipients. To determine the impact of pretransplantation hyperferritinemia on the risk of SOS after HSC transplantation, we retrospectively studied 427 HSCT recipients (179 autologous and 248 allogeneic). Serum ferritin levels were measured before transplantation. Patients with and without a diagnosis of SOS were compared regarding demographics; underlying disease; transplant characteristics; receipt of imatinib, busulfan, total body irradiation, gemtuzumab, vancomycin, acyclovir, or methotrexate; and baseline serum ferritin. Univariate and multivariate (stepwise logistic regression) analyses were performed. SOS was diagnosed in 88 patients (21%) at a median of 10 days (range, 2-29 days) after transplantation. By multivariate analysis, allogeneic HSC transplantation (odds ratio [OR] = 8.25; 95% confidence interval [95% CI], 3.31-20.57), receipt of imatinib (OR = 2.60; 95% CI, 1.16-5.84), receipt of busulfan (OR = 2.18; 95% CI, 1.25-3.80), and ferritin serum level higher than 1000 ng/dL (OR = 1.78; 95% CI, 1.02-3.08) were risk factors for SOS.

A ferritin serum level higher than 1000 ng/dL in the pretransplantation period is an independent risk factor for SOS. The results suggest the need for prospective studies addressing the use of iron chelation in the pretransplantation period

Maradei SC, Maiolino A, de Azevedo AM, Colares M, Bouzas LF, Nucci M.
Bone Marrow Transplantation Center (CEMO), Instituto Nacional de Câncer (INCA), Rio de Janeiro, Brazil

Ferritins: A family of molecules for iron storage, antioxidation and more

noreply@blogger.com (Unknown) — Sun, 14 Jun 2009 15:07:00 +0000

Ferritins are characterized by highly conserved three-dimensional structures similar to spherical shells, designed to accommodate large amounts of iron in a safe, soluble and bioavailable form. They can have different architectures with 12 or 24 equivalent or non-equivalent subunits, all surrounding a large cavity. All ferritins readily interact with Fe(II) to induce its oxidation and deposition in the cavity in a mineral form, in a reaction that is catalyzed by a ferroxidase center. This is an anti-oxidant activity that consumes Fe(II) and peroxides, the reagents that produce toxic free radicals in the Fenton reaction. The mechanism of ferritin iron incorporation has been characterized in detail, while that of iron release and recycling has been less thoroughly studied. Generally ferritin expression is regulated by iron and by oxidative damage, and in vertebrates it has a central role in the control of cellular iron homeostasis. Ferritin is mostly cytosolic but is found also in mammalian mitochondria and nuclei, in plant plastids and is secreted in insects. In vertebrates the cytosolic ferritins are composed of H and L subunit types and their assembly in a tissues specific ratio that permits flexibility to adapt to cell needs. The H-ferritin can translocate to the nuclei in some cell types to protect DNA from iron toxicity, or can be actively secreted, accomplishing various functions. The mitochondrial ferritin is found in mammals, it has a restricted tissue distribution and it seems to protect the mitochondria from iron toxicity and oxidative damage. The various functions attributed to the cytosolic, nuclear, secretory and mitochondrial ferritins are discussed.

Arosio P, Ingrassia R, Cavadini P.
Dipartimento Materno Infantile e Tecnologie Biomediche, Università di Brescia, and A.O. Spedali Civili, Brescia, Italy

Ferritin: Dietary and stored iron as predictors of breast cancer risk

noreply@blogger.com (Unknown) — Thu, 21 May 2009 21:27:00 +0000

Increases in risk of breast cancer in successive generations of migrants to the United States from China and rapid temporal changes in incidence rates in China following social and economic changes clearly implicate environmental factors in the etiology of this disease. Case-control and cohort studies have provided evidence that at least some of these factors may be dietary. Iron, an essential element necessary for cell function, has also been demonstrated to have potential carcinogenic and co-carcinogenic activities.

Dietary and stored iron as predictors of breast cancer risk: A nested case-control study in Shanghai.

Iron overload, which was previously uncommon, has become more common in the United States than iron deficiency and may be increasing in China concurrently with dramatic increases in meat consumption. A case-control study nested in a cohort of women in Shanghai, China, was conducted to evaluate possible associations between risk of proliferative and nonproliferative fibrocystic changes as well as breast cancer and dietary iron intake and plasma ferritin levels.

Plasma ferritin levels and reported dietary iron intake were compared in 346 women with fibrocystic changes, 248 breast cancer cases and 1,040 controls. Increasing ferritin levels were significantly associated with increasing risk of nonproliferative fibrocystic changes (OR: 2.51, 95% CI: 1.16-5.45, p trend = 0.04). Similar, but weaker, trends were observed for proliferative changes and for breast cancer. Risk of breast cancer relative to the risk of fibrocystic changes was associated with dietary iron intake in women with nonproliferative fibrocystic changes (OR: 2.63, 95% CI: 1.04-6.68, p = 0.02).

In conclusion, this study finds significant associations between iron (stored and dietary) and fibrocystic disease and breast cancer

Department of Public Health and Preventive Medicine, Oregon Health and Sciences University, Portland, OR

Methods for reducing nonspecific interaction in antibody–antigen assay via atomic force microscopy

noreply@blogger.com (Unknown) — Fri, 08 Aug 2008 15:29:00 +0000

We developed a method to measure the rupture forces between antibody and antigen by atomic force microscopy (AFM). Previous studies have reported that in the measurement of antibody–antigen interaction using AFM, the specific intermolecular forces are often obscured by nonspecific adhesive binding forces between antibody immobilized cantilever and substrate surfaces on which antigen or nonantigen are fixed. Here, we examined whether detergent and nonreactive protein, which have been widely used to reduce nonspecific background signals in ordinary immunoassay and immunoblotting, could reduce the nonspecific forces in the AFM measurement. The results showed that, in the presence of both nonreactive protein and detergent, the rupture forces between anti-ferritin antibodies immobilized on a tip of cantilever and ferritin (antigen) on the substrate could be successfully measured, distinguishing from nonspecific adhesive forces. In addition, we found that approach/retraction velocity of the AFM cantilever was also important in the reduction of nonspecific adhesion. These insights will contribute to the detection of specific molecules at nanometer scale region and the investigation of intermolecular interaction by the use of AFM.

ARTICLE

Epigallocatechin activates haem oxygenase-1 expression via protein kinase Cδ and Nrf2

noreply@blogger.com (Unknown) — Fri, 08 Aug 2008 15:27:00 +0000

The Nrf2/anti-oxidant response element (ARE) pathway plays an important role in regulating cellular anti-oxidants, including haem oxygenase-1 (HO-1). Various kinases have been implicated in the pathways leading to Nrf2 activation. Here, we investigated the effect of epigallocatechin (EGC) on ARE-mediated gene expression in human monocytic cells. EGC time and dose dependently increased HO-1 mRNA and protein expression but had minimal effect on expression of other ARE-regulated genes, including NAD(P)H:quinone oxidoreductase 1, glutathione cysteine ligase and ferritin. siRNA knock down of Nrf2 significantly inhibited EGC-induced HO-1 expression. Furthermore, inhibition of PKC by Ro-31-8220 dose dependently decreased EGC-induced HO-1 mRNA expression, whereas MAP kinase and phosphatidylinositol-3-kinase pathway inhibitors had no significant effect. EGC stimulated phosphorylation of PKCαβ and δ in THP-1 cells. PKCδ inhibition significantly decreased EGC-induced HO-1 mRNA expression, whereas PKCα- and β-specific inhibitors had no significant effect. These results demonstrate for the first time that EGC-induced HO-1 expression occurs via PKCδ and Nrf2.

ARTICLE

Iron-independent phosphorylation of iron regulatory protein 2 regulates ferritin during the cell cycle.

noreply@blogger.com (Unknown) — Tue, 22 Jul 2008 17:38:00 +0000

Iron regulatory protein 2 (IRP2) is a key iron sensor that post-transcriptionally regulates mammalian iron homeostasis by binding to iron-responsive elements (IREs) in mRNAs that encode proteins involved in iron metabolism (e.g. ferritin and transferrin receptor 1). During iron deficiency, IRP2 binds IREs to regulate mRNA translation or stability whereas during iron sufficiency IRP2 is degraded by the proteasome. Here, we identify an iron-independent IRP2 phosphorylation site that is regulated by the cell cycle. IRP2 S157 is phosphorylated by Cdk1/cyclin B1 during G2/M and is dephosphorylated during mitotic exit by the phosphatase Cdc14A. S157 phosphorylation during G2/M reduces IRP2 RNA-binding activity and increases ferritin synthesis, while S157 dephosphorylation during mitotic exit restores IRP2 RNA-binding activity and represses ferritin synthesis. These data show that reversible phosphorylation of IRP2 during G2/M has a role in modulating the iron-independent expression of ferritin and other IRE-containing mRNAs during the cell cycle.

The Usefulness of the Serum Transferrin Receptor to Serum Ferritin Ratio for Discriminating between Iron Deficiency Anemia and Anemia of Inflammation

noreply@blogger.com (Unknown) — Fri, 18 Jul 2008 16:19:00 +0000

BACKGROUND:
The incidence of iron deficiency anaemia in infants, which is caused by the increased iron demand for rapid growth during this period, is reported to range from 10 to 40%. This age group also suffers from a number of acute illnesses (urinary tract infection, pneumonia and other viral illness). The aim of this study was to evaluate the usefulness of soluble transferrin receptor (sTfR) values and the different methods of calculating the sTfR and serum ferritin (SF) ratio for differentiating anemia of inflammation (AI) from iron deficiency anemia (IDA) or a mixture of these two types of anemia.

METHODS:
173 infants among all the infants who visited Gyeongsang National University Hospital from 2000 to 2006 were enrolled in this study. The hemoglobin (Hb), SF and sTfR values were checked and the infants were divided into the Al subgroup (Hb <11g/dL and SF > 50microgram/L), the IDA subgroup (Hb <11g/dL and SF < 12microgram/L), the normal group (Hb > or =11g/dL and SF > or =12microgram/L), and the unclassified anemia (UCA) group (Hb <11g/dL and SF 12~50microgram/L).

RESULTS:
The mean sTfR and sTfR/Log SF values in the AI group were 3.89 and 10.6microgram/mL, respectively (P<0.01). These values in the IDA group were 1.9 and 36.11, respectively (P<0.01). The mean Log (sTfR/SF) was statistically significant between all the subgroups (1.35 in AI, 3.29 in IDA, 1.76 in Nor and 2.35 in UCA). All the infants in the IDA group had a Log (sTfR/SF) value >2.55 whereas all the infants classified in AI group had a Log (sTfR/SF) value <2.55.

CONCLUSION:
The Log (sTfR/SF) value is a useful criterion for discriminating between AI and IDA.

High Prevalence of Iron Overload in Adult Allogeneic Hematopoietic Cell Transplant Survivors

noreply@blogger.com (Unknown) — Thu, 17 Jul 2008 18:31:00 +0000

Allogeneic hematopoietic cell transplant (HCT) recipients frequently need red blood cell transfusions, and can be at risk for developing iron overload. We studied the prevalence of iron overload in 56 adult allogeneic HCT patients who had survived for a median of 28 (range: 12-151) months from transplant. Patients were initially screened with serum ferritin, and those with serum ferritin >1000 ng/mL underwent R2 magnetic resonance imaging (MRI) of the liver, a sensitive and specific noninvasive imaging technique to measure liver iron concentration (LIC). Iron overload was defined as LIC above normal (>1.8 mg/g dry weight). Nineteen patients had serum ferritin >1000 ng/mL with a median LIC of 7.0 (range: 1.8-28.3) mg/g. The overall prevalence of iron overload was 32% (95% confidence intervals, 20%-46%). The LIC on MRI was moderately correlated with serum ferritin (ρ = .47). Iron overload is a frequent complication of allogeneic transplantation. serum ferritin is a good screening test but does not reliably predict tissue iron overload, and estimation of LIC should be considered before initiating therapy. More studies are needed to determine the impact of iron overload on long-term morbidity and mortality in allogeneic transplant survivors.

ARTICLE

Relation Between Iron-Overload Indices, Cardiac Echo-Doppler, and Biochemical Markers in Thalassemia Intermedia

noreply@blogger.com (Unknown) — Thu, 17 Jul 2008 18:17:00 +0000

Cardiovascular impairment is a major cause of morbidity and mortality in patients with thalassemia intermedia. In this study, echocardiographic assessment of left heart condition was performed in patients with thalassemia intermedia, and its relation to hematologic variables—amino terminal pro-brain natriuretic peptide (NT-proBNP), ferritin, hemoglobin—and liver iron concentration (LIC) was investigated. Echocardiographic assessment was performed using pulse-wave Doppler and tissue Doppler imaging. Data from 74 patients with thalassemia intermedia—35 men, 39 women, mean age 26.5 years (8 to 63) —were randomly selected and evaluated. Blood samples were collected for NT-proBNP levels in a random subgroup of 19 patients. Mean baseline values were hemoglobin 8.4 g/dl (4.9 to 13.1), serum ferritin 902.6 ng/ml (15 to 4,140), LIC 9.0 mg Fe/g (0.5 to 32.1), and NT-proBNP 113.5 pg/ml (16.4 to 371). Correlation between LIC and pulmonary artery systolic pressure was significant, suggesting that iron loading in the liver is indicative of cardiovascular sequelae. NT-proBNP was significantly correlated with the ratio of the left ventricular early rapid filling wave to early diastolic velocity at the mitral annulus (r = 0.50, p = 0.04) and hemoglobin (r = −0.49, p = 0.03), but not with other characteristics assessed. In conclusion, this study has highlighted the importance of using tissue Doppler imaging rather than pulse-wave Doppler to characterize left ventricular diastolic dysfunction in patients with thalassemia intermedia. Demonstration of the correlation of LIC and pulmonary artery systolic pressure independent of left ventricular filling pressures supports our hypothesis that left ventricular diastolic dysfunction does not contribute to the increased pulmonary artery systolic pressure in patients with thalassemia intermedia.

ARTICLE

Serum Bilirubin and Ferritin Levels Link Between Heme Oxygenase-1 Gene Promoter Polymorphism and Susceptibility to Coronary Artery Disease in Diabetic

noreply@blogger.com (Unknown) — Tue, 01 Jul 2008 20:54:00 +0000

Objective: Heme oxygenase (HO) leads to the generation of free iron, carbon monoxide, and bilirubin. A length polymorphism of GT repeat in the promoter of human HO-1 gene has been shown to modulate gene transcription. This study aims to assess the association of the length of (GT)n repeats in HO-1 gene promoter with serum bilirubin, markers of iron status, and the development of coronary artery disease (CAD).

Research design and methods: We screened the allelic frequencies of (GT)n repeats in the HO-1 gene promoter in 986 unrelated individuals that underwent coronary angiography. Serum bilirubin. and markers of iron status were evaluated.

Results: The distribution of numbers of (GT)n repeats was divided into 2 subclasses: class S included shorter (<27) repeats, and class L included longer (27) repeats. Among those with diabetes, subjects with L/L genotype had significantly lower bilirubin levels than those with S/S and S/L genotypes (0.70±0.22 vs. 0.81±0.24 mg/dL, P=0.001) and higher serum ferritin values (4.76±0.72 vs. 4.28±1.05 µg/L for log-ferritin, P=0.001). Compared with those carrying S allele, diabetic subjects with L/L genotype had an almost three-fold increase in CAD risk after controlling for conventional risk factors (odds ratio 2.81, 95% confidence interval [CI] 1.22 to 6.47, P=0.015). Adjusting for both serum bilirubin and ferritin, the effect of HO-1 promoter polymorphism on susceptibility to CAD disappeared.

Conclusions: Length polymorphism in the HO-1 gene promoter is correlated with susceptibility to CAD in diabetic patients and such effect might be conveyed through its influence on serum bilirubin and ferritin.

The effect of iron substrate on mitochondrial haem synthesis in copper deficiency.

noreply@blogger.com (Unknown) — Tue, 01 Jul 2008 20:51:00 +0000

Studies of iron utilization and haem synthesis were carried out with hepatic mitochondria obtained from copper-deficient and pair-fed control rats. Ferric chloride can be used as Fe substrate for mitochondrial haem synthesis in the presence of succinate. Utilization is further enhanced by the addition of FMN. Ferritin does not support haem synthesis in the presence of succinate alone, but does support haem synthesis when FMN is added. Mitochondrial haem synthesis is impaired in Cu deficiency when either FeCl3 or homologous ferritin is used as Fe substrate. The results of the present study suggest that impaired haem synthesis in Cu deficiency occurs at a step following the chemical reduction of Fe substrate.

The role of FERRITIN in immunity and autoimmunity

noreply@blogger.com (Unknown) — Tue, 05 Feb 2008 18:57:00 +0000

Ferritin is a ubiquitous and specialised protein involved in the intracellular storage of iron; it is also present in serum and other biological fluids , although its secretion processes are still unclear. We here review evidence supporting the hypothesis that macrophages play a role in the production and secretion of extracellular ferritin , as well as evidence supporting a novel function as a signalling molecule and immune regulator.

In particular, H-ferritin , which inhibits the proliferation of lymphoid and myeloid cells, may be regarded as a negative regulator of human and murine hematopoiesis. The idea that it also acts as a signalling protein has been supported by the cloning and characterisation of the specific H- ferritin receptor TIM-2, a member of the TIM gene family. A number of studies of the mouse TIM gene family indicate that this protein plays an important role in immune-mediated diseases .

This last finding, together with the fact that ferritin acts as an immuno-suppressor, has allowed us to formulate hypotheses regarding the possible role of alterations of H-ferritin/TIM-2 binding/signalling in the pathogenesis of autoimmune diseases .

Institute of General Pathology, University of Milan, Via Mangiagalli 31, 20133 Milan, Italy. J Autoimmun. 2008 Feb-Mar;30(1-2):84-9.

Screening for hemochromatosis by measuring FERRITIN levels

noreply@blogger.com (Unknown) — Thu, 20 Dec 2007 21:51:00 +0000

Because the penetrance of HFE hemochromatosis is low, traditional population screening measuring the transferrin saturation is unlikely to be cost-effective, as the vast majority of individuals detected neither have clinical disease nor are likely to develop it.

Three independent studies show that only patients with serum ferritin concentrations over 1000 ng/ml are at risk for cirrhosis , one of the main morbidities of hemochromatosis. Among 29,699 white subjects participating in the Scripps-Kaiser hemochromatosis study, only 59 had serum ferritin levels of greater than 1000 ng/ml. Twenty-four had homozygous mutant or compound heterozygous mutant HFE genotypes .

In all but 5 of the other subjects the causes of elevated ferritin was excessive alcohol intake, cancer, or liver disease. Screening for hemochromatosis with serum ferritin levels will detect the vast majority of patients who will be clinically affected, and may detect other clinically significant disease in patients who do not have hemochromatosis genotypes .

Since it is clear that the ferritin level of the vast majority of adult homozygotes for HFE mutations does not rise over long periods of time, excluding subjects with serum ferritin levels /=1000 ng/ml should not result in missed opportunities for early treatment of patients who could benefit.

PMID: 18025154
Waalen J , Felitti VJ , Gelbart T , Beutler E .
Department of Molecular and Experimental Medicine , The Scripps Research Institute, La Jolla, CA, United States.

FERRITIN: Augmentation in restless legs syndrome -low ferritin

noreply@blogger.com (Unknown) — Fri, 23 Nov 2007 17:20:00 +0000

Abstract
Background and purpose: Augmentation is a major problem with dopaminergic therapy for restless legs syndrome (RLS), and predictors of augmentation have not yet been identified. We aimed to analyze the relationship between baseline ferritin level and occurrence of augmentation in a retrospective analysis of a prospective double-blind trial of cabergoline versus levodopa on augmentation in RLS.

Patients and methods: Patients who experienced augmentation were compared to patients who did not experience augmentation.

Results: Augmentation symptoms causing premature discontinuation from the study or which were tolerated (n = 36, ferritin: 85 + 59 ng/ml) were associated with lower levels of serum ferritin compared to patients without augmentation (n = 302, ferritin : 118 + 108 ng/ml, p = 0.0062).

Conclusions: Ferritin as a marker of iron storage may play an important role in the pathophysiology of RLS and may prove to be a biomarker for the development of augmentation under dopaminergic therapy.

Keywords: Restless legs syndrome; Augmentation; Dopaminergic therapy; Ferritin; Iron storage; Cabergoline; Levodopa

Corresponding author. Address: Paracelsus-Elena Klinik, Klinikstrasse 16, 34128 Kassel, Germany. Tel.: +49 561 6009 200; fax: +49 561 6009 126.
doi:10.1016/j.sleep.2007.07.020

FERRITIN

noreply@blogger.com (Unknown) — Sun, 28 Oct 2007 16:26:00 +0000

Ferritin is a water-soluble, iron storage protein found in most animal cells. Its spherical structure is composed of 24 subunits and contains a 7-nm cavity with a ferric oxyhydroxide crystalline core that is capable of storing approximately 4500 iron atoms. Iron passes in and out of the ferritin cavity through 0.7-1.0 nm pores in the outer shell. Up to 25 ferritin isoforms are thought to exist, composed of various combinations of the two primary subunits, H and L, which have molecular weights of 21,000 and 19,000, respectively.Ferritin rich in the Heavy subunit is found in heart muscle, red blood cells, Lymphocytes and monocytes,while that rich in the Light subunit is found in the liver, spleen, and placenta.

Ferritins composed of a higher proportion of H subunits are more acidic (pI as low as 4.8) than the isoforms containing a higher proportion of L subunits (pI 5.3-5.8) Human serum ferritin is primarily composed of the L subunit, which also corresponds with a lower iron content. Liver Ferritinand Spleen Ferritin contain > 12% iron by weight accoring to published reports.

Ferritin is the body's primary iron source for Hemoglobin synthesis; only hemoglobin itself accounts for more of the body's total iron content. When serum iron levels decrease below normal levels, ferritin readily releases its iron stores for use. Serum levels of ferritin are known to closely parallel tissue ferritin levels and are, therefore, indicative of body iron content. As such, clinical tests for ferritin serum levels are used to detect and manage iron-related disorders, such as iron deficiency anemia and iron overload. In addition, high levels of serum ferritin have been associated with malignant disease and tissue damage.