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

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

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

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

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

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.

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

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

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

FERRITIN: Augmentation in restless legs syndrome -low ferritin

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

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.