Total Body Iron Stores Research Articles

I12 Serious infections in onco-hematology and hematopoietic stem cell transplantation. Anti-infective treatment strategies

Ferritin, a major iron storage protein, is essential to iron homeostasis and is involved in a wide range of physiologic and pathologic processes. In clinical medicine, ferritin is predominantly utilized as a serum marker of total body iron stores. In cases of iron deficiency and overload, serum ferritin serves a critical role in both diagnosis and management. Elevated serum and tissue ferritin are linked to coronary artery disease, malignancy, and poor outcomes following stem cell transplantation. Ferritin is directly implicated in less common but potentially devastating human diseases including sideroblastic anemias, neurodegenerative disorders, and hemophagocytic syndrome. Additionally, recent research describes novel functions of ferritin independent of iron storage.

Comparison of plasma ferritin concentration versus the ratio of plasma transferrin receptor/ferritin to estimate total body iron stores: results of four intervention trials

Comparison of plasma ferritin concentration versus the ratio of plasma transferrin receptor/ferritin to estimate total body iron stores: results of four intervention trials

Interpretation of serum ferritin concentrations as indicators of total-body iron stores in survey populations: the role of biomarkers for the acute phase response

Nutritional surveys use acute phase protein (APP) biomarkers such as C-reactive protein (CRP) and alpha1-acid glycoprotein (AGP) to identify the influence of inflammation on the distribution of iron status biomarkers. Few, however, have examined which biomarker better identifies persons with spurious elevations in iron status markers. We explored the relations of APP biomarkers to iron-status biomarkers in infants and school-age children. In screening surveys, we identified a sample of African American infants (n = 351) and Guatemalan school-age children (n = 375). We used a common set of APP and iron-status biomarkers to examine the association between the 2 sets of markers (laboratory variables). The overall prevalence of either inflammation or iron deficiency was <10% in both samples. The log AGP and CRP values were significantly correlated (r = 0.70), but the unexplained variance still was >50%. Serum ferritin-but not transferrin receptor, transferrin receptor index, or serum iron-was related to APP concentrations, but poor positive predictive value (<72%) and low kappa scores were found. Ferritin concentrations >1 geometric SD above the geometric mean were poorly predicted by either elevated AGP or CRP. Qualitative CRP analysis was not effective in identifying persons who had other indications of mild inflammation. These analyses show that a low prevalence of inflammation has little influence on the distribution of ferritin, and 2 common indicators of inflammation do not perform equally well in identifying persons who may have elevations in ferritin due to inflammation.

Chelator Efficacy of Deferasirox and Deferoxamine Determined by SQUID Biosusceptometry.

Chelation treatment of patients with iron overload from chronic blood (RBC) transfusion needs continuous monitoring of iron stores, iron influx rates from RBC, chelation dose rates, and compliance. Molar chelator efficacy depicts the combined effect from these variables. Treatment should always aim to maximize the efficacy of a certain chelator in an individual patient in order to reduce organ damage from iron toxicity. In a prospective trial on the oral chelator deferasirox, a total of 12 patients with b-thalassemia major have been followed by SQUID biomagnetic liver susceptometry in intervals of 6 to 12 months over a time period of up to 38 months under deferasirox. Patients were initially on deferoxamine (DFO, Desferal®) and then participated in an international multi-center trial randomized for s.c. DFO and the oral chelator deferasirox (DSX, Exjade®). Liver iron concentration LIC (μg/g-liver wet weight), liver volumes, RBC transfusion rates, chelation dose rates, and compliance from tablet counts were assessed. Total body iron stores were calculated from total liver iron taking into account that 70 – 90 % of the total body storage iron is accumulated in the liver. For each chelation interval, molar efficacies were calculated from the daily iron input rate due to RBC plus the change in total body iron per interval time (= mobilized iron rate), and the molar dose rate of DFO or DSX (Fischer et al: Ann N Y Acad Sci 2005; 1054: 350–7), equation 1.[Molarefficacy[ɛ]=mobilizedironrate/molarchelatordoserate]LIC values were in the range of 836 to 8404 with a median value of 2424 μg/g-liver, while ferritin levels were between 911 and 13609 μg/l with a median ratio of ferritin-to-LIC of 1.0 ((μg/l)/(μg/g)) (range: 0.4 to 3.2). The median molar dose rates for DFO and DSX were 3.2 and 1.6 mmol/d, respectively. For each patient, the molar efficacies for DFO and DSX were averaged. From these averaged values, a mean molar efficacy ± SD of 13.2 ± 3.4 % and 23.6 ± 10.3 % was found for DFO and DSX, respectively. Relative to DFO, in each patient an increase between 5.5 and 27.1 % was found for DSX (mean: 11.7 ± 7.3 %). Patients with a low efficacy on DFO also had a low molar efficacy on DSX and vice versa (e.g., 8.0 and 13.5 % versus 16.0 and 31.9 %). Compliance assessed from tablet count protocols was larger than 90% and did not change these data significantly. On a larger scale in highly compliant thalassemia patients, a molar efficacy of 17.6 ± 4.8 % was observed (Fischer et al: Brit J Haematol 2003; 121: 938–48). In comparison to that reference value, the molar efficacy of DFO for this patient group was decreased. The reported molar efficacy of 27.9 ± 13.8 % for DSX obtained from biopsy results (Porter et al: Blood 2005; 106(11): 755a) is only insignificantly higher than our value. In summary, we found deferasirox to be two times more efficient than deferoxamine on the same molar dose level, even for patients with a relatively low efficacy under both chelator treatment regimens.

Heme Oxygenase-1

Schmid and coworkers1 were the first to report on the presence of heme oxygenase (HO) in liver microsomes capable of degrading heme to bilirubin, and this activity was subsequently dissociated from cytochrome P-450.2,3 HO catalyzes the first and rate-limiting step in the oxidative degradation of heme (Fe-protoporphyrin-IX) to carbon monoxide (CO), ferrous iron (Fe2+), and biliverdin-IX (Figure 1). The enzyme binds heme in a 1:1 molar complex, and HO-bound heme acts as prosthetic group and substrate. The reaction requires 3 molecules of molecular oxygen (O2) per heme molecule oxidized and reducing equivalents derived from nicotinamide adenine dinucleotide phosphate or nicotinamide adenine dinucleotide (reduced form) and transferred to the oxygenase via nicotinamide adenine dinucleotide phosphate:cytochrome P-450 reductase. Regiospecific oxidation of heme is achieved in a stepwise reaction, with α-meso-hydroxyheme and verdoheme as intermediates, and the dissociation of CO followed by that of Fe2+.4 The release of biliverdin from HO is accelerated by biliverdin reductase, which reduces the green pigment to bilirubin-IX,4 which is then excreted into bile as the glucuronic acid conjugate. Figure 1. Oxidative metabolism of heme by HO and biliverdin reductase, giving rise to CO, iron, biliverdin, and bilirubin. Originally, the interest in HO was related to its well-established function in heme catabolism and the turnover of erythrocytes. For many years, CO and bilirubin were regarded as toxic waste byproducts of the HO reaction, but in 1987, a potential beneficial role of bilirubin was proposed5 based on the in vitro antioxidant activities of the pigment. Over the last decade, however, the interest in HO has shifted greatly from a metabolic to a protective function of the enzyme in a variety of conditions associated with cellular stress and pathologies, and this has been the subject of excellent recent reviews.6,7 The …

The CD8+ T-lymphocyte profile as a modifier of iron overload in HFE hemochromatosis: An update of clinical and immunological data from 70 C282Y homozygous subjects

Hereditary hemochromatosis (HH) is a clinically heterogeneous disease. Among other factors, the individual immunological profile of CD8+ T-lymphocytes has been described to influence the severity of iron overload, with low numbers being negatively correlated with the total amount of body iron stored. With the objective of testing the modifier effect of the individual CD8+ T-lymphocyte profile on the levels of iron stores with age in HH, we reviewed the clinical and immunological data from a group of well-characterized C282Y homozygous HH subjects, regularly followed-up for a period of 20 years. A total of 70 subjects were analyzed. Sixty-four were adults (≥18 years): 42 males (mean age 47 ± 14; range 22–75 years) and 22 females (mean age 46 ± 14; range 19–65 years). Six were younger than 18 years, 5 males (mean age 9 ± 4; range 5–14 years) and 1 female (15 years). The characterization of subjects included measurements, at diagnosis, of the iron parameters, transferrin saturation (TfSat) and serum ferritin, quantification of total body iron stores (TBIS) removed by phlebotomies, presence of associated clinical manifestations, and the T-cell immunophenotype (CD4+ and CD8+ T-lymphocytes) determined by flow cytometry. In general, statistically significant lower values of TfSat (67 ± 17% vs. 89 ± 14%, P = 0.0006) and ferritin levels (58 ± 9 vs. 949 ± 233 ng/ml, P = 0.02) were found in the young subjects in comparison to adults. After the age of 18, however, no further effect of age was significantly found on the biochemical iron parameters either in males or females. A modifier effect of the individual CD8+ T-lymphocyte profile on the association between iron stores and age was demonstrated by multiple regression analysis, where a significant correlation between TBIS and age was found only in males with low (≤0.41 × 10 6/ml) CD8+ T-cell numbers ( R 2 = 0.43, P < 0.0001). In conclusion, in the present population of C282Y homozygous subjects, the CD8+ T-lymphocyte profile could be considered a modifier of the iron overload with increasing age in males, with low numbers predicting a severe outcome.

A study of 82 extended HLA haplotypes in HFE-C282Y homozygous hemochromatosis subjects: relationship to the genetic control of CD8+ T-lymphocyte numbers and severity of iron overload

BackgroundIt has been recently demonstrated that CD8+ T-lymphocyte numbers are genetically transmitted in association with the MHC class I region. The present study was designed with the objective of narrowing the region associated with the setting of CD8+ T-lymphocyte numbers in a population of C282Y homozygous hemochromatosis subjects, in whom a high prevalence of abnormally low CD8+ T-lymphocyte counts has been described.MethodsThe study includes 43 C282Y homozygous subjects fully characterized both phenotypically and genotypically. Clinical characterization includes measurements of iron parameters at diagnosis (transferrin saturation and serum ferritin), total body iron stores and T-cell immunophenotyping determined by flow cytometry. Genetic characterization includes HLA class I alleles (A, B and C) and four additional microsatellite markers (D6S265, D6S2222, D6S105 and D6S2239) spanning 5 Megabases in the 6p21.3 region.ResultsEighty-two extended C282Y carrying haplotypes were defined. Single-locus analysis revealed that the HLA-A region was associated with CD8+ T-cell numbers. Multivariate analysis showed that the combinations of the most common HLA-A alleles (HLA-A*03, -A*02 and -A*01) were associated with significantly lower numbers of CD8+ T-lymphocytes (0.30 ± 0.14 × 106/ml), in comparison with subjects carrying only one copy of those alleles (0.46 ± 0.19 × 106/ml) and subjects without any copy of those alleles (0.79 ± 0.15 × 106/ml;p = 0.0001). No differences were observed in CD8+ T-cell counts among control subjects carrying the same combinations of HLA-A alleles (0.47 ± 0.14; 0.45 ± 0.21 and 0.41 ± 0.17 × 106/ml, respectively), therefore not supporting a direct effect of HLA specificity but rather an indirect association with a locus close to HLA-A. Multivariate analysis showed that the combination of the most common HLA-A alleles also have an impact on the clinical expression of HH in terms of iron stores, in males(p = 0.0009).ConclusionThe present study provides evidence supporting an inextricable link between extended HLA haplotypes, CD8+ T-lymphocyte numbers and severity of iron overload in hereditary hemochromatosis(HH). It gives additional information to better define a candidate region involved in the regulation of CD8+ T-lymphocyte numbers. A new evolutionary hypothesis concerning the inheritance of the phenotype of low CD8+ T-lymphocyte numbers associated with particular ancestral HLA haplotypes carrying the C282Y mutation and its implication on the clinical heterogeneity of HH is discussed.

ENZYME-LINKED IMMUNOSORBENT ASSAY TO QUANTITATE SERUM FERRITIN IN BLACK AND WHITE RUFFED LEMURS (VARECIA VARIEGATA VARIEGATA)

Lemurs in captivity progressively accumulate iron deposits in a variety of organs (hemosiderosis) including duodenum, liver, and spleen throughout their lives. When excessive, the toxic effects of intracellular iron on parenchymal cells, particularly the liver, can result in clinical disease and death. The pathogenesis of excessive iron storage in these species has been attributed to dietary factors related to diets commonly fed in captivity. Tissue iron stores can be directly estimated by tissue biopsy and histologic examination, or quantitated by chemical analysis of biopsy tissue, However, expense and risk associated with anesthesia and surgery prevent routine use of tissue biopsy to assess iron status. A noninvasive means of assessing total body iron stores is needed to monitor iron stores in lemurs to determine whether dietary modification is preventing excessive iron deposition, and to monitor potential therapies such as phlebotomy or chelation. Serum ferritin concentration correlates with tissue iron stores in humans, horses, calves, dogs, cats, and pigs. Serum ferritin is considered the best serum analyte to predict total body iron stores in these species and is more reliable than serum iron or total iron binding capacity, both of which may be affected by disorders unrelated to iron adequacy or excess including hypoproteinemia, chronic infection, hemolytic anemia, hypothyroidism, renal disease, and drug administration. We have developed an enzyme-linked immunosorbent assay to measure serum ferritin in lemurs. The assay uses polyclonal rabbit anti-human ferritin antibodies in a sandwich arrangement. Ferritin isolated from liver and spleen of a black and white ruffed lemur (Varecia variegata variegata) was used as a standard. Ferritin standards were linear from 0 to 50 microg/L. Recovery of purified ferritin from lemur serum varied from 95% to 110%. The within-assay variability was 4.5%, and the assay-to-assay variability for three different samples ranged from 10% to 17%. The assay also measures serum ferritin in several other lemur species.

A New Model for Predicting Venesection Therapy Requirements in Hereditary Hemochromatosis Using Non-Invasive Liver Iron Concentration Measurement.

Newly diagnosed hereditary hemochromatosis subjects are treated with venesection therapy in order to reduce body iron stores. Liver iron concentration (LIC) is the most reliable indicator of body iron stores. Proton transverse relaxation rate imaging (FerriScan®) enables a highly specific and sensitive measurement of LIC [St. Pierre TG, Clark PR, Chuaanusorn W, Fleming A, Jeffrey GP, Olynyk JK, Pootrakul P, Robins E, Lindeman R. Blood 105 ( 2005) 855–861]. In this study FerriScan® was used to follow the LIC and liver volume in 7 newly diagnosed homozygous C282Y hereditary hemochromatosis patients. Baseline LIC values ranged from 3.4 to 16.7 mg Fe/g dry tissue. The total number of venesected units of blood required to lower the LIC of each subject to the upper end of the normal range was initially estimated from body mass and LIC [Angelucci, E., Brittenham, G.M., McLaren, C.E. et al. ( 2000) New Eng. J. Med. 343, 327–331]. The LIC of each subject was measured again after approximately half the estimated total number of units of blood had been removed, and a third time near completion of the venesection therapy. For each subject, a straight line was fitted to the LIC versus venesected blood volume data. The coefficient of variation of the differences between the measured LIC values and the fitted lines (a measure of the precision of the LIC measurements) was found to be 7 %. Total body iron stores were measured by extrapolating the straight line fit through the LIC vs venesected blood volume to zero LIC and using a value of 0.473 mg Fe/mL for the blood iron concentration. Total liver iron content was determined by simultaneous measurement of LIC and liver volume with MRI. The data indicated that the higher the LIC at diagnosis, the higher was the fraction, α, of the total body iron store located in the liver. Hence a linear model relating α to LIC is proposed, α = β x LIC + α0. Linear regression was used on the 21 measurements of LIC in the study to find the following optimum model parameters α0 = 0.169 and β = 0.0274 g wet liver/mg Fe. Using these parameters the total blood volume (TBV) to be removed from a patient to bring the LIC down from an initial value (LICi) to a target value (LICf) can be calculated using TBV = [(LICi – LICf) x V]/(β x LICi + α0) where V is the liver volume. Using the 21 measurements in this study a straight line relationship between measured and predicted numbers of units of blood to bring LIC to 1 mg Fe/g dry tissue was found to have slope 0.99 and Pearson's correlation coefficient of 0.97. The data suggest that simultaneous measurement of LIC and liver volume with MRI (data acquisition time less than 30 minutes) can be used to predict venesection requirements in hereditary hemochromatosis. The measurement of baseline LIC also enables an estimate of the possible visceral or metabolic consequences of the iron burden. For example, in the absence of other complicating factors, a measurement of the LIC multiplied by the age of the subject gives a good predictor of iron induced liver damage [Olynyk, J.K, St. Pierre, T.G., Britton, R.S., Brunt, E.M., and Bacon, B.R. ( 2005) Am. J. Gastro. , 100, 837–841].

Hemoglobin and Ferritin Are Currently the Most Efficient Indicators of Population Response to Iron Interventions: an Analysis of Nine Randomized Controlled Trials

Governments and donor agencies have implemented pilot and large-scale iron fortification programs, but there has been no consensus on the best choice of indicators to monitor population response to these interventions. We analyzed data from 9 randomized iron intervention trials to determine which of the following indicator(s) of iron status show the largest response in a population: hemoglobin (Hb), ferritin, transferrin receptor (TfR), zinc protoporphyrin (ZPP), mean cell volume (MCV), transferrin saturation (TS), and total body-iron store. We expressed the change in each indicator in response to the iron intervention in SD units (SDU) for the intervention group compared with the control group. Ferritin increased by > or =0.2 SDU in all trials and was significant in 7. Hb changed by > or =0.2 SDU in 6 and was significant in 5. TfR increased by > or =0.2 SDU in 5 of 8 interventions in which it was measured and was significant in 4. ZPP increased by > or =0.2 SDU and was significant in 3 of 6 interventions. Excluding Hb, the indicator with the largest change in SDU was ferritin in 4 trials, TS in 2 trials, body-iron store in 2 trials, and TfR in 1. In the 2 cases in which body-iron stores showed the largest change, the change in ferritin was nearly as large. Our results suggest that with currently available technologies, ferritin shows larger and more consistent response to iron interventions than ZPP or TfR. We cannot make confident inference about MCV or TS, which were included in only 4 and 2 trials, respectively. It is possible that the optimal indicator(s) may differ with age, sex, and pregnancy. There were too few trials in each age and sex group to allow us to explore this question.

Hemochromatosis Gene Mutations, Body Iron Stores, Dietary Iron, and Risk of Colorectal Adenoma in Women

Some experimental evidence suggests that iron may play a role in colorectal carcinogenesis, but human data for this role have been conflicting, possibly because of problems related to study design or measurement of iron exposure. We assessed dietary iron intake and genetic and biochemical markers of iron status in a prospective, nested case-control study of women enrolled in the Nurses' Health Study. Among 32 826 women who provided a blood specimen, we identified 527 women with colorectal adenoma and 527 matched control subjects who underwent endoscopy but were not diagnosed with adenoma after blood collection. We assessed iron intake, mutations in the HFE gene that are associated with hereditary hemochromatosis (i.e., H63D and C282Y), and plasma biochemical measures of total body iron, including transferrin saturation and the ratio of the concentrations of transferrin receptors to ferritin. Logistic regression models were used to estimate relative risks (RR) and 95% confidence intervals (CI). All statistical tests were two-sided. Women with any HFE gene mutation had higher total body iron stores, as reflected by higher transferrin saturations (P < .001) and lower levels of the ratio of transferrin receptors to ferritin (P = .02), than women with no HFE gene mutation. However, HFE gene mutations were not associated with risk of adenoma (multivariable RR = 1.08, 95% CI = 0.83 to 1.39; P = .58). Moreover, comparison of extreme categories showed no associations between adenoma and the extent of transferrin saturation (multivariable RR = 0.96, 95% CI = 0.63 to 1.47; Ptrend = .66), the ratio of transferrin receptors to ferritin (multivariable RR = 0.98, 95% CI, 0.60 to 1.60; Ptrend = .99), or dietary iron intake (multivariable RR = 1.04, 95% CI = 0.68 to 1.57; Ptrend = .94). Although our study used several distinct measures of iron status (i.e., genetic mutations, biochemical markers, and dietary intake) and a nested case-control design, we did not observe a role for iron in the pathogenesis of colorectal neoplasia in women.

Stored Iron and Vascular Reactivity

Zheng et al1 report that volunteer blood donors with a high donation frequency have significantly greater flow-mediated dilation than low frequency donors. Iron status among the frequent donors approximated a state of iron depletion by assessment of conventional iron markers. The study provides important support for the “iron hypothesis,” which suggests a protective effect of iron depletion, ie, the absence of storage iron without anemia, against ischemic heart disease.2–4 The blood donor findings suggest a new direction for the study of endothelial iron status in vivo to complement a growing body of work on iron in cultured endothelial cells. In addition, the finding of lower serum nitrotyrosine in frequent donors is consistent with the hypothesis that myeloperoxidase, a powerful emerging cardiovascular risk factor,5–8 is modifiable by manipulation of iron status. See page 1577 In cultured endothelial cells, iron status can be readily manipulated through the use of iron chelators or supplemental iron,9 or by altering the essential fatty acid composition of the culture medium.10 Use of these methods has identified several important effects of iron in endothelial activation and oxidative injury.9,11–20 But the in vitro approach does not define endothelial iron status in vivo, in particular what might represent a physiologically optimal range of endothelial iron concentrations. Iron status parameters such as serum ferritin are imperfect measures of total body iron stores and are likely to be even less adequate in assessing endothelial iron status. There is the additional uncertainty of differences in storage iron concentration in various cell types, even in situations in which total body iron status is well defined. An important premise of the study by Zheng et al1 is that body iron status within the conventionally defined normal range can influence endothelial iron status and endothelial function in vivo. …

Using histamine (H1) antagonists, in particular atypical antipsychotics, to treat anemia of chronic disease via interleukin-6 suppression

Anemia of chronic disease (ACD) is a condition of decreased red cell mass secondary to some other chronic inflammatory condition. In ACD total body iron stores are normal, though serum iron is typically low secondary to iron sequestration by macrophages, and often iron supplementation is not an effective treatment for ACD for the same reason. The pathogenesis of ACD had been poorly understood, but recently there has been important progress: upregulation of interleukin-6 (Il-6) secondary to the underlying chronic inflammatory disease upregulates expression of the protein hepcidin. Upregulation of hepcidin causes anemia by a number of mechanisms: decreased intestinal absorption of iron from the duodenum, increased sequestration of iron by macrophages. Thus, downregulation of Il-6 may represent a most important treatment avenue for ACD. Anti-Il-6 antibodies might be a way to lower Il-6 levels, but such antibodies besides being expensive would have to be given intravenously or intramuscularly, and such large immunogenic molecules may not be appropriate in patients already with a chronic inflammatory condition. Here, we note that an immediately available and potentially effective treatment for ACD is to decrease Il-6 levels by histamine (H1) receptor antagonism, given that histamine acting through the H1 receptor is known to be a potent positive regulator of Il-6. Among the classes of medications that are H1 antagonists we point out that atypical antipsychotic medications such as olanzapine and quetiapine are among the most potent H1 antagonists, and can have simple daily dosing schedules and thus may be particularly useful in ACD.

Iron deficiency anemia in children with exstrophy of the cloaca.

The clinical records of twenty-five children with exstrophy of the cloaca (EC) were retrospectively reviewed to evaluate the prevalence and the clinical characteristics of iron deficiency anemia (IDA). Five of the 25 children with EC (20 %) exhibited IDA at some point. Their ages at the time of diagnosis were between 1.9 and 13.0 years. In the four cases where IDA was thought to be related to iron malabsorption secondary to short-bowel syndrome, its treatment required longer periods of iron supplementation to correct the anemia and to restore the total body iron stores. Physicians caring for children with EC should monitor for and treat IDA as part of a comprehensive management plan.

Enzyme‐linked immunosorbent assay to quantitate serum ferritin in the northern fur seal (Callorhinus ursinus)

AbstractSerum ferritin concentration correlates with tissue iron stores in humans, horses, calves, dogs, cats, and pigs. Serum ferritin is considered the best serum analyte to predict total body iron stores in these species, and is more reliable than serum iron or total iron‐binding capacity, both of which may be affected by disorders unrelated to iron adequacy or excess (including hypoproteinemia, chronic infection, hemolytic anemia, hypothyroidism, renal disease, and drug administration). Iron overload has been documented to result in hemochromatosis in captive northern fur seals (Callorhinus ursinus); therefore, we developed an enzyme‐linked immunosorbent assay (ELISA) to measure serum ferritin in this species. The assay uses two murine anti‐canine ferritin monoclonal antibodies in a sandwich arrangement that was originally used in an ELISA to measure serum ferritin in dogs. Ferritin isolated from fur seal liver was used as a standard. Ferritin standards were linear from 0 to 50 ng/ml. Recovery of purified ferritin from fur seal serum varied from 89% to 99%. The within‐assay variability was 6%, and the assay‐to‐assay variability for two different samples was 10% and 16%. Zoo Biol 23:79‐84, 2004.© 2004 Wiley‐Liss, Inc.

Association between hemochromatosis (HFE) gene mutation carrier status and the risk of colon cancer.

Iron is a pro-oxidant that may promote carcinogenesis. Mutations in the hemochromatosis (HFE) gene are associated with increased total body iron stores in some individuals. We assessed the risk of colon cancer among individuals with and without HFE gene mutations. We performed a population-based, case-control study in North Carolina. Case patients with colon cancer and control subjects provided information on multiple environmental exposures, including total iron intake and nonsteroidal anti-inflammatory drug (NSAID) use. They also provided a venous blood sample, from which DNA was extracted, amplified, and subjected to diagnostic restriction enzyme mapping to detect two major HFE gene mutations, C282Y and H63D. Data were analyzed with Fisher's exact test and logistic regression. All statistical tests were two-sided. Thirteen hundred and eight subjects participated (475 case patients, 833 control subjects). The allele frequencies of the H63D and C282Y mutations were greater among case patients (0.11 and 0.046, respectively) than among control subjects (0.09 and 0.044, respectively; P =.14 and P =.85, respectively). When we controlled for age, race, sex, red meat consumption, NSAID use, and total iron intake, subjects with any HFE gene mutation were more likely to have colon cancer than subjects with no HFE gene mutations (adjusted odds ratio [OR] = 1.40, 95% confidence interval [CI] = 1.07 to 1.87). The magnitude of the effect was similar for both the H63D (adjusted OR = 1.44, 95% CI = 1.04 to 1.98) and C282Y mutations (adjusted OR = 1.39, 95% CI = 0.88 to 2.19). The risk of colon cancer associated with an HFE gene mutation was similar for those who did and did not have a family history of colon cancer. Among those with HFE mutations, cancer risk increased with increasing age and total iron intake. HFE gene mutations are associated with an increased risk of colon cancer. Cancer risk is greatest in mutation carriers who are older or consume high quantities of iron.

1049 Hepatic iron concentration and total body iron stores in genetic hemochromatosis and thalassemia major

1049 Hepatic iron concentration and total body iron stores in genetic hemochromatosis and thalassemia major

Relationship of Body Iron Stores to Levels of Serum Ferritin, Serum Iron, Unsaturated Iron Binding Capacity and Transferrin Saturation in Patients with Iron Storage Disease

None of the methods for assessing total body iron burden in patients with hemochromatosis is satisfactory. Although it is commonly believed that a relationship exists between serum ferritin levels and total iron burden, the extent of this relationship has not previously been documented. In the present investigation we measured the total body iron burden of 88 patients with putative hemochromatosis, 54 of whom were homozygotes for the 845G→A (C282Y) mutation. The total body iron stores were estimated from the volume of red cells removed during therapeutic phlebotomy corrected for an estimated 2 mg/day dietary iron absorbed during the phlebotomy period; the amount of storage iron was compared to the serum ferritin, serum iron, unsaturated iron binding capacity, and transferrin saturation before the beginning of phlebotomy. The serum ferritin proved to be the best predictor of body iron stores. The correlation between all of the analytes and the body iron burden was greater in patients homozygous for the C282Y mutation than in those who were not, including the compound heterozygotes for C282Y and H63D. The body iron burden tended to be greater in patients homozygous for the C282Y mutation than the other patients at any other given ferritin level. We conclude that the serum ferritin level does provide some information regarding total iron burden but even in the case of C282Y homozygotes, the correlation is not very strong.

Iron metabolism and requirements in early childhood: do we know enough?: a commentary by the ESPGHAN Committee on Nutrition.

*University of Lancashire, Lancashire, United Kingdom; †University of Milano, Milano, Italy; ‡University of Lund, Malmo, Sweden; §Hopital des Enfants Malades, Paris, France; Hopital Necker Enfants-Malades, Paris, France, ¶Umea University, Umea, Sweden; #University of Munich, Munich, Germany; **Free University of Amsterdam, Amsterdam, The Netherlands; ††Royal Veterinary and Agricultural University, Frederiksberg, Denmark; ‡‡CHUV University Hospital, Lausanne, Switzerland; §§University of Liege, Liege, Belgium; Medical University of Warsaw, Warsaw, Poland; and ¶¶University of Glasgow, Glasgow, United Kingdom

Consensus document for transfusion-related iron overload

B LOOD TRANSFUSION is a common treatment option in patients with sickle cell disease (SCD). Stroke and other sicklingrelated complications that are characteristic of the disease occur less frequently with blood transfusions and hence provide the rationale for the use of transfusion in treatment of patients with SCD. An adverse consequence of repeated blood transfusions in patients with SCD is transfusion-related iron overload, which ultimately results in end-organ damage caused by accumulation of excessive tissue iron. Management of iron overload involves two fundamental approaches. The first approach is to minimize iron uptake by more judicious use of transfusions or to use alternate technologies such as exchange transfusions (manual or erythrocytapheresis) to reduce the rate of total body iron buildup. The second approach is to use iron chelation therapy to reduce total body iron stores. A team of practitioners and researchers skilled in identification and management of transfusion-related iron overload in patients with SCD (or the thalassemias) held a 2-day conference, the goal of which was to provide guidelines for management of blood transfusion and transfusion-related iron overload in patients with SCD. The process included a series of presentations, which are published in this supplement. The discussions included the use of blood transfusions in patients with SCD, blood product use, administration techniques, assessment of iron overload, alternative methods for assessing total body iron stores, management options for iron overload, and chelation therapy compliance. This document summarizes several areas of consensus for treatment guidelines; however, some issues remain controversial and are discussed in the individual presentations in this supplement. These issues still need further research before overall consensus can be reached.