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Concept: Transferrin

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Anemia often complicates the course of Inflammatory Bowel Disease (IBD). Hepcidin, a liver-produced peptide hormone, is a key mediator of anemia of chronic disease (ACD). We hypothesized that hepcidin is significantly elevated in anemic CD patients and that hepcidin may cause iron restriction and, therefore, mediate ACD. METHODS: We enrolled 17 patients with CD and ACD recruited from the Cedars-Sinai IBD Center. Routine blood tests included hemoglobin (Hgb), hematocrit, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Anemia was defined as hemoglobin <12g/dL and <13.5g/dL, in men and women, respectively. ACD was diagnosed on the basis of a combination of the following: a) normal or elevated ferritin b) lowered serum iron and total iron binding capacity and c) normal percent iron saturation. Serum and urine hepcidin, as well as IL-6 levels were also measured. Patients with documented iron-deficiency anemia were excluded. RESULTS: There was an excellent correlation between urine (expressed as ng/mg of creatinine) and serum hepcidin levels expressed as ng/ml (r=0.853, p<0.001). We also found a strong positive correlation between serum hepcidin and ferritin levels (r=0.723, p=0.0015). There was a positive correlation between serum hepcidin and IL-6 levels (r=0.546, p=0.023). We found a strong negative correlation between serum hepcidin concentrations and Hgb levels (r=0.528, p=0.029). CONCLUSION: We demonstrate that ACD in CD is characterized by high serum IL-6 and hepcidin levels, which negatively correlate with Hgb levels. Our data support the hypothesis that IL-6-driven hepcidin production mediates ACD in patients with CD.

Concepts: Hemoglobin, Red blood cell, Anemia, Inflammatory bowel disease, Iron deficiency anemia, Transferrin, Ferritin, Total iron-binding capacity

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OBJECTIVES: To evaluate in a large, nationally representative cohort the association between high serum transferrin saturation (TS) and hospital length of stay and mortality in older adults. DESIGN: Prospective cohort. SETTING: Longitudinal analyses of the Third National Health and Nutrition Examination Survey linked to Medicare claims from 1991 through 2006. PARTICIPANTS: Medicare beneficiaries aged 65 and older at baseline. MEASUREMENTS: Transferrin saturation collected on each participant at baseline was characterized as <20.0%, 20.0% to 54.9%, and 55.0% and greater. Length of stay in the hospital and death in the hospital were primary outcomes. Analyses were adjusted for age, sex, race and ethnicity, education, and severity of illness. RESULTS: Individuals hospitalized during the study period (79.4%) with high (odds ratio (OR) = 2.54, 95% confidence interval (CI) = 1.05-6.12) or low (OR = 1.31, 95% CI = 1.07-1.62) TS had a significantly greater risk of death than those with moderate TS. Individuals with high TS had longer average length of stay per hospitalization (11.1 days, (standard error, SE 1.7 days), P = .01) than those with moderate TS (8.4 (0.3) days). Individuals with high TS also had more hospital days per year (8.6 (2.0) days, P = .04) than those with moderate TS (6.7 (0.5) days). CONCLUSION: High TS is associated with longer length of stay and death in the hospital (unweighted N = 3,847, weighted N = 28,395,464).

Concepts: Epidemiology, Death, Hospital, Gerontology, Ageing, Normal distribution, Transferrin, Transferrin saturation

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Abstract Anemia is a global health issue with disproportionately high prevalence in women. In addition to being an independent risk factor for decreased quality of life and increased morbidity and mortality, anemia in women has been linked to unfavorable outcomes of pregnancy and other issues for children born to anemic women. Iron deficiency is the leading cause of anemia in many populations. Guidelines recommend proactive screening for anemia, particularly in the preoperative setting. Once anemia is diagnosed, treatment should be based on etiology (most commonly, iron deficiency followed, in order of prevalence, by inflammation or chronic disease). Iron supplementation (oral and intravenous) offers safe and effective treatment for anemia associated with iron deficiency. Anemia of chronic disease may be more challenging to treat, and attention must be given to the underlying disease, along with use of hematinic agents. Given its enormous impact on the health and well-being of women and the availability of simple and effective treatment options, anemia should never be left unmanaged.

Concepts: Hemoglobin, Medicine, Epidemiology, Anemia, Iron deficiency anemia, Transferrin, Human iron metabolism, Microcytic anemia

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Highly proliferative cells have a dramatically increased need for iron which results in the expression of an increased number of transferrin receptors (TFR). This insight makes the transferrin receptor on these cells an excellent candidate for targeted therapeutics. In this regard, it is critical to understand at a molecular level exactly how the TFR interacts with its ligand, hTF. Understanding of the hTF/TFR pathway could, in theory, maximize the use of this system for development of more effective small molecules or toxin-conjugates to specifically target cancer cells. Many strategies have been attempted with the objective of utilizing the hTF/TFR system to deliver drugs; these include conjugation of a toxin or drug to hTF or direct targeting of the TFR by antibodies. To date, in spite of all of the effort, there is a conspicuous absence of any successful candidate drugs reaching the clinic. We suggest that a lack of quantitative data to determine the basic biochemical properties of the drug carrier and the effects of drug-conjugation on the hTF-TFR interaction may have contributed to the failure to realize the full potential of this system. This review provides some guidelines for developing a more quantitative approach for evaluation of current and future hTF-drug conjugates.

Concepts: Protein, Molecular biology, Hormone, Receptor, Cell signaling, Receptor antagonist, Transferrin, Transferrin receptor

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Two reference measurement procedures are presented here that allow the determination of the iron saturation in human transferrin, based on different molecular properties. The results, directly derived from the number of ions bound to the protein molecule, are traceable to the SI. Up to now, the iron saturation has only been deduced indirectly from the amount-of-substance ratio of serum iron to transferrin in serum. Interlaboratory tests have shown the need for more accurate methods, as the results from many participant test samples for both parameters do not lie within the acceptable range of deviation given by relevant guidelines when different methods or kits are applied. Using isotope dilution, an HPLC ICP-MS procedure was developed in compliance with the requirements of a primary reference measurement procedure. In this manner, the iron saturation was measured with an associated relative expanded measurement uncertainty of 4%. Based on the results, a straightforward Raman procedure was evolved, which allows the determination of the iron saturation in transferrin with an associated relative expanded uncertainty of 7%.

Concepts: Oxygen, Measurement, Metrology, Test method, Uncertainty, Transferrin, Transferrin saturation, Total iron-binding capacity

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Background: Evidence shows that iron deficiency in adulthood may affect cognitive performance, possibly by disrupting neurotransmitter regulation or brain energy metabolism. Women of reproductive age (WRA) are among those who are most vulnerable to iron deficiency; however, they have been largely ignored in the literature relating iron status to cognition.Objective: Our aim was to determine the efficacy of iron-biofortified beans in improving cognition in WRA compared with control beans.Methods: A double-blind, randomized intervention study was conducted in 150 women aged 18-27 y with low iron status (ferritin <20 μg/L). Women were randomly assigned to consume iron-biofortified beans (86.1 ppm iron) or control beans (50.1 ppm iron) daily for 18 wk. Iron status was assessed based on hemoglobin, ferritin, transferrin receptor, and body iron values and on cognitive performance on 5 computerized tasks at baseline and endline.Results: Groups did not differ on any variables at baseline. Per protocol analyses revealed that consumption of the biofortified beans resulted in a 17% larger improvement in the speed of spatial selective attention; a nearly 7-fold larger improvement in the speed, a 68% greater improvement in the efficiency, and a >2-fold greater improvement in the specificity of memory retrieval; and a >2-fold larger improvement in the speed and a >3-fold larger improvement in the efficiency of memory search-all of which are relative to consumption of the control beans (P < 0.01 for all comparisons).Conclusions: Cognitive performance is sensitive to iron status, and consumption of iron-biofortified beans for 18 wk improved cognitive performance, especially the efficiency of search and the speed of retrieval on memory tasks, in young adult women. This trial was registered at clinicaltrials.gov as NCT01594359.

Concepts: Better, Hemoglobin, Psychology, Improve, Iron, Attention, Iron deficiency anemia, Transferrin

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BACKGROUND & AIMS: Celiac disease is an increasingly recognized disorder in Caucasian populations of European origin. Little is known about its prevalence in non-Caucasians. Although it is thought to be a cause of iron deficiency anemia, little is known about the extent to which celiac disease contributes to iron deficiency in Caucasians, and especially non-Caucasians. We analyzed samples collected from participants in the Hemochromatosis and Iron Overload Screening (HEIRS) study to identify individuals with iron deficiency and assess the frequency of celiac disease. METHODS: We analyzed serum samples from white men (25 y old or older) and women (50 y old or older) who participated the HEIRS study; cases were defined as individuals with iron deficiency (serum level of ferritin ≤12 mg/L) and controls were those without (serum level of ferritin >100 mg/L in men and >50 mg/L in women). All samples were also analyzed for human recombinant tissue transglutaminase immunoglobulin A; positive results were confirmed by an assay for endomysial antibodies. Patients with positive results from both celiac disease tests were presumed to have untreated celiac disease, and those with a positive result from only 1 test were excluded from analysis. We analyzed HLA genotypes and frequencies of celiac disease between Caucasians and non-Caucasians with iron deficiency. RESULTS: Celiac disease occurred in 14 of 567 of cases (2.5%) and in only 1 of 1136 controls (0.1%; Fisher’s exact test, P=1.92 10(-6)). Celiac disease was more common in Caucasian cases (14/363, 4%) than non-Caucasian cases (0/204; P=.003). Only 1 Caucasian control and no non-Caucasian controls had celiac disease. The odds of celiac disease in individuals with iron deficiency was 28-fold (95% confidence interval, 3.7-212.8) that of controls; 13/14 cases with celiac disease carried the DQ2.5 variant of the HLA genotype. CONCLUSIONS: Celiac disease is associated with iron deficiency of Caucasians. Celiac disease is rare among non-Caucasians-even among individuals with features of celiac disease, such as iron deficiency. Celiac disease is also rare among individuals without iron deficiency. Men and post-menopausal women with iron deficiency should be tested for celiac disease.

Concepts: Hemoglobin, Iron, Iron deficiency anemia, Coeliac disease, Transferrin, Human iron metabolism, Fisher's exact test, Exact test

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Background. Unbound iron binding capacity (UIBC) in serum, which is s-total iron binding capacity (2 times s- transferrin) minus s-iron, may be a more accurate marker of empty iron stores than serum transferrin saturation. Previously we have shown this for healthy females of childbearing age. Methods. Now we used receiver operating characteristic (ROC) curve analysis to compare the diagnostic accuracy of s-iron, s-transferrin, s-transferrin saturation and s-UIBC in diagnosing empty iron stores in 29,251 female and 19,652 male outpatients. Empty iron stores were defined as s-ferritin less than 10, 15 or 20 μg/L. Results. At all definitions of empty iron stores s-UIBC had a better diagnostic accuracy than the other tests in both male and female outpatients, with an area under the ROC curve of 0.85-0.97. Also in subpopulations with elevated s-CRP or low b-hemoglobin s-UIBC was more accurate than the other tests. All tests performed better in males than in females, and generally they were more accurate in adults than in children. Conclusion. When diagnosing empty iron stores calculation of s-UIBC is a better way to utilize the information in s-iron and s-transferrin than the calculation of s-transferrin saturation.

Concepts: Male, Female, Receiver operating characteristic, Transferrin, Transferrin saturation, Serum iron, Total iron-binding capacity

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Background: Studies on benefits of intravenous iron therapy among hemodialysis patients with functional iron deficiency anemia have shown conflicting results. We conducted a meta-analysis to assess the efficacy and safety of intravenous iron in this subset of patients. Methods: We searched MEDLINE (through December 2012), the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov for single-arm studies and randomized controlled trials (RCT) that examined the effect of intravenous iron for functional iron deficiency anemia in hemodialysis patients on anemia parameters and markers of oxidative stress and inflammation. Studies of absolute iron deficiency were excluded. Random-effect model meta-analyses were used to compute changes in outcomes of interest. Results: We identified 34 studies (2,658 patients), representing 24 single-arm studies, and 10 parallel-arm RCT. In the analyses of the study arms, intravenous iron therapy resulted in a significant increase in hemoglobin, serum ferritin, transferrin saturation rate, serum iron, reticulocyte hemoglobin content as well as a significant decrease in the percentage of hypochromic erythrocytes and erythropoietin dose. There were significant increases in plasma malonyldialdehyde level and thiobarbituric acid-reactive substances, and a decrease in neutrophil respiratory burst. The analyses of the RCT revealed less robust net changes in these parameters, and there was no increased risk of adverse events including infections, cardiac events and mortality. Conclusions: Intravenous iron therapy for functional iron deficiency anemia in hemodialysis patients improves anemia parameters but exerts some effects on markers of oxidative stress that are of unclear clinical significance. The long-term safety and efficacy of this treatment strategy requires further study. © 2014 S. Karger AG, Basel.

Concepts: Hemoglobin, Iron, Randomized controlled trial, Anemia, Iron deficiency anemia, Transferrin, Iron deficiency, Serum iron

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Sodium iron chlorophyllin (SIC), a water-soluble chlorophyll derivative, has been used as a food additive for green coloration. In the present study, a subchronic toxicity study of SIC was performed in male and female F344 rats with oral administration in diet at concentrations of 0%, 0.2%, 1.0%, and 5.0% for 13 weeks. No mortalities, abnormal clinical signs, and hematological changes were observed in any of the groups during the experiment. Significant reduction of body weight gain was noted in 5.0% males. In serum biochemistry, serum transferrin levels were significantly increased in 5.0% males and females. Relative spleen weights of both sexes were markedly reduced with 5.0% SIC as compared to the controls, and absolute weights of spleen were also significantly decreased in males. On histopathological assessment, diffuse hypertrophy of acinar cells in the parotid gland was observed in all examined 5.0% males and females, but not in the other groups. Based on the histopathology of the parotid glands, the no-observed-adverse-effect level (NOAEL) of SIC in the present study was estimated to be 1.0% (609 mg/kg bw/day for males and 678 mg/kg bw/day for females).

Concepts: Male, Female, Iron, Pancreas, Gender, Sex, Gamete, Transferrin