Iron Abstracts 1

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Hypersegmented neutrophilic granulocytes in iron deficiency anaemia

         (Beard and Weintraub 1969) Download

Apparent folate deficiency in iron-deficiency anaemia

         (Roberts, St John et al. 1971) Download

Associations of iron metabolism genes with blood manganese levels: a population-based study with validation data from animal models

         (Claus Henn, Kim et al. 2011) Download

BACKGROUND: Given mounting evidence for adverse effects from excess manganese exposure, it is critical to understand host factors, such as genetics, that affect manganese metabolism. METHODS: Archived blood samples, collected from 332 Mexican women at delivery, were analyzed for manganese. We evaluated associations of manganese with functional variants in three candidate iron metabolism genes: HFE [hemochromatosis], TF [transferrin], and ALAD [delta-aminolevulinic acid dehydratase]. We used a knockout mouse model to parallel our significant results as a novel method of validating the observed associations between genotype and blood manganese in our epidemiologic data. RESULTS: Percentage of participants carrying at least one copy of HFE C282Y, HFE H63D, TF P570S, and ALAD K59N variant alleles was 2.4%, 17.7%, 20.1%, and 6.4%, respectively. Percentage carrying at least one copy of either C282Y or H63D allele in HFE gene was 19.6%. Geometric mean (geometric standard deviation) manganese concentrations were 17.0 (1.5) mug/l. Women with any HFE variant allele had 12% lower blood manganese concentrations than women with no variant alleles (beta = -0.12 [95% CI = -0.23 to -0.01]). TF and ALAD variants were not significant predictors of blood manganese. In animal models, Hfe(-/-) mice displayed a significant reduction in blood manganese compared with Hfe(+/+) mice, replicating the altered manganese metabolism found in our human research. CONCLUSIONS: Our study suggests that genetic variants in iron metabolism genes may contribute to variability in manganese exposure by affecting manganese absorption, distribution, or excretion. Genetic background may be critical to consider in studies that rely on environmental manganese measurements.

Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases

         (Kell 2009) Download

BACKGROUND: The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular 'reactive oxygen species' (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. REVIEW: We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation).The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible.This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, since in some circumstances (especially the presence of poorly liganded iron) molecules that are nominally antioxidants can actually act as pro-oxidants. The reduction of redox stress thus requires suitable levels of both antioxidants and effective iron chelators. Some polyphenolic antioxidants may serve both roles.Understanding the exact speciation and liganding of iron in all its states is thus crucial to separating its various pro- and anti-inflammatory activities. Redox stress, innate immunity and pro- (and some anti-)inflammatory cytokines are linked in particular via signalling pathways involving NF-kappaB and p38, with the oxidative roles of iron here seemingly involved upstream of the IkappaB kinase (IKK) reaction. In a number of cases it is possible to identify mechanisms by which ROSs and poorly liganded iron act synergistically and autocatalytically, leading to 'runaway' reactions that are hard to control unless one tackles multiple sites of action simultaneously. Some molecules such as statins and erythropoietin, not traditionally associated with anti-inflammatory activity, do indeed have 'pleiotropic' anti-inflammatory effects that may be of benefit here. CONCLUSION: Overall we argue, by synthesising a widely dispersed literature, that the role of poorly liganded iron has been rather underappreciated in the past, and that in combination with peroxide and superoxide its activity underpins the behaviour of a great many physiological processes that degrade over time. Understanding these requires an integrative, systems-level approach that may lead to novel therapeutic targets.

Blood manganese concentration is elevated in iron deficiency anemia patients, whereas globus pallidus signal intensity is minimally affected

         (Kim, Park et al. 2005) Download

OBJECTIVES: To determine whether blood manganese (Mn) concentration is elevated in patients with iron deficiency anemia (IDA), and whether this affects signal intensities in the globus pallidus. METHODS: Twenty-seven patients with IDA and 10 control subjects were tested for blood Mn, and brain magnetic resonance images (MRI) were also examined. Seventeen of the 27 patients were followed-up after iron therapy. RESULTS: IDA patients had a mean blood Mn concentration of 2.05 +/- 0.44 microg/dl, which was higher than controls. The mean pallidal index (PI) of anemic patients was not different from that of controls. There was a correlation between log blood Mn and PI (rho = 0.384, P = 0.048; n = 27) in IDA patients. None of the patients showed increased signals in the globus pallidus in T1-weighted MRI. Blood Mn levels decreased and hemoglobin levels increased after iron therapy (P < 0.05). CONCLUSION: Although blood Mn is elevated in IDA patients, there is no increase in globus pallidus MRI signal intensity. These findings stand in contrast to those of our other studies showing patients with chronic liver disease or occupational Mn exposure have elevated signal intensities remarkably.


References

Beard, M. E. and L. R. Weintraub (1969). "Hypersegmented neutrophilic granulocytes in iron deficiency anaemia." Br J Haematol 16(1): 161-3. [PMID: 5795207]

Claus Henn, B., J. Kim, et al. (2011). "Associations of iron metabolism genes with blood manganese levels: a population-based study with validation data from animal models." Environ Health 10: 97. [PMID: 22074419]

Kell, D. B. (2009). "Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases." BMC Med Genomics 2: 2. [PMID: 19133145]

Kim, Y., J. K. Park, et al. (2005). "Blood manganese concentration is elevated in iron deficiency anemia patients, whereas globus pallidus signal intensity is minimally affected." Neurotoxicology 26(1): 107-11. [PMID: 15527878]

Roberts, P. D., D. J. St John, et al. (1971). "Apparent folate deficiency in iron-deficiency anaemia." Br J Haematol 20(2): 165-76. [PMID: 5548484]