Effects of iron deficiency and iron overload on manganese uptake and deposition in the brain and other organs of the rat

Manganese (Mn) is an essential trace element at low concentrations, but at higher concentrations is neurotoxic. It has several chemical and biochemical properties similar to iron (Fe), and there is evidence of metabolic interaction between the two metals, particularly at the level of absorption from the intestine. The aim of this investigation was to determine whether Mn and Fe interact during the processes involved in uptake from the plasma by the brain and other organs of the rat. Dams were fed control (70 mg Fe/kg), Fe-deficient (5-10 mg Fe/kg), or Fe-loaded (20 g carbonyl Fe/kg) diets, with or without Mn-loaded drinking water (2 g Mn/L), from day 18-19 of pregnancy, and, after weaning the young rats, were continued on the same dietary regimens. Measurements of brain, liver, and kidney Mn and nonheme Fe levels, and the uptake of 54Mn and 59Fe from the plasma by these organs and the femurs, were made when the rats were aged 15 and 63 d. Organ nonheme Fe levels were much higher than Mn levels, and in the liver and kidney increased much more with Fe loading than did Mn levels with Mn loading. However, in the brain the increases were greater for Mn. Both Fe depletion and loading led to increased brain Mn concentrations in the 15-d/rats, while Fe loading also had this effect at 63 d. Mn loading did not have significant effects on the nonheme Fe concentrations. 54Mn, injected as MnCl2 mixed with serum, was cleared more rapidly from the circulation than was 59Fe, injected in the form of diferric transferrin. In the 15-d-rats, the uptake of 54Mn by brain, liver, kidneys, and femurs was increased by Fe loading, but this was not seen in the 63-d rats. Mn supplementation led to increased 59Fe uptake by the brain, liver, and kidneys of the rats fed the control and Fe-deficient diets, but not in the Fe-loaded rats. It is concluded that Mn and Fe interact during transfer from the plasma to the brain and other organs and that this interaction is synergistic rather than competitive in nature. Hence, excessive intake of Fe plus Mn may accentuate the risk of tissue damage caused by one metal alone, particularly in the brain.     

Newly recognized causes of atherosclerosis: the role of microorganisms and of vascular iron overload

We have hypothesized that shear stresses at sites of increased vascular turbulence may foster atherogenesis by two previously unknown mechanisms: The first involves Herpes virus activation, which can provoke direct or inflammatory cell-mediated endothelial damage while altering the vascular surface to a highly procoagulant entity. The second derives from red blood cell fragmentation, with resulting uptake by endothelium of released heme groups. In this instance the opening of the heme ring by induced endothelial heme oxygenase frees iron, which sensitizes cells to damage by oxidants--for instance, those generated by closely apposed inflammatory cells. An additional injurious effect of released heme results from its potent catalysis of LDL oxidation--a process specifically and rapidly inhibited by oral supplementation of vitamin E. Although heme-protein's deleterious actions can be counteracted by the plasma constituents haptoglobin and hemopexin, we suggest that these may not be sufficiently present in "sanctuary" sites of vessel walls such as in intramural hemorrhages associated with atherosclerotic intimal tears.     

Hyperferritinaemia in the absence of iron overload

We present a case of a 3-month-old boy presenting with fulminating meningococcal septicaemia associated with extensive peripheral gangrene requiring amputation of three limbs. The surgical management options and the role of early fasciotomy are discussed.     

Clinical management of iron overload

HHC is a common inherited disorder, characterized by iron accumulation in the liver, heart, pancreas, and other organs. The clinical consequences of systemic iron loading are diverse and not always improved with iron reduction therapy. The most important prognostic factor at the time of diagnosis is the presence or absence of hepatic fibrosis or cirrhosis. Those without significant hepatic fibrosis may be expected to have a normal life expectancy with phlebotomy therapy. The availability of genetic testing for HHC has significantly changed the diagnostic approach to this disorder. Although liver biopsy remains vital to determining prognosis, genetic testing is increasingly used in the diagnosis and family screening of patients with HHC.     

Hepatocellular carcinoma and African iron overload

Both hepatocellular carcinoma (HCC) and iron overload are important health problems in Africa. Chronic hepatitis B virus (HBV) infection is recognised as a major risk factor for HCC, but iron overload in Africans has not been considered in pathogenesis. Up to half the patients with HCC in Africa do not have any recognised risk factors such as preceding chronic HBV infection, and other risk factors remain unidentified. HCC is an important complication of HLA-linked haemochromatosis, an iron loading disorder found in Europeans. It is proposed that African iron overload might also be a risk factor for HCC.     

Tuberculosis and iron overload in Africa: a review

Both pulmonary tuberculosis and dietary iron overload are common conditions in sub-Saharan Africa. The incidence of tuberculosis has increased markedly over the last decade, primarily as a result of the rapid spread of infection with the human immunodeficiency virus (HIV). Dietary iron overload affects up to 10% of adults in rural populations and is characterized by heavy iron deposition both in parenchymal cells and in macrophages. Mycobacterium tuberculosis grows within macrophages and, at the same time, the antimicrobial function of macrophages is important in the body's defence against tuberculosis. In vitro, the loading of macrophages with iron reduces the response of these cells to activation by interferon-gamma and diminishes their toxicity against micro-organisms. In the clinical setting, dietary iron overload appears to increase the risk for death from tuberculosis even in the absence of the acquired immunodeficiency syndrome. The combination of dietary iron overload and infection with the HIV, with impaired function of both macrophages and T-cells, may make patients especially vulnerable to tuberculosis. It is possible that the prevention and treatment of dietary iron overload could contribute to the control of tuberculosis in African populations.     

Effect of blood letting on serum aminotransferase levels of patients with chronic hepatitis C and iron overload

We found in the Ca2+ channel alpha1C subunit gene a new repetitive element of three paired exon 45/46-related sequences. We also identified a new exon 45/46-related sequence in the human genome and mapped it by fluorescence in situ hybridization to the 12p11.2 and 12p13.2-p13.1 bands. These positions are not recognized by DNA probes generated from the 5'- and 3'-terminal regions of the alpha1C gene. A possible existence of a new genomic homologue of the alpha1C subunit gene is discussed.     

Chronic iron overload in rats induces oval cells in the liver

The frequency of bcl-2 protein expression was evaluated using immunocytochemical staining during the progression of human and rat prostate cancer from an androgen-sensitive nonmetastatic to an androgen-independent metastatic phenotype. Previous studies (A. S. Shabaik et al., J. Urol. Pathol., 3: 17-27, 1995) demonstrated that 0 of 20 high-grade prostatic intraepithelial neoplasias and only 3 (7%) of 41 pathologically localized stage B human prostatic cancers had detectable bcl-2 staining. In the present study, 5 (17%) of 30 lymph node metastases from pathologically disseminated D1 disease and 14 (52%) of 27 bone metastases from pathologically disseminated D2 disease expressed detectable bcl-2 protein. These data demonstrate that there is a statistically significant (P < 0.05) association between expression of bcl-2 and the progression of human prostatic cancer cells to a metastatic phenotype. Such bcl-2 expression is not absolutely required, however, for either androgen independence or metastatic ability by human prostatic cancer cells. Likewise, within a series of eight distinct Dunning R3327 rat prostatic cancer sublines, which differ widely in their progressional state, there is also a significant association (P < 0. 05) between bcl-2 expression and progression (four of six androgen-independent rat sublines expressed bcl-2 protein). Again in this rodent system, bcl-2 expression is not an absolute requirement for either androgen independence or metastatic ability. For example, the androgen-independent highly metastatic Dunning AT-3 subline, while expressing bax protein, does not express bcl-2 protein. If such AT-3 cells are genetically engineered to express bcl-2, these expressing cells are now cross-resistant to a variety of mechanistically diverse noxious insults (e.g., viral infection or exposure to antimetabolites, alkylating agents, or agents which elevate the intracellular free Ca2+). The ability of bcl-2 to inhibit the programmed death of AT-3 cells induced by these agents involves a late step in the death process, since the early induction of expression of a series of genes associated with apoptosis is not impaired by bcl-2 expression. These data demonstrate that the development of androgen independence and/or metastatic ability can be associated with the expression of bcl-2 protein but that bcl-2-independent mechanisms also exist for such progression.     

Dietary conjugated linoleic acid reduces plasma lipoproteins and early aortic atherosclerosis in hypercholesterolemic hamsters

Conjugated linoleic acid is a collective term used to designate a mixture of positional and geometric isomers of linoleic acid in which the double bonds are conjugated. Unlike linoleic acid, there is a paucity of information regarding the effect of dietary conjugated linoleic acid on plasma lipoproteins and aortic atherosclerosis. Therefore, fifty hamsters were divided into five groups of ten and fed 0 (Control), 0.06 (LOW), 0.11 (MEDIUM), and 1.1 (HIGH) en% conjugated linoleic acid or 1.1 en% linoleic acid. Blood samples were taken at 4, 8 and 11 weeks for plasma lipid analyses and for plasma tocopherol assay at sacrifice. Animals fed the conjugated linoleic acid-containing diets collectively had significantly reduced levels of plasma total cholesterol, non-high density lipoprotein cholesterol, (combined very low and low density lipoprotein) and triglycerides with no effect on high density lipoprotein cholesterol, as compared to CONTROLs. Linoleic acid-fed animals relative to CONTROLs also had reduced plasma total cholesterol, non-high density lipoprotein cholesterol and triglycerides, but only the latter was statistically significant. Compared to the CONTROL group, plasma tocopherol/total cholesterol ratios determined from plasma pools for the LOW, MEDIUM and HIGH conjugated linoleic acid and linoleic acid groups were increased by 48%, 48%, 86% and 29%, respectively, suggesting a tocopherol-sparing effect, at least for the conjugated linoleic acid treatment. Morphometric analysis of aortas revealed less early atherosclerosis in the conjugated linoleic acid and linoleic acid-fed hamsters compared to the CONTROL group.     

Iron-manganese interactions in the evolution of iron deficiency

Since the publication of prior reviews on this topic, substantial clinical experience with a variety of operative strategies to prevent ischaemic cord complications has been reported. The available data on angiographic localisation of critical intercostal vessels, and, in particular, the evoked potential response to cross-clamping in patients indicates that risk of paraplegia varies considerably even among patients with equivalent TAA extent. Factors such as individual development of the ASA, patent critical intercostals, and the particulars of collateral circulation when intercostal aortic ostia are already occluded likely account for this variability. Information available from SSEP monitoring relative to the dynamic course of cord ischaemia with cross-clamping, and the parallel, if not, frustrating experience with angiographic localisation and intercostal vessel reconstruction indicates that a narrow temporal threshold of cord ischaemia with clamping is present in many patients. This reinforces the importance of both expeditious clamp intervals, critical intercostal re-anastomoses, and the desirability of neuroprotective manoeuvres during cross-clamp induced cord ischemia. As suggested in compelling experimental work our contemporary clinical experience, and predicted by prior reviewers, regional cord hypothermia provides significant promise for limiting or eliminating, in particular, immediate perioperative deficits. Avoidance of postoperative hypotension, spinal cord oedema, and preservation of critical intercostal vessels are additional strategies necessary to impact the development of delayed deficits favourably.     

MRI appearances of fascioliasis complicating liver iron overload

A case of hepatic fascioliasis with an unusual appearance on MRI due to liver iron overload is presented. The diagnosis of fascioliasis was based on positive serological tests and the presence of eggs in the bile. Hepatic lesions of fascioliasis exhibited hyperintense signals on T1 weighted images as well as proton density and T2 weighted images. Histological study of biopsy specimens from the lesions showed central necrosis and peripheral fibrosis with inflammatory cells including eosinophils. Abundant iron deposition in hepatocytes and Kupffer cells was found in specimens from the surrounding liver. These findings suggested that this appearance on MR images was probably due to a decrease in signal intensity in surrounding liver.     

The frequency and development of tissue iron deficiency in 6 iron deficiency anemia patients with plummer-vinson syndrome

The physical signs of tissue iron deficiency include smooth and red tongue, angular stomatitis, koilonychia, and pica. The incidence of these conditions is unknown in Japan. We evaluated the frequency and development of tissue iron deficiency in 353 patients with iron deficiency anemia. The frequency of tissue iron deficiency was 6.8%; papillary atrophy of the tongue, 5.4%; abnormal nails, 5.4%; angular stomatitis, 1.1%; Plummer-Vinson syndrome, 1.7%; and pica, 0.06%. These findings were compared with the date collected by Wintrobe and Beveridge. The development and incidence of tissue iron deficiency correlated significantly with the severity of iron deficiency anemia.     

Iron overload in the rat pancreas following portacaval shunting and dietary iron supplementation

Reproduction of pancreatic iron overload in an animal model has been difficult to achieve primarily because of the first-pass extraction of iron by the liver. We hypothesized that portacaval shunting would avoid this hepatic phenomenon and increase pancreatic iron deposition. An end-to-side portacaval shunt was surgically created in male Sprague-Dawley rats, and they were subsequently fed a carbonyl iron-supplemented diet for 17 weeks. This resulted in marked iron accumulation in the pancreas (1621 +/- 188 micrograms/g) compared to minimal deposition in sham-operated rats fed the same diet (138 +/- 53 micrograms/g). Iron deposition in the acinar and centroacinar cells was confirmed histologically by Gomori staining, as well as by ultrastructural examination. Iron overloading was associated with enhanced oxidative stress evidenced by a twofold increase in the levels of glutathione disulfide and thiobarbituric acid-reactive substances. Also, adducts of proteins with malondialdehyde and 4-hydroxynonenal were demonstrated in acinar and ductal cells. Other apparent consequences of iron overload were a 50% reduction in pancreatic amylase content and a decrease in pancreatic protein concentration. These hypotrophic changes were associated with a reduced mass of zymogen granules in the acinar cells noted histologically. Our results show that a combination of portacaval shunting and carbonyl iron feeding achieve pancreatic iron overload and support the role of oxidative stress in the pathogenesis of iron-induced damage in the pancreas.     

The effect of low-dose aspirin and dipyridamole upon atherosclerosis in the rabbit

To examine the effect of antiplatelet therapy upon atherosclerosis in an animal model, aspirin and dipyridamole were administered to female New Zealand rabbits while they were fed a 2% cholesterol diet. Four experimental groups of 15 animals were established: Group I (Control), no medication; Group II, aspirin, 40 mg orally five days a week; Group III, dipyridamole, 25 mg orally five days a week; Group IV, aspirin and dipyridamole. After seven weeks, the animals were sacrificed and their aortas were removed and stained. Group means of the percentage of total aortic lumenal surface occupied by gross atheromata were calculated and statistically compared with the control group mean: Group I - 49%, Group II 36%, p = NS, Group III - 47%, Group IV - 25%, p less than .01. Histologic sections of each aorta confirmed the stained areas to be atheromata of varying complexity. The lesions in animals treated with dipyridamole alone exhibited a distinct increase in smooth muscle cell proliferation. For animals receiving a combination of aspirin and dipyridamole the lesions were smaller and less advanced than those in the control group. These findings indicate that experimental atherosclerosis in rabbits is modified by the administration of anti-platelet agents and that atheroma formation is significantly inhibited when aspirin and dipyridamole are given in combination.