Altered Iron Status Research Articles

Hemochromatosis gene mutations, liver function tests and iron status in alcohol‐dependent patients admitted for detoxification

Screening of target populations for hemochromatosis (HFE) gene allele status has been recommended. Alcoholic liver disease may be associated with iron overload and there is evidence of excessive alcohol consumption among patients with hereditary hemochromatosis. This study determined the HFE gene allele status in alcohol-dependent patients and explored the associations between iron status, liver enzymes, and HFE status. A total of 151 consecutive patients admitted for alcohol detoxification were tested for HFE mutations, iron status, and liver function tests. The prevalence data were compared with those from a New Zealand population. manova was used to compare liver function tests and iron status for subjects with different HFE mutations. Three compound heterozygotes, one homozygote for C282Y, and one homozygote for H63D were found among the 151 patients. For the remaining 146 patients, there was no difference in the distribution of heterozygote status by allele, compared to the general New Zealand population. No HFE mutation: general population 64.4%, alcohol-dependent patients 64.4%; H63D: general population 23.6%, alcohol-dependent patients 28.1%; C282Y: general population 11.9%, alcohol-dependent patients 7.5% (P = 0.20). There was no relationship between liver function tests or iron status and HFE mutation status among the study group. No evidence has been found in the present that HFE allele status prevalence is different from the general population or associated with different liver function or iron status among alcohol-dependent patients. The cause of altered iron status among alcohol-dependent patients does not appear to be related to HFE status.

Increased manganese uptake by primary astrocyte cultures with altered iron status is mediated primarily by divalent metal transporter

Neurotoxicity due to excessive brain manganese (Mn) accumulation can occur via occupational exposure to aerosols or dusts that contain extremely high levels (>1–5 mg Mn/m 3) of Mn, or metabolic aberrations (decreased biliary excretion). Given the putative role of astrocytes in regulating the movement of metals across the blood-brain barrier, we sought to examine the relationship between iron (Fe) status and Mn transport in astrocytes. Furthermore, our study examined the effect of Fe status on astrocytic transferrin receptor (TfR) and divalent metal transporter (DMT-1) levels and their relationship to Mn uptake, as both have been implicated as putative Mn transporters. All experiments were carried out in primary astrocyte cultures derived from neonatal rats when the cells reached full confluency (about three weeks in culture). Astrocytes were incubated for 24 h in astrocyte growth medium (AGM) containing 200 μM desferroxamine (ID), 500 μM ferrous sulfate (+Fe), or no compound (CN). After 24 h, 5 min 54Mn uptake was measured and protein was harvested from parallel culture plates for DMT-1 and TfR immunoblot analysis. Both iron deprivation (ID) and iron overload (+Fe) caused significant increases ( p < 0.05) in 54Mn uptake in astrocytes. TfR levels were significantly increased ( p < 0.05) due to ID and decreased in astrocytes exposed to +Fe treatments. As expected, DMT-1 was increased due to Fe deprivation, but surprisingly, DMT-1 levels were also increased due to +Fe treatment, albeit not to the extent noted in ID. The decreased TfR associated with +Fe treatment and the increased DMT-1 levels suggest that DMT-1 is a likely putative transporter of Mn in astrocytes.

Iron status of the free-living, elderly Framingham Heart Study cohort: an iron-replete population with a high prevalence of elevated iron stores

Although iron deficiency occurs commonly in vulnerable groups of women of reproductive age, infants, and children, less is known about the iron nutriture of the elderly. Our objective was to evaluate the iron status of a noninstitutionalized, elderly US population, with a particular focus on 2 concerns unique to the elderly: 1) potential confounding effects of chronic disease on iron measures and 2) increased occurrence of elevated iron stores. Multiple iron measures, including serum ferritin (SF), transferrin saturation, mean cell volume, and hemoglobin, were used to evaluate the prevalence of iron deficiency (ID), iron deficiency anemia (IDA), and other measures of iron nutriture in 1016 elderly white Americans aged 67-96 y from the Framingham Heart Study. "Diseased" subjects were defined as those with possible pathologically altered iron measures due to inflammation, infection, elevated liver enzymes, hereditary hemochromatosis, or cancer. The effect of altered iron status on various prevalence estimates was assessed. The elderly subjects had a low prevalence of ID (2.7%), IDA (1.2%), and depleted iron stores (3%; SF < 12 microg/L). In contrast, 12.9% had elevated iron stores (SF > 300 microg/L in men and SF > 200 microg/L in women), of which only 1% was attributable to chronic disease. The prevalence of ID, IDA, and depleted iron stores was unaffected by the presence of chronic disease. The Framingham Heart Study cohort is an iron-replete elderly population with a high prevalence of elevated iron stores in contrast with a low prevalence of iron deficiency, with insignificant effects of chronic disease on these iron status estimates. The likely liability in iron nutriture in free-living, elderly white Americans eating a Western diet is high iron stores, not iron deficiency.

Indicators of erythrocyte formation and degradation in rats with either vitamin A or iron deficiency

Vitamin A deficiency produces anemia and altered iron status. In this study with rats we tested two hypotheses regarding vitamin A deficiency: (1) that it impairs erythropoiesis, leading to an increased red cell turnover, and (2) that it inhibits the glycosylation of transferrin. Erythropoietic activity was assessed indirectly by determining the myeloid:erythroid ratio in bone marrow smears, the number of erythroid colonies in the red pulp of spleen, the blood reticulocyte index, and zinc protoporphyrin and plasma transferrin receptor concentrations. Transferrin glycosylation was assessed by measuring the sialic acid content of transferrin. The effects of vitamin A deficiency were compared with those of iron deficiency. Iron deficiency produced anemia and low iron levels in organs. Vitamin A deficiency produced low levels of plasma and hepatic retinol, and it induced decreased plasma total iron-binding capacity and raised iron levels in tibia and spleen. Short- but not long-term iron deficiency reduced the number of erythroid colonies in spleen; vitamin A deficiency had no influence. Neither iron nor vitamin A deficiency influenced the myeloid:erythroid ratio in bone marrow smears and the blood reticulocyte production. Plasma transferrin receptor and erythrocyte zinc protoporphyrin concentrations were not affected by vitamin A deficiency but increased with iron deficiency. Vitamin A deficiency did not stimulate erythrocyte breakdown, as indicated by unaltered plasma lactate dehydrogenase activity and reduced plasma total bilirubin levels. Both vitamin A and iron deficiencies raised the proportion of multiple sialylated transferrins in plasma. Thus, we have not found evidence that vitamin A deficiency affects erythropoiesis and erythrocyte turnover. The iron accumulation in spleen and bone marrow may be related to reduced iron transport due to inhibition of transferrin synthesis rather than inhibition of transferrin sialylation.

Transferrin and transferrin receptor function in brain barrier systems.

1. Iron (Fe) is an essential component of virtually all types of cells and organisms. In plasma and interstitial fluids, Fe is carried by transferrin. Iron-containing transferrin has a high affinity for the transferrin receptor, which is present on all cells with a requirement for Fe. The degree of expression of transferrin receptors on most types of cells is determined by the level of Fe supply and their rate of proliferation. 2. The brain, like other organs, requires Fe for metabolic processes and suffers from disturbed function when a Fe deficiency or excess occurs. Hence, the transport of Fe across brain barrier systems must be regulated. The interaction between transferrin and transferrin receptor appears to serve this function in the blood-brain, blood-CSF, and cellular-plasmalemma barriers. Transferrin is present in blood plasma and brain extracellular fluids, and the transferrin receptor is present on brain capillary endothelial cells, choroid plexus epithelial cells, neurons, and probably also glial cells. 3. The rate of Fe transport from plasma to brain is developmentally regulated, peaking in the first few weeks of postnatal life in the rat, after which it decreases rapidly to low values. Two mechanisms for Fe transport across the blood-brain barrier have been proposed. One is that the Fe-transferrin complex is transported intact across the capillary wall by receptor-mediated transcytosis. In the second, Fe transport is the result of receptor-mediated endocytosis of Fe-transferrin by capillary endothelial cells, followed by release of Fe from transferrin within the cell, recycling of transferrin to the blood, and transport of Fe into the brain. Current evidence indicates that although some transcytosis of transferrin does occur, the amount is quantitatively insufficient to account for the rate of Fe transport, and the majority of Fe transport probably occurs by the second of the above mechanisms. 4. An additional route of Fe and transferrin transport from the blood to the brain is via the blood-CSF barrier and from the CSF into the brain. Iron-containing transferrin is transported through the blood-CSF barrier by a mechanism that appears to be regulated by developmental stage and iron status. The transfer of transferrin from blood to CSF is higher than that of albumin, which may be due to the presence of transferrin receptors on choroid plexus epithelial cells so that transferrin can be transported across the cells by a receptor-mediated process as well as by nonselective mechanisms. 5. Transferrin receptors have been detected in neurons in vivo and in cultured glial cells. Transferrin is present in the brain interstitial fluid, and it is generally assumed that Fe which transverses the blood-brain barrier is rapidly bound by brain transferrin and can then be taken up by receptor-mediated endocytosis in brain cells. The uptake of transferrin-bound Fe by neurons and glial cells is probably regulated by the number of transferrin receptors present on cells, which changes during development and in conditions with an altered iron status. 6. This review focuses on the information available on the functions of transferrin and transferrin receptor with respect to Fe transport across the blood-brain and blood-CSF barriers and the cell membranes of neurons and glial cells.

Effect of chronic chloroquine administration on iron loading in the liver and reticuloendothelial system and on oxidative responses by the alveolar macrophages

The ability of chloroquine to alter iron loading in the liver, spleen, and alveolar macrophages was investigated in iron-loaded or -depleted rats. Chloroquine significantly reduced incorporation of iron into the liver, spleen, and alveolar macrophages of animals loaded in vivo with iron dextran. The ability of these macrophages to respond to oxidative stress was assayed by their capacity to release reactive nitrogen intermediates after lipopolysaccharide (LPS) stimulation. A significant reduction in nitrite release was observed in primary cultures of macrophages isolated from chloroquine/iron dextran-administered rats in comparison to macrophages lavaged from rats iron-loaded alone. Macrophages isolated from iron-deficient rats showed a significant increase in nitrite after LPS stimulation, whereas nitrite release in the macrophages lavaged from the rats which had also received chloroquine during the iron depletion regime was much lower. These results indicate that the use of agents which decrease the iron content and diminish the oxidative response of the cell to altered iron status may be of therapeutic value in patients with iron loading, particularly of the reticuloendothelial system.

Iron nutrition in rural home bound elderly persons.

The objective of this study was to describe the iron status of a sample of rural elderly home-delivered meals recipients as determined by a relatively non-invasive capillary blood sampling system. Fifty-six persons were assessed in their homes. The incidence of iron deficiency was considerable and was similar to incidences reported in other elderly populations. Females were at higher risk for iron deficiency than males despite a similar low dietary iron intake of 10-11 mg/day in both genders. Data were collected on drug use, general health conditions and other variables that may alter iron status in the elderly but they had no significant statistical effects in this study. We interpret this data on a high prevalence of iron deficiency in females as suggestive that they are at considerable risk of iron deficiency due to a lifelong poorer iron status than men.

Feeding of excessive cystine and cysteine enhances defects of dietary copper deficiency in rats by differential mechanisms involving altered iron status.

We have reported that excess cystine feeding exaggerates the defects of dietary copper deficiency in rats by a mechanism not involving oxidative stress and altered copper status. This study was conducted to examine whether this exacerbation is caused by a mechanism involving altered iron status and to compare the influences of cystine and cysteine feeding on the defects of copper deficiency. Male Wistar rats were fed copper-adequate or copper-deficient diet with supplementation of L-cystine or L-cysteine (2%) for 10 days or 21 days. Copper-deficient diet increased heart weight, caused anemia, reduced plasma iron and elevated liver iron. These defects were exacerbated by supplemental cystine. Cysteine feeding also exacerbated the defects of dietary copper deficiency including anemia, increased heart weight, and reduced plasma iron, although cysteine feeding had no influence on liver iron concentration. Supplemental cysteine reduced apparent absorption of iron, while supplemental cystine did not. These results suggest that cystine feeding enhances the defects of copper deficiency by a mechanism involving impaired mobilization of iron from liver into blood, and that cysteine feeding enhances the defects of copper deficiency by a mechanism involving reduced intestinal absorption of iron.

Influence of acute inflammation on iron and nutritional status indexes in older inpatients.

To investigate the relations between acute inflammation, as shown by high C-reactive protein (CRP) serum levels, and laboratory indexes of iron and nutritional status and to ascertain whether the presence of acute inflammation affects the diagnostic reliability of these indexes. Cross-sectional study. Geriatric ward for rehabilitation. A total of 163 patients, 77 men and 86 women aged 60 years or older. CRP values > 1 mg/dL were considered to indicate the presence of acute inflammation. Iron status was explored by measuring erythrocyte mean cell volume (MCV), hemoglobin (Hb), serum iron (Fe), TIBC, percent transferrin saturation (% TS) and ferritin (SF). Nutritional status was determined by albumin (Alb) and prealbumin (pre-Alb) serum levels. In the whole series, CRP correlated significantly with all iron status variables except erythrocyte MCV (directly with SF, inversely with the others) and correlated inversely with Alb and pre-Alb. Mean values of iron status variables were significantly different in patients with inflammation and those without: SF was higher and the other variables lower. Patients with low % TS (< 16%) showed a pattern consistent with iron deficiency. Compared to the group with normal values, they had more severe anemia, lower MCV, Fe, and SF, and higher TIBC; mean Alb, pre-Alb, and CRP values were not significantly different. The prevalence of inflammation was 50% (39.5% in the group with normal % TS). A similar pattern was observed in patients with microcytosis (MCV < 84 fL) associated with low % TS; dividing this subgroup according to SF values (low, < 30 micrograms/L) did not provide more information because patients with acute inflammation were excluded. Patients with acute inflammation present altered iron status indexes that resemble those observed in the anemia of chronic disease. Fe, TIBC and SF lose diagnostic value. The concomitant presence of microcytosis and low % TS, and to a lesser extent the presence of one of these alterations, is suggestive of iron deficiency associated with inflammation and may warrant gastrointestinal tract investigations and ferrous salt treatment. Protein-calorie malnutrition seems to enhance the effects of inflammation on iron status indexes.

Control of cellular iron homeostasis by iron-responsive elements in vivo.

It has recently been proposed that cellular iron homeostasis in mammalian cells is regulated at the post-transcriptional level by the reciprocal control of transferrin receptor and ferritin mRNA expression via an iron-regulatory factor. This iron-regulatory factor has been shown to be a cytoplasmic aconitase which can bind to iron-responsive elements in the corresponding mRNAs with greater or lesser affinity as a function of the iron status of the cell. In the present study, we show that in vivo the affinity of iron-regulatory factor for iron-responsive elements in liver reflects the long-term iron status of the tissue in animal models for iron overloading and iron deficiency, when combined with altered transferrin saturation and serum iron levels. In contrast hepatic iron overload achieved without altering such haematopoeitic indices, had a less pronounced effect. In both spleen and heart, the affinities of iron-regulatory factor changed in parallel with both altered iron status and haematological markers. In brain and duodenum, there were no consistent changes in iron-regulatory-factor activity with iron loading or depletion. Iron-regulatory-factor activity in kidney responded in an as yet unexplained manner.

Transferrin and Iron Uptake by the Brain: Effects of Altered Iron Status

Transferrin (Tf) and iron uptake by the brain were measured in rats using 59Fe-125I-Tf and 131I-albumin (to correct for the plasma content of 59Fe and 125I-Tf in the organs). The rats were aged from 15 to 63 days and were fed (a) a low-iron diet (iron-deficient) or, as control, the same diet supplemented with iron, or (b) a chow diet with added carbonyl iron (iron overload), the chow diet alone acting as its control. Iron deficiency was associated with a significant decrease and iron overload with a significant increase in brain nonheme iron concentration relative to the controls. In each dietary treatment group, the uptake of Tf and iron by the brain decreased as the rats aged from 15 to 63 days. Both Tf and iron uptake were significantly greater in the iron-deficient rats than in their controls and lower in the iron-loaded rats than in the corresponding controls. Overall, iron deficiency produced about a doubling and iron overload a halving of the uptake values compared with the controls. In contrast to that in the brain, iron uptake by the femurs did not decrease with age and there was relatively little difference between the different dietary groups. 125I-Tf uptake by the brains of the iron-deficient rats increased very rapidly after injection of the labelled proteins, within 15 min reaching a plateau level which was maintained for at least 6 h. The uptake of 59Fe, however, increased rapidly for 1 h and then more slowly, and in terms of percentage of injected dose reached much higher values than did 125I-Tf uptake.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of dietary iron source on measures of iron status among female runners.

The purpose of the present investigation was to determine whether female runners who consume a modified vegetarian diet are predisposed to iron deficiency. Two groups of female runners who were matched for age, weight, aerobic capacity, miles run per week, and number of pregnancies were obtained for this study. One group (N = 9) regularly consumed a modified vegetarian diet (MV, less than 100 g red meat.wk-1), while the other group (N = 9) consumed a diet which included red meat (RM). Serum ferritin values were significantly (P less than 0.05) lower for the MV group (X +/- SE, 7.4 +/- 1.4 ng.100 ml-1) than for the RM group (19.8 +/- 4.2 ng.100 ml-1). Total iron binding capacity (TIBC) of the serum was also significantly different between the two groups of subjects (MV, 366.5 +/- 12.2 micrograms.100 ml-1; RM, 327.2 +/- 9.6 micrograms.100 ml-1). While dietary iron intake was comparable for the two groups (MV, 14.7 +/- 2.0 mg.d-1; RM, 14.0 +/- 2.2 mg.d-1, the bioavailability of the dietary iron was significantly different (MV, 0.66 +/- 0.08 mg.d-1; RM, 0.91 +/- 0.10 mg.d-1). As the presence of heme iron (from meat, fish, and poultry) increases the bioavailability of dietary iron, the results of the present investigation suggest that vegetarian athletes have altered iron status due to the form in which their dietary iron is consumed.

Iron status in children undergoing tonsillectomy and its short-term modification following surgery.

Red cell and iron status parameters were studied in a group of 44 children undergoing tonsillectomy for recurrent throat infections and in a control group of 40 healthy children. In the patient group, before tonsillectomy, 8 children presented a latent iron deficiency and 15 a decrease in serum ferritin levels. This altered iron status can be attributed to a reduced intestinal iron absorption, due to recurrent infections. One and seven days following surgery there was a significant fall in serum iron, serum transferrin and transferrin saturation, in parallel with an increase of serum ferritin and alpha-2 globulins levels. These modifications cannot be attributed to the blood loss, as proven by the constancy of haemoglobin level and of other red cell parameters, but to an unspecific reaction to surgical stress, as observed in fever, traumas and inflammation. They reflect an altered processing of iron, with a temporary block of its release to plasma and an increased storage within the reticuloendothelial cells.

Physiological Changes in Elite Male Distance Runners Training for Olympic Competition.

In Brief: Nine elite male distance runners were evaluated by comprehensive periodic monitoring of selected blood chemistry variables, percent body fat and lean body mass, and cardiopulmonary performance as they prepared for the 1984 Olympic Summer Games in Los Angeles. The most consistent changes included a decrease in percent body fat (5.4% to 4.6%, p <.05) and an increase in anaerobic threshold. Compared with a healthy, untrained group matched for age, sex, and height, the runners showed measurable differences in resting pulmonary function, including elevated pulmonary diffusing capacity, maximum voluntary ventilation, and peak expiratory flow rate. Consistent deviations in indexes of iron stores and metabolism were also noted. The extent to which such altered iron status compromises training and competitive performance or may be restored by iron supplementation needs further investigation.