Low vitamin a intake affects milk iron level and iron transporters in rat mammary gland and liver

Marginal vitamin A deficiency is common and can result in a secondary iron (Fe) deficiency. A positive correlation between maternal Fe status and milk Fe was observed in lactating women supplemented with both vitamin A and Fe but not with Fe alone, suggesting effects of vitamin A on mammary gland Fe transport. We hypothesized that low vitamin A intake during lactation elicits differential effects on mammary gland and liver Fe transport and storage proteins, thus affecting milk Fe concentration but not maternal Fe status. We fed rats a control (CON, 4 RE/g) or a marginal vitamin A diet (AD, 0.4 RE/g) through midlactation. Effects on plasma, milk, liver and mammary gland Fe and vitamin A concentrations, and divalent metal transporter-1 (DMT1), ferroportin (FPN), ferritin (Ft), and transferrin receptor (TfR) expression were determined. Dams fed AD were not vitamin A or Fe deficient. Milk and liver vitamin A and Fe and mammary gland Fe concentrations were lower in rats fed AD compared with rats fed CON. Liver TfR expression was higher, whereas mammary gland TfR expression was lower in rats fed AD compared with rats fed CON. Liver Ft was unaffected, whereas mammary gland Ft was lower in rats fed AD compared with rats fed CON. Liver and mammary gland DMT1 and FPN protein levels were lower in rats fed AD compared with rats fed CON. Our results indicate that the mammary gland and liver respond differently to marginal vitamin A intake during lactation and that milk Fe is significantly decreased due to effects on mammary gland Fe transporters, putting the nursing offspring at risk for Fe deficiency.     

Response of rat mammary gland transferrin receptors to maternal dietary iron during pregnancy and lactation

Mammalian milk iron (MFe) concentration decreases during lactation. In human attempts to increase MFe through supplementing the mother with iron during lactation have failed and no correlation between maternal iron status or intake and MFe has been determined, suggesting a regulatory mechanism. In contrast MFe in lactating rats can be affected by very high or low amounts of ingested iron. We previously described a transferrin receptor (TfR) mechanism that controls iron entry into rat mammary tissue. In this study lactating rats were used to determine effects of varying dietary iron during gestation and lactation on mammary TfR and MFe. Dams fed low-iron diets had a small increase in TfR, lower hematological indices (p less than 0.005), and lower MFe (p less than 0.005) than did controls or dams fed high iron. Dams fed the high-iron diet had a significant increase in TfR without a concomitant increase in MFe. There was no correlation between MFe and TfR. These findings suggest that control of MFe lies after iron entry into mammary tissue.     

Iron supplementation during infancy--effects on expression of iron transporters, iron absorption, and iron utilization in rat pups

BACKGROUND: Studies conducted in human infants suggest developmental changes in the regulation of iron absorption; however, little is known about the molecular mechanisms regulating iron absorption during infancy. Two intestinal iron transporters, divalent metal transporter 1 (DMT1) and ferroportin 1 (FPN1), were recently identified. OBJECTIVE: The objective was to investigate at a molecular level the regulation of iron absorption during infancy in a rat pup model. We examined the developmental expression of DMT1 and FPN1 and the effects of iron supplementation on their expression and on iron absorption and utilization during infancy. DESIGN: Rat pups were given daily oral doses of 0, 30, or 150 microg Fe from day 2 to day 20 after birth. On days 10 and 20 after birth, (59)Fe absorption, tissue minerals, and intestinal DMT1, FPN1, and ferritin expression were examined. To assess developmental expression, DMT1 and FPN1 were examined in control rats from days 1 to 50 after birth. RESULTS: Intestinal DMT1 and FPN1 were significantly affected by age; expression increased dramatically by day 40. On day 10, no significant effect of iron supplementation on DMT1 and FPN1 gene expression or on iron absorption was observed. By day 20, DMT1 and FPN1 expression and iron absorption had decreased significantly with iron supplementation. CONCLUSIONS: During early infancy, rat pups are unable to down-regulate intestinal iron transporters or iron absorption in response to iron supplementation, whereas down-regulation occurs during late infancy. The current findings provide evidence of the developmental regulation of iron absorption, which emphasizes the need for caution when giving iron supplements to infants at an early age.     

A high dietary lipid intake during pregnancy and lactation enhances mammary gland lipid uptake and lipoprotein lipase activity in rats.

Rats fed a diet with high fat concentration produce larger amounts of milk with a higher lipid concentration than rats fed a lower fat diet. This investigation was designed to study the relationship between dietary fat intake, mammary gland lipid uptake and lipogenesis in rat dams fed, during pregnancy and lactation, one of two purified diets, with equal energy density, containing 2.5 (LL) or 20 g fat/100 g diet (HL). Milk lipid concentration and fatty acid composition were determined at d 14 of lactation. Mammary gland lipogenesis, lipoprotein lipase (LPL) activity and the uptake of [1-(14)C]triolein by the mammary gland and its transfer to the pups was measured. The intestinal absorption of oral (14)C-lipid, (14)CO(2) production and the amount of (14)C-lipid transferred to the pups (milk clot + pups carcass) were significantly higher in the HL group than in the LL group (P < 0.05). Mammary gland lipogenesis was 75% lower and LPL activity was 30% higher in the HL group (P < 0.05). Medium-chain fatty acids (C6-C14) excretion was 46% lower and that of long-chain fatty acids was 142% (P < 0.001) higher in the HL group than in the LL group. The higher milk lipid excretion in the rats fed a high-fat diet resulted from a larger uptake of dietary lipid by the mammary gland, indicated by a larger transfer of (14)C-lipid to the pups and by a higher LPL activity in the mammary gland.     

Iron, zinc, and copper concentrations in breast milk are independent of maternal mineral status

BACKGROUND: Little is known about the regulation of iron, zinc, and copper in breast milk and the transport of these minerals across the mammary gland epithelium. OBJECTIVE: The objective was to study associations between breast-milk concentrations of iron, zinc, and copper and maternal mineral status. DESIGN: Milk samples from 191 Swedish and Honduran mothers were collected at 9 mo postpartum. Iron, zinc, and copper concentrations were measured by atomic absorption spectrometry. Blood samples from mothers were analyzed for plasma zinc and copper and 4 indexes of iron status: hemoglobin, plasma ferritin, soluble transferrin receptors, and zinc protoporphyrin. Complementary food energy (CFE) intake was used as an inverse proxy for breast-milk intake. RESULTS: Mean (+/-SD) breast-milk concentrations of iron were lower in the Honduran than in the Swedish mothers (0.21 +/- 0.25 compared with 0.29 +/- 0.21 mg/L; P < 0.001), and mean breast-milk concentrations of zinc and copper were higher in the Honduran than in the Swedish mothers [0.70 +/- 0.18 compared with 0.46 +/- 0.26 mg/L (P < 0.001) and 0.16 +/- 0.21 compared with 0.12 +/- 0.22 mg/L (P = 0.001), respectively]. Milk iron was positively correlated with CFE intake (r = 0.24, P = 0.001) but was not significantly correlated with any iron-status variable. Milk zinc was negatively correlated with CFE intake (r = -0.24, P = 0.001) but was not significantly correlated with maternal plasma zinc. Milk copper was not significantly correlated with CFE intake or maternal plasma copper. CONCLUSIONS: Milk iron, zinc, and copper concentrations at 9 mo postpartum are not associated with maternal mineral status, which suggests active transport mechanisms in the mammary gland for all 3 minerals. Milk iron concentrations increase and milk zinc concentrations decrease during weaning [corrected]     

Impaired milk folate secretion is not corrected by supplemental folate during iron deficiency in rats

Decreased milk folate secretion in iron-deficient rat dams contributes to the impairment of folate metabolism in nursing pups. The present study was designed to assess whether impaired milk folate secretion secondary to iron deficiency is due to a decrease in the supply of folate to the mammary gland or to an inability of the mammary gland to effectively use folate. Rats were fed diets containing 0.5, 2.0 or 7.0 mg folate/kg and 8 (-Fe) or 250 (+Fe) mg Fe/kg throughout gestation and until d 17 of lactation. Regardless of dietary Fe content, maternal plasma, red blood cell, liver and kidney folate concentrations correlated with dietary folate content (r = 0.75-0.85, p less than 0.0001). With the exception of plasma folate level, which was 46% lower for -Fe than +Fe dams fed 0.5 mg folate/kg, no other differences in indices of folate status were noted between +Fe and -Fe dams. Dietary folate content had a direct impact on milk folate content in +Fe dams but not in -Fe dams. Mammary tissue methionine synthase and folylpolyglutamate synthetase activities were not depressed in Fe deficiency; rather, mean activities were elevated among -Fe dams fed 0.5 mg folate/kg. In conclusion, the reduction in milk folate secretion during Fe deficiency is not due to a decrease in the amount of folate supplied to the mammary gland; rather, the defect causing this reduction is specific to the mammary gland.     

Adolescent vitamin A intake alters susceptibility to mammary carcinogenesis in the Sprague-Dawley rat

We tested the hypothesis that adolescent dietary vitamin A intake impacts mammary gland development and subsequent sensitivity to carcinogenesis. Sprague-Dawley rats were fed a purified diet that was vitamin A deficient, adequate (2.2 mg retinyl palmitate/kg diet), or supranutritional (16 mg retinyl palmitate/kg diet) from 21 to 63 days of age, the period of adolescent mammary gland development. At 73 days of age, rats were given 1-methyl-1-nitrosourea (25 mg/kg body wt i.p.) and monitored for mammary tumors. Tumors appeared earlier and more frequently in rats fed vitamin A-deficient or -supplemented diets. Vitamin A deficiency during adolescence was associated with alveolar mammary gland development and precocious milk protein expression, while supplementation was associated with ductal gland development and suppression of milk protein expression. Differences in circulating estradiol and mammary gland estrogen receptor-alpha, and estrogen-responsive progesterone receptor mRNA were not observed, suggesting that the effects of vitamin A on mammary gland development and carcinogenesis are estrogen independent. Mammary expression of another hormone receptor that regulates milk protein expression, the glucocorticoid receptor, was also unaffected. These results demonstrate that vitamin A intake during adolescence alters mammary gland differentiation and indicate that a narrow range of vitamin A intake during adolescence protects against carcinogenesis.     

Marginal maternal Zn intake in rats alters mammary gland Cu transporter levels and milk Cu concentration and affects neonatal Cu metabolism

Marginal zinc intake is common and leaves women particularly vulnerable to Zn deficiency due to increased demand for Zn as a consequence of reproduction. Zn deficiency during pregnancy and lactation has been associated with secondary affects on copper metabolism in the offspring; however, the underlying mechanisms are unknown. The effects of marginal maternal Zn intake on maternal and neonatal Cu metabolism were determined in rats. Plasma, milk and tissue Cu and Zn concentrations and plasma and milk ceruloplasmin (Cp) activity were measured in dams fed a control (CON, 25 mg Zn/kg diet) or a marginal Zn diet (ZD, 10 mg Zn/kg diet) and their suckling pups. There was no effect on maternal tissue Cu or Zn or milk Zn concentration; however, plasma Cp activity was higher in dams fed ZD, suggesting that Cp activity may be a useful marker for identifying marginal Zn status. Rats fed ZD had high mammary gland Ctr1, Atp7A and Atp7B levels, milk Cp activity and Cu concentration. Immunostaining and differential centrifugation indicated that ZD also altered Ctr1 and Atp7A localization in the mammary gland. Pups from dams fed ZD had higher small intestine Cu and lower plasma Cu than CON pups. These results suggest that marginal maternal Zn intake during pregnancy and lactation increase mammary gland Cu transporter levels and alter their localization, resulting in high milk Cu levels, possibly in response to transiently elevated plasma Cu levels. The combination of high milk Cu concentration and immature neonatal Cu transport exposes the suckling neonate to excess Cu; however, whether this occurs in humans is not yet known.     

Enzymes of the taurine biosynthetic pathway are expressed in rat mammary gland

Taurine is the most abundant free amino acid in the body and is present at high concentrations during development and in the early milk. It is synthesized from cysteine via oxidation of cysteine to cysteinesulfinate by the enzyme cysteine dioxygenase (CDO), followed by the decarboxylation of cysteinesulfinate to hypotaurine, catalyzed by cysteine sulfinic acid decarboxylase (CSAD). To determine whether the taurine biosynthetic pathway is present in mammary gland and whether it is differentially expressed during pregnancy and lactation, and also to further explore the possible regulation of hepatic taurine synthesis during pregnancy and lactation, we measured mammary and hepatic CDO and CSAD mRNA and protein concentrations and tissue, plasma and milk taurine concentrations. CDO and CSAD mRNA and protein were expressed in mammary gland and liver regardless of physiological state. Immunohistochemistry demonstrated the expression of CDO in ductal cells of pregnant rats, but not in other mammary epithelial cells or in ductal cells of nonpregnant rats. CDO was also present in stromal adipocytes in mammary glands of both pregnant and nonpregnant rats. Our findings support an upregulation of taurine synthetic capacity in the mammary gland of pregnant rats, based on mammary taurine and hypotaurine concentrations and the intense immunohistochemical staining for CDO in ductal cells of pregnant rats. Hepatic taurine synthetic capacity, particularly CSAD, and taurine concentrations were highest in rats during the early stages of lactation, suggesting the liver may also play a role in the synthesis of taurine to support lactation or repletion of maternal reserves.     

Effect of dietary restriction during lactation on cardiac output, organ blood flow and organ weights of rats

Cardiac output, organ blood flow and organ weights were examined in rats assigned at d 0 of lactation to a control (C) group fed ad libitum or an acutely restricted (AR) group fed 50% of the intake of C dams. Dams in each group were assigned to subgroups for measurement of milk yield or cardiac output, blood flow and organ weights. At d 14 of lactation, cardiac output and blood flow were measured with radiolabeled microspheres and milk yield with the tritiated water method. In AR dams cardiac output was 55% of that of C dams, but cardiac output relative to body weight did not differ between groups. Mammary gland blood flow and weight were reduced in AR dams. The weight of the kidneys, gastrointestinal tract and liver of the AR dams was less than that of C dams; however, relative blood flow to these organs did not differ between groups. Milk yield was reduced by 58% in AR dams compared to C dams. We conclude that dietary restriction during lactation negatively affects absolute cardiac output, blood flow to the mammary glands and milk yield, and that the reduced milk yield is associated with the decrease in mammary gland weight and blood flow.     

铜缺乏对大鼠铁代谢影响的研究

目的研究铜缺乏对大鼠铁营养状况和肝脏转铁蛋白受体mRNA及铁调素mRNA的影响。方法 48只雄性SD大鼠按体重随机分为4组,每组12只,正常对照组(Ⅰ组),铁正常铜完全缺乏组(Ⅱ组),铁正常铜轻度缺乏组(Ⅲ组),铁/铜轻度缺乏组(IV组)。喂饲8周后处死,取大鼠肝脏、脾脏和血清,测定血红蛋白,血清铜、血清铁、血清转铁蛋白受体、血清铁蛋白、肝脏铁和铜含量、脾脏铁和铜含量,并用逆转录-聚合酶链反应(RT-PCR)法检测各组大鼠肝脏转铁蛋白受体(TfR)和铁调素mRNA的表达水平。结果与正常对照组相比,铜缺乏使血清铁、血清铁蛋白含量显著降低(P0.05),血清转铁蛋白受体水平、肝脾脏铁含量显著升高(P0.05),铜缺乏时肝脏TfRmRNA表达增强,而肝脏铁调素mRNA表达下降。结论铜缺乏可能通过影响铁吸收、储存、转运来影响体内铁的营养状况。铜缺乏对大鼠铁调素mRNA的表达与IRE-IRP途径调节的转铁蛋白受体mRNA的表达均产生影响。     

Maternal zinc deficiency raises plasma prolactin levels in lactating rats

There is an inverse relation between zinc (Zn) intake and plasma prolactin in men and nonpregnant women. Whether a relation exists in lactating women is unknown, despite the potential consequences of perturbations in prolactin regulation on lactation performance. We examined the effects of low Zn intake on prolactin concentration, the prolactin regulatory pathway in the pituitary gland, and lactation performance in lactating rats. Female rats were fed diets containing 7 (zinc deficient; ZD), 10 (marginally zinc deficient; MZD) or 25 mg Zn/kg (control) from 70 d preconception to lactation d 11. Rats were killed, pituitary glands dissected, and tissues and plasma collected and analyzed for prolactin concentration. Pituitary gland pituitary factor 1 (Pit-1), dopamine 2 receptor (D2R), and prolactin receptor mRNA expression were measured in the pituitary gland. Liver, mammary gland, plasma, and milk Zn were measured. Milk intake of the pups was also recorded. Plasma prolactin concentration was higher in rats fed the ZD (125.9 microg/L) diet compared with control rats (21.7 microg/L). Pituitary gland prolactin concentration was higher in rats fed the ZD diet (69.8 mg/g total protein) compared with controls (29.0 mg/g). Plasma Zn concentration was lower in rats fed the MZD and ZD diets, and mammary gland and milk Zn concentrations were lower in rats fed the ZD diet compared with control rats. Rats fed the ZD diet had lower D2R, prolactin receptor, and Pit-1 mRNA levels, whereas rats fed the MZD diet had lower prolactin receptor and Pit-1 mRNA levels compared with control rats. Milk intake was lower in pups of rats fed the MZD and ZD diets. Our results suggest that marginal Zn nutriture may compromise milk production despite increased prolactin levels. In addition, increased circulating prolactin concentration is not due to altered nursing behavior, but may be due to alterations in the prolactin regulatory pathway in the pituitary gland.     

Maternal Iron Status in Pregnancy and Child Health Outcomes after Birth: A Systematic Review and Meta-Analysis

In pregnancy, iron deficiency and iron overload increase the risk for adverse pregnancy outcomes, but the effects of maternal iron status on long-term child health are poorly understood. The aim of the study was to systematically review and analyze the literature on maternal iron status in pregnancy and long-term outcomes in the offspring after birth. We report a systematic review on maternal iron status during pregnancy in relation to child health outcomes after birth, from database inception until 21 January 2021, with methodological quality rating (Newcastle-Ottawa tool) and random-effect meta-analysis. (PROSPERO, CRD42020162202). The search identified 8139 studies, of which 44 were included, describing 12,7849 mother–child pairs. Heterogeneity amongst the studies was strong. Methodological quality was predominantly moderate to high. Iron status was measured usually late in pregnancy. The majority of studies compared categories based on maternal ferritin, however, definitions of iron deficiency differed across studies. The follow-up period was predominantly limited to infancy. Fifteen studies reported outcomes on child iron status or hemoglobin, 20 on neurodevelopmental outcomes, and the remainder on a variety of other outcomes. In half of the studies, low maternal iron status or iron deficiency was associated with adverse outcomes in children. Meta-analyses showed an association of maternal ferritin with child soluble transferrin receptor concentrations, though child ferritin, transferrin saturation, or hemoglobin values showed no consistent association. Studies on maternal iron status above normal, or iron excess, suggest deleterious effects on infant growth, cognition, and childhood Type 1 diabetes. Maternal iron status in pregnancy was not consistently associated with child iron status after birth. The very heterogeneous set of studies suggests detrimental effects of iron deficiency, and possibly also of overload, on other outcomes including child neurodevelopment. Studies are needed to determine clinically meaningful definitions of iron deficiency and overload in pregnancy.     

Milk folate secretion is not impaired during iron deficiency in humans

The purpose of this study was to examine whether maternal iron and/or folate status influences human milk folate secretion and is responsible for growth faltering of Otomi infants in Capulhuac, Mexico. Breast-feeding mothers (n = 71) were randomized at 22 +/- 13 d (baseline) postpartum to receive a daily multivitamin supplement containing folic acid (400 microg) with and without iron (18 mg). Mothers provided blood and milk samples at baseline, and at 82 +/- 15 and 138 +/- 18 d postpartum. Iron supplementation significantly improved hematocrit and transferrin receptor concentrations but had no influence on maternal folate status or milk folate or iron concentrations. Forty-three percent of mothers (29/68) had low blood folate concentrations at baseline, whereas only 6% (4/66) had low blood folate concentrations at approximately 138 d postpartum. Milk folate concentrations did not differ between Fe-deficient and Fe-sufficient women and provided adequate levels of dietary folate by approximately 82 d postpartum. While milk iron concentrations were unrelated to maternal iron status, they decreased during lactation, and, by approximately 138 d, they provided only 55% of the current recommendation. In conclusion, milk folate concentrations appear to be well preserved during maternal iron deficiency; hence, faltering growth among infants in Capulhuac, Mexico is unlikely the result of reduced milk folate concentration secondary to maternal Fe deficiency. However, milk Fe concentrations showed a temporal decline. Whether the disjuncture between recommended and actual Fe intakes among infants born with low Fe reserves and weaned to foods low in bioavailable Fe has functional consequences is worthy of further investigation.     

Assessment of iron status using plasma transferrin receptor in pregnant women with and without human immunodeficiency virus infection in Malawi

BACKGROUND: Although anemia is highly prevalent during pregnancy and is common during human immunodeficiency virus (HIV) infection, anemia and iron status have not been well characterized in HIV-infected pregnant women. OBJECTIVE: To gain insight into iron status in HIV-infected pregnant women using plasma transferrin receptor and related indicators of anemia. STUDY DESIGN: Plasma transferrin receptor, ferritin, alpha1-acid glycoprotein, C-reactive protein and hemoglobin concentrations were measured in pregnant women, gestational age 18-28 weeks, seen in an urban antenatal clinic in Blantyre, Malawi. RESULTS: The prevalence of anemia among 662 HIV-positive and 190 HIV-negative pregnant women was 73.1% and 50.0%, respectively (P<0.0001). Among HIV-positive and HIV-negative women, median plasma transferrin receptor concentrations were 24.4 and 24.1 nmol/l (P=0.5), respectively, and median plasma ferritin concentrations were 17.8 and 20.8 microg/l (P<0.05), respectively. There was a large overlap in plasma transferrin receptor concentrations among women with and without anemia. Using the combination of hemoglobin and ferritin as a standard, the sensitivity and specificity of plasma transferrin receptor in diagnosing iron deficiency anemia was estimated at 45.9% and 68.1%, respectively. CONCLUSION: The use of plasma transferrin receptor concentrations as an indicator of iron deficiency anemia may be limited in pregnant women with chronic inflammation and infection.     

Concentration and distribution pattern of selected micronutrients in preterm and term milk from urban Brazilian mothers during early lactation

The purpose of this study was to assess the concentration and binding pattern of zinc, iron, folate and vitamin B12 in milk of Brazilian women of low socioeconomic status giving birth at term or preterm, during early lactation. Protein, fat, total solids and ash concentrations were also determined. Protein and zinc concentrations decreased significantly as lactation proceeded whereas milk fat and folate increased with the lactation period. Total solids, ash, iron and vitamin B12 remained unchanged. Zinc was present mainly in the whey fraction while less than half of the total iron was present in this fraction, with no significant change due to stage of lactation. Unsaturated folate and vitamin B12 binding capacities and percentage of saturation of the folate binding protein increased with the stage of lactation. The vitamin B12 binding protein was highly unsaturated in all samples. There was no significant difference between term and preterm samples in the parameters investigated. Correlation analysis between milk components indicated significant relationships between total solids and fat, total zinc and whey zinc, folate and total folate binding capacity, unsaturated and total folate binding capacity, and unsaturated and total B12 binding capacity. In general, the nutrient concentrations found in this study are in good agreement with published data on milk composition of women from developed countries, with the possible exceptions of folate, which was lower, and iron, which was higher. The correlation of folate concentration with its binding protein found in this work supports the hypothesis of a regulatory role for folate levels in milk exerted by the folate binding protein in the mammary gland.     

Use of rat models to mimic alterations in iron homeostasis during human alcohol abuse and cirrhosis.

With alcoholism, there are marked disturbances in iron homeostasis that are linked to alterations in serum transferrin and ferritin concentrations. This study identifies rat models of alcohol abuse that closely mimic these disturbances. Male rats were placed in one of the following three protocols: (1) pair-feeding of liquid diets for 1-8 weeks; (2) agar-block feeding for 8 weeks; or (3) generation of cirrhosis with CCl(4). Serum samples were analyzed for ferritin, transferrin, and iron levels, and the transferrin iron saturation and ferritin/transferrin ratios were calculated. Liver iron concentrations were also determined. Serum transferrin levels were elevated in animals fed alcohol for 8 weeks in pair-feeding and agar-block feeding protocols, but reduced in rats with cirrhosis. Serum ferritin concentration was reduced in rats fed ethanol in the liquid diet, but increased in rats consuming ethanol in agar blocks, in rats pair-fed the liquid control diet, and in rats with cirrhosis. This finding was mirrored by liver nonheme iron concentrations in all experimental groups, but not in the corresponding control groups. Serum iron levels were significantly elevated only in rats fed the liquid control diet. There was a progressive decrease in transferrin iron saturation and ferritin/transferrin ratios for animals fed ethanol in the liquid diet, but not when ethanol was ingested from agar blocks. The development of cirrhosis resulted in elevated liver iron concentrations and doubled ferritin/transferrin ratios. It is concluded that these models may be used to study disturbances in iron homeostasis that occur during alcohol abuse and the (subsequent) development of liver disease.     

Reducing Iron Content in Infant Formula from 8 to 2 mg/L Does Not Increase the Risk of Iron Deficiency at 4 or 6 Months of Age: A Randomized Controlled Trial

Many infant formulas are fortified with iron at 8–14 mg/L whereas breast milk contains about 0.3 mg/L. Another major difference between breast milk and infant formula is its high concentration of lactoferrin, a bioactive iron-binding protein. The aim of the present study was to investigate how reducing the iron content and adding bovine lactoferrin to infant formula affects iron status, health and development. Swedish healthy full-term formula-fed infants (n = 180) were randomized in a double-blind controlled trial. From 6 weeks to 6 months of age, 72 infants received low-iron formula (2 mg/L) fortified with bovine lactoferrin (1.0 g/L) (Lf+), 72 received low-iron formula un-fortified with lactoferrin (Lf−) and 36 received standard formula with 8 mg of iron/L and no lactoferrin fortification as controls (CF). Iron status and prevalence of iron deficiency (ID) were assessed at 4 and 6 months. All iron status indicators were unaffected by lactoferrin. At 4 and 6 months, the geometric means of ferritin for the combined low-iron groups compared to the CF-group were 67.7 vs. 88.7 and 39.5 vs. 50.9 µg/L, respectively (p = 0.054 and p = 0.056). No significant differences were found for other iron status indicators. In the low-iron group only one infant (0.7%) at 4 months and none at 6 months developed ID. Conclusion: Iron fortification of 2 mg/L is an adequate level during the first half of infancy for healthy term infants in a well-nourished population. Adding lactoferrin does not affect iron status.     

Anemia and iron metabolism in patients with type-2 diabetes mellitus

INTRODUCTION: Nowadays the iron status in chronic illnesses can be judged by non-invasive methods, too. The soluble transferrin receptor, that is also measurable in most laboratories, means a leap forward among the new markers. AIMS: The authors examined the prevalence of anemia and the iron status of type-2 diabetic patients with markers of the iron metabolism. They studied the clinical applicability of these laboratory procedures. METHODS: Concentration of iron, transferrin, ferritin and soluble transferrin receptor levels of healthy and diabetic patients were compared with a Mann-Whitney U-test. They examined the incidence and the type of anemia, the cause of the elevation in soluble transferrin receptor levels, and the effect of inflammation and nephropathy on the iron status. Relationship of the transferrin saturation, the concentration of ferritin and soluble transferrin receptor levels were depicted by graphic representations. RESULTS: The authors have found difference between the transferrin levels of women and men in contrast to the literature (z = 3.56; p < 0.05). The reference intervals of the ferritin levels of the control and patient groups also showed a significant difference between women and men (z = 7.59; z = 5.69; p < 0.05). 7% of the patients have suffered from anemia. 23% of the patient group had nephropathy, 10% of this subgroup was anemic, and further 8% of this subgroup had iron distribution disorder. 6% of the patients had elevated soluble transferrin receptor levels. Anemia or iron metabolism alteration was found only in 14% of the cases with elevated C-reactive protein levels. CONCLUSIONS: According to these findings ferritin reference levels of healthy people can not be used in diabetes mellitus similarly to other chronic illnesses. It seems that anemia is not frequent in diabetes mellitus. There is no connection between nephropathy and anemia, and not all of the inflammatory conditions are accompanied with iron metabolism disturbance. The soluble transferrin receptor can be interpreted only together with the other markers. In the opinion of the authors, the iron status of an individual can be judged with the collective use of all markers in chronic diseases, too.     

Calcium and iron absorption--mechanisms and public health relevance

Studies on human subjects have shown that calcium (Ca) can inhibit iron (Fe) absorption, regardless of whether it is given as Ca salts or in dairy products. This has caused concern as increased Ca intake commonly is recommended for children and women, the same populations that are at risk of Fe deficiency. However, a thorough review of studies on humans in which Ca intake was substantially increased for long periods shows no changes in hematological measures or indicators of iron status. Thus, the inhibitory effect may be of short duration and there also may be compensatory mechanisms. The interaction between Ca and Fe may be a lumenal event, affecting Fe uptake through DMT1 (divalent metal transporter 1) at the apical membrane. However, it is also possible that inhibition occurs during Fe transfer into circulation, suggesting roles for the serosal exporter ferroportin (FPN) and hephaestin. We explored these possibilities in human intestinal Caco-2 cells cultured in monolayers. Iron transport ((59)Fe) and expression of DMT1, FPN, and hephaestin were assessed after 1.5 and 4 hours with 0 or 100 μM CaCl(2.) Although Ca did not affect Fe uptake or DMT1 expression at 1.5 hours, FPN abundance at the basolateral membrane decreased, resulting in increased cellular Fe retention and decreased Fe efflux. After 4 hours, DMT1 and FPN expression increased and there was increased FPN at the membrane, suggesting a rebound effect. Thus, the effect of Ca on Fe absorption may be of short duration and adaptation may occur with time. This may explain why studies on long-term Ca supplementation of different groups fail to show any adverse effects on Fe status.