Does obesity increase risk for iron deficiency? A review of the literature and the potential mechanisms

Increasing obesity is a major global health concern while at the same time iron-deficiency anemia remains common worldwide. Although these two conditions represent opposite ends of the spectrum of over- and under-nutrition, they appear to be linked: overweight individuals are at higher risk of iron deficiency than normal-weight individuals. Potential explanations for this association include dilutional hypoferremia, poor dietary iron intake, increased iron requirements, and/or impaired iron absorption in obese individuals. Recent evidence suggests obesity-related inflammation may play a central role through its regulation of hepcidin. Hepcidin levels are higher in obese individuals and are linked to subclinical inflammation; this may reduce iron absorption and blunt the effects of iron fortification. Thus, low iron status in overweight individuals may result from a combination of nutritional (reduced absorption) and functional (increased sequestration) iron deficiency. In this review, we focus on subclinical inflammation in obesity, and its effect on hepcidin levels, as the most plausible explanation for the link between iron deficiency and obesity.     

Copper metabolism in iron-deficient maternal and neonatal rats

Groups of rats were fed diets providing 8 ppm iron (-Fe) and 250 ppm iron (+Fe) throughout pregnancy and lactation. In spite of the increase in apparent absorption of iron in pregnant -Fe dams, iron deficiency anemia developed, resulting in decreased iron levels in placenta, amniotic fluid and fetal liver. Copper concentration of amniotic fluid was elevated in -Fe dams. On day 17 of lactation, -Fe dams and their suckling pups had hematologic evidence of iron deficiency. While liver and spleen iron decreased in 17-day-old pups, levels of copper increased. Subcellularly, the greatest increase in hepatic copper in -Fe pups was found in the cytosol, thus the increased copper deposition is not similar to copper loading. Serum ceruloplasmin activity was significantly elevated in -Fe lactating dams and was slightly, but not significantly, increased in -Fe pregnant dams and suckling pups.     

Retention of cadmium in cadmium-naive normal and iron-deficient rats as well as in cadmium-induced iron-deficient animals

The retention of cadmium was investigated in cadmium-naive normal and iron-deficient rats in comparison to rats with cadmium-induced iron deficiency. Rats subchronically (4 weeks) exposed to dietary cadmium (28, 56, 112 ppm Cd and 28 ppm Fe) received a radioactively labeled dose of 2 mumol Cd/kg body wt; acutely (no cadmium exposure with diet) treated rats received doses between 1 and 8 mumol Cd/kg body wt. Two animals of each group received iron (1 mumol/kg as 59FeSO4 in order to monitor iron absorption in parallel. After a period of 4 weeks of feeding a cadmium-fortified diet, the test dose was administered and after a 2-weeks period 109Cd and of 59Fe retention was determined. The results showed in part an unexpected pattern of cadmium retention: subchronic feeding of cadmium induced iron deficiency. This implies an immediate interaction between the two metals with regard to intestinal transfer of iron. The retention of iron was increased in the Cd-induced anemia to the same extent as that in iron deficiency induced by iron restriction. Cadmium retention in iron deficiency induced by iron withdrawal also showed a marked increase, which implies that iron deficiency stimulates the intestinal transfer system for both metals in a similar way. Contrary to this effect, the cadmium retention in cadmium-induced iron deficiency was reduced to about 30% of control values. A self-induced aggravation of the body cadmium burden, as a consequence of the iron deficiency which is known to result from subchronic exposure to feeding of dietary cadmium, was thus excluded.     

Effects of low levels of dietary lead and iron on hepatic RNA, protein, and minerals in young Japanese quail

Day-old Japanese quail were fed purified diets containing either 0.2 (control), 5.4, or 16.2 ppm lead as the acetate with either 25 (deficient) or 100 ppm (adequate control) iron for 2 weeks. Iron deficiency caused decreases in hemoglobin, iron, and manganese in the liver, and hepatic RNA synthesis. Iron deficiency also caused increased concentrations of lead, calcium, and molybdenum in the liver. Lead supplements caused increased concentrations of lead in the liver, and with adequate dietary iron, each supplemental lead level caused a slight decrease in the concentration of RNA in the liver. Treatment had no effect on DNA or protein synthesis, body weight, or liver weight in relation to body weight. These low levels of dietary lead did not cause the same adverse metabolic effects observed by others with higher levels of lead; however, iron deficiency increased lead uptake by the liver and affected RNA synthesis.     

Determinants of copper-deficiency anemia in rats

Indicators of copper and iron metabolism were studied in pregnant rats and their 90-d-old offspring fed copper-sufficient or copper-deficient diets containing marginal or adequate levels of iron from the beginning of pregnancy until the offspring were 90 d of age. Offspring had more severe signs of copper deficiency (including anemia, hypertrophy of the heart, decreased activity of ferroxidase I and II, depression of growth and death) than the dams. In both dams and offspring, copper deficiency resulted in anemia when dietary iron was marginal but not when it was adequate. Liver iron was elevated in copper-deficient male offspring, but not in female offspring. Anemia and growth retardation were more pronounced in copper-deficient males than in females, despite similarly low levels of ferroxidase I and II. Iron absorption was reduced by copper deficiency only in female offspring. Activity of 59Fe in various tissues 6 or 48 h after gavage did not reveal any other effect of copper deficiency on iron metabolism. Thus age at the time copper-deficient diets were introduced, sex and dietary iron strongly influence the effect of copper deficiency.     

Iron deficiency anemia.

The most severe consequence of iron depletion is iron deficiency anemia (IDA), and it is still considered the most common nutrition deficiency worldwide. Although the etiology of IDA is multifaceted, it generally results when the iron demands by the body are not met by iron absorption, regardless of the reason. Individuals with IDA have inadequate intake, impaired absorption or transport, physiologic losses associated with chronological or reproductive age, or chronic blood loss secondary to disease. In adults, IDA can result in a wide variety of adverse outcomes including diminished work or exercise capacity, impaired thermoregulation, immune dysfunction, GI disturbances, and neurocognitive impairment. In addition, IDA concomitant with chronic kidney disease or congestive heart failure can worsen the outcome of both conditions. In this review, the prevalence of IDA related to confounding medical conditions will be described along with its diverse etiologies. Distinguishing IDA from anemia of chronic disease using hematologic measures is reviewed as well. In addition, current diagnostic strategies that are inclusive of clinical presentation, biochemical tests, and differential diagnosis will be outlined, followed by a discussion of treatment modalities and future research recommendations.     

Studies of marginal zinc deprivation in rhesus monkeys: II. Pregnancy outcome

A marginal state of zinc deficiency was induced in the pregnant nonhuman primate, Macaca mulatta, by feeding a diet containing 4 ppm zinc beginning at conception. Pregnancy outcome of marginally zinc-deficient monkeys (ZD) was compared to both pair-fed (PF) and ad libitum fed (AL) control animals (100 ppm zinc). Stillbirths, abortions, and delivery complications were more frequent in both ZD and PF dams than in AL controls; no malformations were detected (maternal plasma zinc was normal during organogenesis). Male ZD neonates weighed significantly less than same sex controls; also, in relation to colony norms, 7/8 ZD males, 2/8 ZD females, and 1/10 PF controls were of low birth weight. Further, plasma zinc and iron levels were lower in ZD neonates than in AL and PF controls. ZD neonates also had reduced muscle tonus. Birth weight and maternal plasma zinc concentration were negatively correlated in ZD group but positively correlated in AL and PF groups. Indeed, maternal plasma zinc concentration alone did not identify a state of zinc deficiency which impaired fetal growth in monkeys.     

Cellular growth in iron-deficient rats: effect of pre- and postweaning iron repletion

Effects of iron deficiency and repletion pre- and postweaning on cell growth in young rats were studied. Pregnant dams were fed 6 or 250 ppm iron. On d 2 of lactation, half of the dams in each group were fed the opposite diet. On d 17, cell growth in the crossed-over groups was similar to controls showing that cellular development is impaired only when the iron deficiency is present during gestation and lactation. In a second experiment pup littermates of dams fed 6 (D), 12 (M) and 250 (C) ppm iron were weaned to either the same diet as fed to their dams DD, MM or CC; repleted with iron DC, MC; or fed the deficient diet CD until 42 d of age. After dietary iron repletion, cell numbers in thymus (DC and MC) and liver (DC) were greater than those of deficient littermates, but were less than those of controls (CC). Iron repletion postweaning reduced the cardiac hypertrophy (DC vs. DD and MC vs. MM) and increased splenic cell number compared to unrepleted deficient littermates (DC vs. DD). Thus, the severity and reversibility of impaired cellular growth is dependent on the timing and severity of the deficiency and the organ affected.     

Toxicity of nickel to a soil-dwelling springtail, Folsomia fimetaria (Collembola: Isotomidae).

Exposure of the collembolan Folsomia fimetaria L. to nickel via soil caused significant mortality and reduced growth and reproductive output. Nickel may be present in elevated concentrations due to anthropogenic discharge. Although collembolans are very numerous and important organisms in the soil ecosystem, the effect of nickel has not previously been studied on these organisms. The aim of this study was to investigate the toxic effects of high soil nickel concentrations on the collembolan F. fimetaria following a 3-week exposure in a loamy sand spiked with nickel up to 1000 mg Ni/kg. A 10% decrease in adult female numbers at 427 mg Ni/kg and at 645 mg Ni/kg for adult male numbers was observed for nickel-spiked soil. Juvenile numbers were reduced at 701 mg Ni/kg following a 3-week exposure. The corresponding EC50 values were 786 mg Ni/kg for females, 922 mg Ni/kg for males, and 859 mg Ni/kg for juveniles. The reproductive output seems to be the most sensitive parameter being reduced at soil nickel concentrations above 173 mg Ni/kg (EC10). Adult growth was not affected by soil nickel concentrations up to 1000 mg Ni/kg, but juvenile growth was reduced at concentrations above 480 mg Ni/kg (EC10).     

Iron deficiency and reduced work capacity: a critical review of the research to determine a causal relationship

The causal relationship between iron deficiency and physical work capacity is evaluated through a systematic review of the research literature, including animal and human studies. Iron deficiency was examined along a continuum from severe iron-deficiency anemia (SIDA) to moderate iron-deficiency anemia (MIDA) to iron deficiency without anemia (IDNA). Work capacity was assessed by aerobic capacity, endurance, energetic efficiency, voluntary activity and work productivity. The 29 research reports examined demonstrated a strong causal effect of SIDA and MIDA on aerobic capacity in animals and humans. The presumed mechanism for this effect is the reduced oxygen transport associated with anemia; tissue iron deficiency may also play a role through reduced cellular oxidative capacity. Endurance capacity was also compromised in SIDA and MIDA, but the strong mediating effects of poor cellular oxidative capacity observed in animals have not been demonstrated in humans. Energetic efficiency was affected at all levels of iron deficiency in humans, in the laboratory and the field. The reduced work productivity observed in field studies is likely due to anemia and reduced oxygen transport. The social and economic consequences of iron-deficiency anemia (IDA) and IDNA have yet to be elucidated. The biological mechanisms for the effect of IDA on work capacity are sufficiently strong to justify interventions to improve iron status as a means of enhancing human capital. This may also extend to the segment of the population experiencing IDNA in whom the effects on work capacity may be more subtle, but the number of individuals thus affected may be considerably more than those experiencing IDA.     

Fetal iron balance in the rat

Maternal and fetal iron balance through pregnancy was examined in the rat. The 20th day was selected for detailed study because of the peak iron requirements at that time. The standard diet provided a borderline iron supply to the fetus due to the limited availability of its iron for absorption. When a more available form of iron was used, normal fetal development occurred over a range of dietary iron content from 16 to 2500 mg/kg. At a level of 5 to 8 mg/kg, there was attrition of placental tissues with frequent fetal death and resorption. When the iron-deficient pregnancy was sustained, both maternal and fetal iron deficiency were present. At progressively higher levels of dietary iron, feto-placental iron content was constant despite a progressive increase in maternal iron stores. Fetal iron supply appeared to be determined primarily by plasma iron concentration, and, at normal levels, about 25% of transferrin iron passing through the uterine vasculature, was removed by the intact placentas. Low levels of plasma iron resulted in damage to fetal tissues and reduced the capacity of placental tissues to take up iron. At high levels of plasma iron, plasma iron turnover initially increased 5-fold over basal levels in nonpregnant animals due to increased placental uptake. However, with continued hyperferremia, uptake was regulated so as to maintain fetal iron at a normal level. A comparison of these data with human iron requirements explained the occurrence of both maternal and fetal iron deficiency in the rat, but only maternal iron deficiency in the human.     

Studies on the role of nickel in the ruminant

Lambs were fed 6 to 7% of metabolic body weight per day of a basal purified diet low in nickel (65 ppb) or the basal diet plus 5 ppm nickel for a 97 day period in an attempt to demonstrate an essential role for nickel in the ovine. Weight gains for the entire period and digestibility of dry matter and of protein at 28 and 56 days were not different between the two groups. At 28 days, but not at 56 days, urinary nitrogen was less and percentage retention of absorbed nitrogen was greater in the supplemented lambs. Total serum proteins were higher at 56 days and serum alanine transaminase was higher throughout the experiment in the nickel supplemented lambs, but only significantly so at 56 days. When lambs were given an oral dose of 65Ni, the low nickel lambs tended to excrete more in the feces and retained less in the kidney, lung, and liver at 72 hours post dosing. The major excretory route of nickel was via the feces. The kidney retained the highest concentration of 65Ni of the organs examined.     

Obesity as an Emerging Risk Factor for Iron Deficiency

Iron homeostasis is affected by obesity and obesity-related insulin resistance in a many-facetted fashion. On one hand, iron deficiency and anemia are frequent findings in subjects with progressed stages of obesity. This phenomenon has been well studied in obese adolescents, women and subjects undergoing bariatric surgery. On the other hand, hyperferritinemia with normal or mildly elevated transferrin saturation is observed in approximately one-third of patients with metabolic syndrome (MetS) or nonalcoholic fatty liver disease (NAFLD). This constellation has been named the “dysmetabolic iron overload syndrome (DIOS)”. Both elevated body iron stores and iron deficiency are detrimental to health and to the course of obesity-related conditions. Iron deficiency and anemia may impair mitochondrial and cellular energy homeostasis and further increase inactivity and fatigue of obese subjects. Obesity-associated inflammation is tightly linked to iron deficiency and involves impaired duodenal iron absorption associated with low expression of duodenal ferroportin (FPN) along with elevated hepcidin concentrations. This review summarizes the current understanding of the dysregulation of iron homeostasis in obesity.     

Effects of Increasing Levels of Nickel Contamination on Structure of Offshore Nematode Communities in Experimental Microcosms

A microcosm experiment was used to examine the effects of nickel on offshore nematode communities of a Tunisian coastal zone (Southwestern Mediterranean Sea). Sediments were contaminated with three nickel concentrations [low (250 ppm), medium (550 ppm) and high (900 ppm)], and effects were examined after 30 days. Results showed significant differences between nematode assemblages from undisturbed controls and those from nickel treatments. Most univariates measures, including diversity and species richness, decreased significantly with increasing level of Ni contamination. Results from multivariate analyses of the species abundance data demonstrated that responses of nematode species to the nickel treatments were varied: Leptonemella aphanothecae was eliminated at all the nickel doses tested and seemed to be intolerant species to nickel contamination; Daptonema normandicum, Neochromadora trichophora and Odontophora armata which significantly increased at 550 ppm nickel concentration appeared to be “opportunistic” species at this dose whereas Oncholaimus campylocercoides and Bathylaimus capacosus which increased at all doses tested (250, 550 and 900 ppm) seemed to be “nickel-resistant” species.     

Zinc deficiency and impaired platelet aggregation in guinea pigs

Previous studies have shown that acute zinc deficiency results in impaired platelet aggregation in humans and rats as well as decreased sensitivity to such aggregating agents as ADP, arachidonate and collagen. This study was designed to evaluate the effect of zinc deficiency on platelet function and other pathology in the guinea pig. Guinea pigs of mixed sex were fed a purified diet based on soybean protein (1 ppm Zn) or a similar control diet (100 ppm Zn). In one trial weanling guinea pigs, weighing about 150 g, were fed the diets for 22 days. Those fed the basal diet failed to grow after 2 weeks, and food consumption decreased at this time although it did not become cyclic. They developed skin lesions; zinc concentrations were decreased in plasma, red cells and liver. There was no effect on the packed cell volume. Guinea pigs weighing 350 g and fed the basal diet for 18 days showed little or no effect on growth rate and food intake, but tissue zinc levels were decreased. Plasma zinc dropped significantly within 24 hours. Platelet aggregation in response to minimal levels of ADP and a prostaglandin endoperoxide analog (U-44069) was severely impaired. Aggregation in response to bovine thrombin (1 unit/ml) was significantly delayed, but the partial response in the presence of indomethacin was not affected by zinc deficiency. The results suggest that impaired platelet aggregation is a general sign of zinc deficiency in mammals and that the function of the physiological eicosanoids is impaired.     

2009年唐山市路北区儿童指血中五种微量元素的调查分析

目的:了解路北区0~6岁儿童指血中钙、镁、铜、铁、锌的变化规律,提高0~6岁儿童不同年龄段幼儿保健水平。方法:采用原子吸收法测定钙、镁、铜、铁、锌的含量。结果:男女儿童指血中钙、镁、铜含量差异无统计学意义,铁缺乏率最高为婴儿期女童组,有随年龄增加铁缺乏率最高组向学龄前组转化的趋势;锌缺乏率最高为婴儿期男童组,也有随年龄增加向学龄前组发展的趋势。结论:路北区0~6岁儿童指血中钙、镁、铜含量不缺乏,趋于合理。铁、锌在不同程度上存在缺乏状况,应加强保健指导,促进两种元素的吸收,改善铁、锌缺乏状况。     

Factors affecting iron absorption and the role of fortification in enhancing iron levels

Iron is an important micronutrient required for a number of biological processes including oxygen transport, cellular respiration, the synthesis of nucleic acids and the activity of key enzymes. The World Health Organization has recognised iron deficiency as the most common nutritional deficiency globally and as a major determinant of anaemia. Iron deficiency anaemia affects 40% of all children between the ages of 6 and 59 months, 37% of mothers who are pregnant and 30% of women between the ages of 15 and 49 years worldwide. Dietary iron exists in two main forms known as haem iron and non-haem iron. Haem iron is obtained from animal sources such as meat and shows higher bioavailability than non-haem iron, which can be obtained from both plant and animal sources. Different components in food can enhance or inhibit iron absorption from the diet. Components such as meat proteins and organic acids increase iron absorption, while phytate, calcium and polyphenols reduce iron absorption. Iron levels in the body are tightly regulated since both iron overload and iron deficiency can exert harmful effects on human health. Iron is stored mainly as haemoglobin and as iron bound to proteins such as ferritin and hemosiderin. Iron deficiency affects individuals at increased risk due to factors such as age, pregnancy, menstruation and various diseases. Different solutions for iron deficiency are applied at individual and community levels. Iron supplements and intravenous iron can be used to treat individuals with iron deficiency, while various types of iron-fortified foods and biofortified crops can be employed for larger communities. Foods such as rice, flour and biscuits have been used to prepare fortified iron products. However, it is important to ensure the fortification process does not exert significant negative effects on organoleptic properties and the shelf life of the food product.     

Effect of iron on serum 25-hydroxyvitamin D and 24,25-dihydroxyvitamin D concentrations.

In 13 of 17 infants (aged 10.5 +/- 4.3; mean +/- SD mo) with iron-deficiency anemia, the serum 24,25-dihydroxyvitamin D concentration was below the normal range and in 9 of these 13 the serum 25-hydroxyvitamin D concentration was below the normal range despite the fact that these infants received 10 micrograms vitamin D/d from the age of 1 mo. The infants were treated with intramuscular iron dextran (Imferon). The iron-dextran treatment increased the hemoglobin and serum iron concentrations as well as 25-hydroxyvitamin D and 24,25-dihydroxyvitamin D concentrations. It is known that iron deficiency impairs fat and vitamin A intestinal absorption. Therefore, it is suggested that absorption of vitamin D may also be impaired. This may contribute to the development of vitamin D deficiency. Iron supplementation may have improved the absorption of vitamin D in the small intestine and hence increased the vitamin D concentration in the plasma.     

Postweaning carnitine supplementation of iron-deficient rats

Severe iron deficiency in the suckling and weanling rat is associated with lipid accumulation in serum and liver, impaired ketogenesis in the suckling pup and low levels of carnitine in some tissues. Carnitine has been effective in reducing high triacylglycerol levels in humans and rats. This study examined tissue triacylglycerol concentrations of iron-deficient rats supplemented with carnitine or iron. Iron-adequate (C) and iron-deficient (D) pups were weaned to diets containing 38 ppm Fe (c) or 6 ppm Fe (d) with or without 0.2% DL-carnitine (Carn) resulting in six experimental treatments: CcCarn, DdCarn, Cc, Cd, Dc, Dd. Males received the diets for 2 wk and female littermates for 4. After 2 and 4 wk, carnitine supplementation significantly increased carnitine content in liver, heart and skeletal muscle by 30-60% in rats from control and Fe-deficient dams. Carnitine treatment significantly lowered the triacylglycerol level in liver of 49-d-old Fe-deficient females, but did not affect other tissues at either time point compared to other dietary treatments. Fe supplementation did not increase carnitine content in tissues, but did reduce triacylglycerol levels in liver by 4 wk and in skeletal muscle at both time points. Possible mechanisms by which iron and carnitine may lower lipids are discussed.     

Effects of dietary nickel and protein on growth, nitrogen metabolism and tissue concentrations of nickel, iron, zinc, manganese and copper in calves

Thirty male calves were used in a 2 X 3 factorial arrangement of treatments to determine the effects of dietary nickel and protein on performance, urease activity and tissue concentrations of nickel, iron, zinc, copper and manganese. Protein levels evaluated were 10.0, 12.25 and 14.5%, and nickel was supplemented at a level of 0 or 5 mg/kg of diet. Nickel did not affect growth during the 140-d study but tended to increase efficiency of gain in calves fed 14.5% protein. Rumen fluid urease activity was increased by nickel only in animals receiving the low protein diet. Urease activity in rumen fluid was higher in calves fed 10.0% than in animals fed 12.25% or 14.5% protein. Neither nickel nor protein affected urease activity in rumen epithelium. Increasing dietary protein resulted in increased urease in cecal digesta. Lung, liver, kidney and serum nickel concentrations were increased by supplemental nickel. A nickel X protein interaction was noted for kidney nickel. Nickel supplementation increased kidney nickel to a greater degree in calves fed 10.0% protein than in calves fed higher protein levels. Nickel supplementation reduced iron concentrations in lung, liver and muscle and manganese concentrations in muscle. Increased dietary protein decreased iron in liver and spleen but increased manganese concentrations in heart. These findings indicate that dietary protein influences responses of ruminants to nickel supplementation and relatively small increases in dietary nickel and protein can influence metabolism of other trace elements.