Minerals

Chapter 5 Minerals • Macroelements: Calcium, Phosphorus, Sodium, Potassium,Chlorium, Magnesium, • Microelements(Trace elements): Iron,Zinc,Copper,Selenium, Fluoride,Manganese, Chromium,Iodine and other trace elements.

Calcium • Calcium is responsible for structural functions involving the skeleton and soft tissues and regulatory functions such as neuromuscular transmission of chemical and electrical stimuli, cellular secretion, and blood clotting. More than 99% of body calcium is in the skeleton.

• Calcium is the most abundant divalent cation in the human body, making up 1.5-2.0% of its total weight. All living things possess powerful mechanisms to conserve calcium and to maintain constant cellular and extracellular fluid (ECF) calcium concentrations.''3 The physiological functions of calcium are so vital to survival that in the face of severe dietary deficiency or abnormal losses, the same mechanisms can demineralize bone to prevent even minor hypocalcemia. Bone provides a vital and readily available source of calcium for the maintenance of normal ECF calcium concentrations, ≈ 50% of which is ionized (Ca2+) and physiologically active.

• The endocrine system that helps maintain calcium homeostasis in vertebrates is integrated and complex. It involves the interaction of two polypeptide hormones, parathyroid hormone (PTH) and calcitonin (CT), and a sterol hormone, 1,25dihydroxycholecalciferol (calci-triol).

• Biosynthesis and secretion of the polypeptide hormones are regulated by a negative feedback mechanism involving ECF Ca2+ The biosynthesis of calcitriol from the major circulating metabolite of vitamin D, 25hydroxycholecalciferol (calcidiol), takes place in the kidney and is regulated by PTH and CT as well as by concentrations of calcium and phosphate in the ECF.

• Other hormones, such as insulin, cortisol, growth hormone, thyroxine, epinephrine, estrogen, and testosterone, together with several growth factors (e.g., the insulin-like growth factors IGF1 and 2) and some compounds not yet identified, as well as certain physical phenomena, have roles in modifying and regulating organ responses to PTH, CT, and calcitriol.

Plasma Calcium • Plasma calcium is distributed in three major fractions:ionized, protein-bound, and complexed. The ionized form (Ca2+ ), the only biologically active species, constitutes 46-50% of total calcium. The proteinbound fraction, roughly equivalent to the ionized fraction in amount, is biologically inert.

• The normal range for total serum calcium is narrow (2.2-2.5 mmol/L) and the same is true for the ionized fraction. Thus, values for total calcium <2.2 mmol/L, assuming that plasma protein concentrations are normal, reflect clinically significant hypocalcemia, and values >2.5 mmol/L reflect hypercalcemia. Hypocalcemia produces a myriad of symptoms and, when severe, can result in tetany and possibly convulsions. Hypercalcemia can produce functional changes in most organ systems, which may lead to a confusing variety of symptoms and objective findings.

Calcium Economy • The amounts of dietary calcium required to maintain metabolic balance (dietary intake equal to urinary and fecal excretion) vary with physiological need, intestinal absorption, and kidney retention. Dietary deprivation of calcium induces adaptive changes in the production and secretion of the calciotropic hormones that minimize the development of negative balance of these two ions

• only 30-50% of ingested calcium is normally absorbed (fractional absorption). With decreased intake, serum calcium decreases slightly, and the sequence of events depicted in the left limbs of the feedback loops in the figure is activated.

• In severe chronic dietary deficiency of

calcium in normal subjects, increased PTH secretion stimulates increased plasma calcitriol production, which increases fractional intestinal calcium absorption. It also reduces renal calcium excretion, but this response is less important because of the relatively small percentage of filtered calcium that is excreted. Such changes reduce the consequences of this perturbation on overall body calcium economy.

• The tradeoff for this adaptive response is chronic hyper-parathyroidism, a condition that can induce progressive demineralization of bones. Thus, as is the case for most adaptive mechanisms, they are beneficial when applied over a relatively short period of time, but when applied chronically, can have destructive effects of considerable consequence. The intestine plays the major adaptive role in dietary calcium deficiency,

Main functions of calcium • • • • • • • • •

Functions Structure role

examples bone and teeth calcium is present as calcium phosphate (hydroxyapatite)crystals Muscle contraction calcium binds to troponin C Nerve impulse transmission calcium is realsed in response to hormones and neurotransmitters Blood clotting co-enzyme for coagulation Ion transport and cell signalling intracellular second messenger

Deficiency and excess of calcium • Deficiency 1.In children leads to rickets 2.In adults leads to osteomalacia,that is defective mineralization of bone

Eexcess hypercalcaemia Ca2+ is deposited in many organs, particularly arteries, liver,heart, and kidney, leading to tissue calcification

3.In postmenopausal women this may interferee with organ it may contribute to osteoporosis, function and in the kidney, i.e.loss of bone mass results in the formation of renal stone

Table 1. Recommended dietary allowances for calcium Category and age

RDA(mg/day)

Infants 0-0.5 year

400

0.5-1.0 year

600

Children,1-10 years

800

Adolescents and adults 11-24 years 25 to ≥50 years

1200 800

Iron • Iron deficiency is the most common nutritional deficit worldwide and yet it can be successfully prevented on a population basis. • Total body iron averages ≈ 3.8 g in men and ≈ 2.3 g in women. The iron-containing compounds in the body are grouped into two categories, functional (known to serve a metabolic or enzymatic function) and storage (used for storage and transport of iron).

• Approximately two-thirds of total body iron is functional iron, and most of this is in the form of hemoglobin within circulating erythrocytes. Other iron-containing enzymes and myoglobin make up about 15% of functional iron. About one-third of total body iron in men is in the form of iron stores, whereas in women storage iron accounts for only about one-eighth.

• Nutritional iron deficiency is commonly regarded as an insufficient iron supply to meet the need for functional iron after storage iron has been depleted. At the cellular level, iron deficiency can also result from insufficient release of storage iron despite ample iron intake and stores---e.g., anemia of chronic disease. Under circumstances of iron overload, iron stores become disproportionately large, and in severe cases can be more than 10× the functional iron component.

Physiology • Among iron compounds serving major biological functions, the best known are heme-containing: hemoglobin for oxygen transport, myoglobin for muscle storage of oxygen, and cytochromes for oxidative production of cellular energy in the form of ATP.

Hemoglobin • Hemoglobin plays a critical role in transferring oxygen from lung to tissues. Its structure of four hemes and four globin chains provides an efficient mechanism to combine with oxygen without being oxidized. A remarkable feature of hemoglobin is its ability to become almost fully oxygenated during the short erythrocyte transit time in pulmonary circulation, and then to become largely deoxygenated as erythrocytes traverse tissue capillaries.

• A number of factors affect the oxygen affinity of hemoglobin as measured by the oxygen dissociation curve: partial pressure of oxygen, pH, temperature, and organic phosphate content. With moderate anemia, biochemical changes to improve oxygen unloading to tissues compensate for the reduced oxygen carrying capacity of blood. With severe anemia, however, the markedly reduced hemoglobin content decreases oxygen delivery and can lead to chronic tissue hypoxia. Even though a lack of iron is the most common reason for anemia, many other pathological conditions can affect hemoglobin or erythrocyte production, leading to anemia and a reduced oxygen carrying capacity of blood.

Myoglobin • Myoglobin consists of a single heme with a single globin chain. Myoglobin is present only in muscles, where it accounts for ≈ 5 mg/g of tissue. The primary function of myoglobin is to transport and store oxygen within muscle and to release it to meet increased metabolic needs during muscle contraction. Myoglobin makes up ≈ 10% of total body iron. In rats, skeletal muscle myoglobin decreases with iron deficiency.

Cytochromes • Cytochromes are heme-containing compounds critical to respiration and energy metabolism through their role in mitochondrial electron transport. Cytochromes a, b, and c are essential to the production of cellular energy by oxidative phosphorylation: they serve as electron carriers in transforming adenosine diphosphate (ADP) to adenosine triphosphate (ATP), the primary energy-storage compound. Animals with significant iron deficiency show depleted levels of cytochromes b and c and limited rates of oxidation by the electron transport chain.

• Cytochrome c is a pink protein and is the most easily isolated and best characterized of the cytochromes. Like myoglobin, cytochrome c is made up of one globin chain and one heme group containing one iron atom. The cytochrome c concentration in man ranges from 5 to 100 µ g/g of tissue, and is highest in tissues such as heart muscle that have a high rate of oxygen utilization.

• Cytochrome P450 is located in microsomal membranes of liver cells and intestinal mucosal cells. The primary function of this cytochrome is the breakdown of various endogenous compounds and chemicals or toxins from external sources by oxidative degradation.

Other iron-containing enzymes • Nonheme iron-containing enzymes such as the ironsulfur complexes of NADH dehydrogenase and succinate dehydrogenase are also involved in energy metabolism. These enzymes are required for the first reaction in the electron transport chain, and account for more iron in mitochondria than do cytochromes. In iron-deficient rats, these dehydro-genases are severely depleted. • Another group of iron-containing enzymes known as hydrogen peroxidases act on reactive molecules that are by-products of oxygen metabolism.

• Other enzymes that require iron for their function include aconitase, an enzyme of the tricarboxylic acid cycle; phosphoenolpyruvate carboxykinase, a rate-limiting enzyme in the gluconeogenic pathway; and ribonucleotide reductase, an enzyme required for DNA synthesis.

Iron Deficiency • Iron deficiency is the most common nutritional deficiency in the United States and worldwide, affecting mainly older infants, young children, and women of childbearing age. In developing countries it is estimated that 30-40% of young children and premenopausal women are affected by iron deficiency. Young children are most susceptible to iron deficiency because they require relatively high amounts of iron for rapid growth during the first 2 years of life, and their usual diet is low in iron unless added as a nutritional supplement.

Stages of iron deficiency •

A number of hematological and biochemical tests reflecting different aspects of iron metabolism are used to characterize the iron nutritional status. • Serum ferritin is the test of choice for assessing iron stores. • Stainable iron of a bone marrow aspirate can be used for the same purpose but involves a more elabo-rate and somewhat painful procedure. • Serum iron concentration (Fe), total iron binding capacity (TIBC), andtransfer-Tin saturation (Fe/TIBC) reflect iron supply to tissues.

• Protoporphyrin, the precursor of heme, is elevated in erythrocytes when the supply of iron for heme synthesis is insufficient. • Transferrin receptors respond to an insufficient iron supply to cells and be-come elevated on cell surfaces and in plasma. • Erythrocyte size--measured as mean corpuscular volume (MCV)and hemoglobin concentration are reduced as a consequence of significant iron deficiency. • Another measure reflects the variability of erythrocyte size and is called red cell distribution width (RDW). This value is elevated in iron deficiency, when red cell size becomes increasingly variable.

• Anemia occurs when hemoglobin production is sufficiently depressed to result in a hemoglobin concentration or hematocrit below the central 90% or 95% of range for healthy persons of the same age and sex. • A diagnosis of iron-deficiency anemia is made when anemia is accompanied by laboratory evidence of iron deficiency, such as low serum ferritin, or when there is a rise in hemoglobin in response to iron treatment.

• Iron status is expressed as one of five stages ranging from iron overload to severe iron deficiency. • Overload • Normal • Depleted stores: • Iron deficiency • Iron deficiency anemia

The dignosis of iron deficiency • 1 、 Iron deficiency,ID ： SF<30µ g/L; • 2 、 Iron deficiency erythropoiesis,IDE ） : SF<30µ g/L, FEP>0.9µ mol/L or FEP/Hb(× 102 ） >0.81 • 3 、 Iron deficiency anemia, IDA ） : SF<30µ g/L,FEP>0.94µ mol/L or FEP/Hb(× 102 ） >0.81;Hb<120g/L

•4、

subclinical ID+IDE

• Iron depletion can be categorized into three stages ranging from mild to severe. • The first stage involves only decreased iron stores as measured by decreased serum ferritin. This stage is not associated with adverse physiological consequences, but does represent increased vulnerability from long-term marginal iron balance that might progress to a more severe deficiency with functional consequences. With low iron stores, there is a compensatory increase in iron absorption that often helps prevent progression to more severe stages.

• The second stage of iron depletion is characterized by biochemical changes that reflect a lack of sufficient iron for normal production of hemoglobin and other essential iron compounds, but as yet there is no frank anemia. • Typically there is decreased transferrin saturation or increased erythrocyte protoporphyrin, serum transferrin receptor, or RDW. Because the hemoglobin concentration does not yet fall below levels considered indicative of anemia, this stage is often described as iron deficiency without anemia.

• The third stage of iron depletion is frank irondeficiency anemia, which varies in severity according to how low the hemoglobin concentration is. • In the United States, most cases of iron-deficiency anemia among children and women are mild, characterized by a hemoglobin within 10 g/L of the lower limit of normal for that group. Iron deficiency, however, can result in severe anemia, defined as hemoglobin <70g/L by the World Health Organization. In certain developing countries, severe iron deficiency anemia is common.

Consequences of Iron Deficiency • Anemia • Work performance • Behavior and intellectual performance • Body temperature regulation • Immunity and resistance to infections • Lead poisoning • Adverse pregnancy outcomes

Prevention of Iron Deficiency • Iron deficiency can be prevented by increasing the content and bioavailability of iron in the diet. Iron absorption is improved by including meat, fish, poultry, and ascorbic acid-rich foods in meals, and by decreasing consumption of tea and milk with meals. • Iron-fortified cereal products augment the iron content of the diet; those with added ascorbic acid also enhance iron absorption. • Increased use of iron supplements, increased iron fortification of foods, increased use of birth-control pills which decrease menstrual blood loss, and increased intake of ascorbic acid.

• Iron fortification:Ferrous sulfate is commonly used to fortify infant formula and other products sold in cans and jars, as well as bread and other bakery products that have a short shelf-life. • Iron supplementation: The absorption of iron from tablets or liquid supplements is influenced by dose, iron stores of the recipient, whether it is taken with or between meals, and whether it is taken alone or as part of a vitamin-mineral supplement.

Treatment for Iron Deficiency • Ferrous sulfate is the least expensive and most widely used form of oral iron. A total dose equivalent to 60 mg of elemental iron (300 mg ferrous sulfate) per day is ample for an adult if given between meals, first thing in the morning, or at bedtime. For infants ≈ 1 year of age, 30 mg/day (2-3 mg/kg) of elemental iron first thing in the morning rarely causes side effects; this dose is also appropriate and adequate for older children and adolescents.

• A response to treatment should be evident after 1 month, when the deficit in hemoglobin is partially corrected, usually with a rise >10 g/L. Even after a significant hemoglobin response, iron treatment should be continued for another 2-3 months. If there is no correction of anemia after 1 month of iron treatment, further laboratory evaluation (e.g., with serum ferritin) is indicated to either confirm the presence of iron deficiency or determine other causes of anemia.

Iron Requirement and Recommended Daily Allowances • Estimates of average requirements for absorbed iron in adults are based on careful experimental measurements of iron losses. The amount of additional iron that is needed by growing infants and children is calculated from average weight gain and estimates of iron necessary to supply that gain, with iron as hemoglobin, myoglobin, and iron enzymes.

• The current RDA for iron is based on average iron stores of 300 mg and average daily iron losses of 1 mg for men and 1.5 mg for women.110 With a factor of variation of 1.25, the estimated requirement for absorbed iron is 1.3 mg/day for men and 1.8 mg/day for women. Assuming 1015% absorption of dietary iron in the United States, the estimated RDA is 10 mg/day for men and 15 mg/day for women. Pregnant women face increased iron demand for fetal and maternal tissue growth, and their RDA is 30 mg/day.

• For nursing mothers, the iron needed to produce breast milk is approximately 0.15-0.3 mg/day, which is equivalent to the iron saved by cessation of menstrual blood loss during lactation, and therefore their iron requirement is the baseline 15 mg/day. • For infants and children 6 months-3 years of age, the iron RDA of 10 mg/day is calculated on the need for 1 mg absorbed iron/kg/day. • For preterm or low-birth-weight infants, the requirement is 2 mg/kg/day because of lower iron stores at birth and greater rate of growth than term or normal-weight infants.

Dietary Sources of Iron • Breast milk is a better source of iron than nonfortified formula or cow's milk. • Meat is a good source of iron because much of it is in the form of heme iron, which is absorbed 2-3 × more completely than nonheme iron. In addition, factors in meat promote nonheme iron absorption from the entire meal. • Nonheme iron absorption can be enhanced by ascorbic acid ingested with the meal.

Iron Excess and Toxicity • Acute iron toxicity or poisoning • Hemolytic anemia of preterm infants • Chronic iron toxicity and iron overload • Hereditary hemochromatosis • Iron overload from excessive oral intake • Iron overload from repeated transfusions for severe anemia

Relationship between iron status and risk of disease

• Iron status and risk of cancer • Iron status and risk of coronary heart disease

ZINC • The zinc content of the human body (1.52.5 g) approaches that of iron. This level is maintained with absorption of about 5 mg/day. • Zinc is absorbed from the small intestine, primarily the duodenum and jejunum but also the ileum. • Absorption of zinc also occurs from rat colon.

• Homeostatic control of zinc metabolism involves a balance between absorption of dietary zinc and endogenous secretions through adaptive regulation programmed by the dietary zinc supply. • The intestine is the key organ in maintaining that balance. When isolated from systemic influences and pancreatic secretions, the intestine retains evidence of adaptation to absorption programmed by previous dietary intake

Physiological (Biochemical) Function • The biochemical functions of zinc that determine physiological effects have received extensive study. • Three different functions--catalytic, structural, and regulatory---define the role of zinc in biology.

Catalytic roles • Catalytic roles are found in enzymes from all six classes of enzymes.92 Examples are the RNA nucleotide transferases (RNA polymerases I, II, and III), alkaline phosphatase, and the carbonic anhydrases

The structural function • The structural function of zinc is a rapidly expanding area of biological investigation. Structural roles for zinc in metalloenzymes exist. The cytosolic enzyme CuZn superoxide dismutase (Cu/Zn SOD) is an example; copper functions at the catalytic site whereas zinc has a role in structure.10 The zinc finger motif in proteins repre-sents an extremely important structural role.

Regulatory function • A third generalized biochemical role for zinc is as a stimulator of transacting factors responsible for regulating gene expression. The only wellstudied example of this role is in the expression of MT or MT-like proteins. • The basic components are a metal-binding transcription factor (MTF) and an MRE in the promoter of the regulated gene. The MTF acquires zinc in the cell cytosol or nucleus and then is able to interact with the MRE to stimulate transcription.

• Beneficial effects of zinc in protection against various noxious agents (including organic compounds), χ and γ radiation, and infectious agents (endotoxins, etc.) have been well documented. • Zinc may act as a regulator of apoptotic cell death. The biochemical role has not been defined. At high zinc levels (>500µ mol/L), in vitro evidence suggests that zinc inhibits apoptosis induced by glucocorticoids."' Zinc may act by endonuclease inactivation, poly(ADP-ribose) synthetase inhibition, or stimulation of protein kinase C activity.

Role of zinc in the body • Functions • • • • • • •

deficiency

Co-factors of over 100 Causes growth retardation, Enzymes,e.g. Hypogonadism, and delayed Dehydrogenase,e.g.LDH wound healing Peptidases Carbonic anhydrase Enzymes of DNA and protein synthesis these effects are Superoxide dismutase mainly a result of

• Transcription factors are thought to contain ‘ decreased activity of zinc finger’ that enable them to bind DNA the enzymes of DNA synthesis

Deficiency • The reduction in growth with reduced zinc in the diet is coincident with a reduction in endogenous losses. • Reduced zinc intake clearly results in thymic atrophy in pigs and cattle and reduced T-helper cell function in mice. Total parenteral nutrition (TPN) without adequate zinc leads to decreased natural killer cell activity. • Reduced plasma zinc concentrations are common in inflammatory bowel disease, which may indicate reduced zinc absorption or increased zinc losses, and may respond to zinc therapy.

Requirement and Status Assessment • The World Health Organization estimates lactating women need to absorb 5.5 mg Zn/day. • Physiological factors undoubtedly influence the zinc requirement to some extent. RDAs are determined on the basis of age, sex, pregnancy, and lactation. • The RDA for zinc is 5 mg/day for infants, 10 mg/day for children under 10 years, 15 mg/day for males over 10 years, 12 mg/day for females over 10 years, 15 mg/day during pregnancy, and 19 and 16 mg/day for lactation during the first and second 6 months, respectively.

Food and other resources • Foods vary greatly in their inherent zinc content, with red meat and shellfish constituting the best sources of zinc. Foods of vegetable origin tend to be low in zinc except for the embryo portion of grains, such as wheat germ. • The presence of phytic acid in plant products is a major factor that limits zinc bioavailability from these sources.

• Zinc bioavailability is greater from human milk than cow's milk or soy protein. • Zinc supplements, either zinc alone or combined mineral or vitamin-mineral preparations, are widely used. Reasons for using zinc supplements include concern that dietary intake may not provide sufficient zinc (as in a vegetarian diet) or belief that zinc has health-promoting properties.

Excess and toxixity • Acute zinc toxicity results in gastric dis-tress, dizziness, and nausea. • Death has occurred with large TPN doses of zinc. • Gastric problems are observed in chronic toxicity. • Among other chronic effects are reductions in immune function (decrease in lymphocyte stimulation to phytohemagglutinin) and highdensity lipoprotein (HDL) cholesterol reported with very high supplements (300 mg zinc/day).

• A depression in lymphocyte stimulation was not observed at 100 mg zinc/ day. In contrast, supplementation at 150 mg zinc/day in females decreased low-density lipoprotein and lowered serum ceruloplasmin ferroxidase activity. No significant changes in HDL were found. • Hypocupremia observed when sickle cell anemia patients were treated with 150 mg zinc/day resulted from a zinc-induced copper deficiency.

Role of zinc in the body • Functions • • • • • • •

deficiency

Co-factors of over 100 Causes growth retardation, Enzymes,e.g. Hypogonadism, and delayed Dehydrogenase,e.g.LDH wound healing Peptidases Carbonic anhydrase Enzymes of DNA and protein synthesis these effects are Superoxide dismutase mainly a result of

• Transcription factors are thought to contain ‘ decreased activity of zinc finger’ that enable them to bind DNA the enzymes of DNA synthesis