Essential Minerals

C H A P T E R

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Essential Minerals MACROMINERALS Calcium, phosphorus, potassium, sodium, chloride, magnesium, and iron are, overall, only 3.2%–3.3% of a normal adult body weight. However, despite these relatively low levels, these minerals play essential physiological roles.

Sodium (Na) A normal adult has 60 mEq. of sodium per kilogram of body weight, a total amount of approximately 4200 mEq. (∼100 g); 55% of the sodium is in extracellular fluids (ECFs), 40% is in bone, and the rest is found in the intracellular compartment. The body contains two types of sodium deposits, one that can be easily exchanged between body compartments and another that is not readily available for exchange. The first corresponds to the sodium present in the intra- and extracellular spaces and almost half of that contained in bone. The second deposit is less dynamic and is confined to the bone matrix. Sodium and chloride are the major electrolytes of the extracellular compartment and the main determinants of the water volume in that space. Sodium is maintained at relatively high and potassium at relatively low concentrations in the extracellular space compared to

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the intracellular space, due to the activity of the Na+,K+-ATPase. Natural sources. Sodium concentration in biological media tends to parallel that of chloride. Milk, meat, eggs, and vegetables provide only 10% of the sodium consumed daily. The salt added to food is the main source. The 43% of NaCl mass corresponds to sodium. Sodium intake varies between 100 and 200 mEq./day (6–12 g of NaCl); to maintain the balance, a similar amount is eliminated. Sodium intake is influenced by salt appetite and it is regulated by the renin–angiotensin system; the mechanism of thirst also plays a significant role in sodium uptake and dilution. Absorption. Practically all of the ingested sodium is absorbed in the intestine. Less than 5% is excreted with the feces. Sodium enters the enterocytes by several different mechanisms driven by the Na+ gradient created by the Na+,K+ATPase. A small portion can use the paracellular pathway, through the tight junctions between enterocytes. From the brush border, Na+ passes to the basolateral membrane, where the Na+,K+ATPase transports it into the interstitial space and from there it reaches the blood. Plasma sodium concentration is normally maintained between 135 and 145 mEq./L (average 320 mg/dL); in interstitial fluid it is slightly lower due to the Gibbs–Donnan equilibrium.

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In the intracellular space the Na+ level is much lower, with an average of 10 mEq./L. This great difference in concentrations on either side of the plasma membrane is maintained by the activity of the Na+,K+-ATPase. Sodium is responsible for half of the osmotic pressure in the ECF compartment. Excretion. Na+ is excreted mainly by urine (more than 90% of total). Na+ is also eliminated through skin with sweat, which has a concentration of approximately 50 mEq./L. The liquid evaporated by insensible perspiration is practically free of Na+. Only when the temperature is high, under strong physical activity or fever, Na+ and water loss via sweating becomes important. Excretion of Na+ also takes place in the intestine. The amount of Na+ lost via this route is very small (not more than 2 mEq./day), but increases markedly in cases of severe diarrhea or via catheters placed in the digestive tract. Renal handling of sodium. Regulation of Na+ excretion by the kidney is essential in maintaining body salt and water balance. In normal adults, the renal glomeruli filter approximately 27,000 mmol of Na+ per day. More than 99% is reabsorbed back by the renal tubules; only 150 mmol are excreted with the urine. Excretion of Na+ in urine is adjusted to the intake to maintain Na+ balance. If the amount of sodium in foods is completely suppressed, the Na+ excreted in urine falls to undetectable levels after 24–48 h. Most of the sodium filtered in glomeruli is reabsorbed in proximal convoluted tubules (∼60%–70%), the rest in the loop of Henle (∼25%) and distal and collecting tubules (∼5%–10%). Sodium reabsorption in the tubules is controlled by several hormones:

Aldosterone is responsible for 5%–10% of total Na+ reabsorption. It acts on the distal nephron (principal cells of the collecting duct), where it stimulates the expression of new Na+ channel molecules and increases the activity of preexisting Na+ channel units in the apical membrane of the cells. It also stimulates the Na+,K+-ATPase in the basolateral membrane of the cells, which in addition to enhance Na+ reabsorption, promotes K+ secretion to the tubular fluid. Due to the stimulatory action of the proton ATPase, aldosterone favors the renal excretion of H+. Aldosterone also promotes Na+ absorption in the colon. Atrial natriuretic peptide (ANP) stimulates Na+ excretion when there is an expansion of the ECF. ANP increases glomerular filtration pressure and reduces Na+ reabsorption in the renal collecting duct.

Angiotensin II regulates Na+ reabsorption in the proximal convoluted tubule. It also promotes Na+ and water absorption in proximal intestine. This effect contributes to increase plasma volume and blood pressure. Other effects of angiotensin II are secondary to its ability to activate aldosterone synthesis and secretion.

Na+ daily requirements. An intake of 500 mg/day is the minimum amount of Na+ recommended. Ingestion of larger amounts is not advisable; in patients with hypertension and cardiac failure, Na+ from the diet must be reduced to diminish the effects on the volume of the ECF. Alterations of Na+ homeostasis. Failure of the mechanisms that control Na+ balance results in an alteration of body salt and fluid volume homeostasis. Total Na+ content in the body can vary due to changes in either its intake or output. There are no effective mechanisms to adjust sodium intake in response to changes in the vascular volume and Na+ regulation is mainly achieved by changes in salt handling by the kidney. Disorders resulting in sodium accumulation in the body tend to increase the interstitial space fluid volume, with production of edema. This situation occurs in congestive heart failure, hypoalbuminemia, renal diseases that affect sodium excretion, and hyperaldosteronism. On the other hand, Na+ depletion occurs in severe diarrhea, fistulas or drainage of intestinal

 



Macrominerals

fluids, excessive sweating without salt replacement, extensive burns that cause fluid and electrolytes loss through the skin, inability to reabsorb sodium by kidney tubules, or hypoaldosteronism. The plasma Na+ concentration does not always reflect changes in total body Na+ content. Sodium retention may not be manifested by hypernatremia. Hypernatremia occurs when there is relative excess of sodium with respect to water, or when there is proportionately greater loss of water than sodium. Hypernatremia can appear even when there is a sodium deficit. Hyponatremia occurs when sodium loss exceeds water loss, or when water is in relative excess compared to sodium. This leads to hyponatremia due to fluid dilution, which can occur even if the total body content of Na+ is normal or increased. Its symptoms include cramps, nausea, vomit, dizziness, shock, and even coma. Given the amount of sodium added to foods, deficiency of dietary Na+ is extremely rare. It can result from profuse sweating (of 3% or more of body weight). Sodium and hypertension. Increased Na+, whatever is the cause that originates it, results in increase in effective vascular volume and blood pressure elevation. Salt restriction is effective in lowering blood pressure. A reduction of 4 g daily in salt intake causes a drop from 5 to 3 mmHg in systolic and diastolic pressures in hypertensive patients, and from 2 to 1 mmHg in normotensive patients.

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Potassium (K)

the plasma membrane is maintained by the activity of the Na+,K+-ATPase, which introduces K+ from the extracellular space into the cell. Potassium has two main functions: (1) it plays an important role in cell metabolism, for example, it is essential for protein and glycogen synthesis. (2) The relationship between the K+ extracellular and intracellular concentrations is the major determinant of plasma membrane resting potential, required for the generation of action potentials, which are critical for nerve and muscle function. Natural sources. Potassium is widely distributed in foods, especially fruits, plants, and meats. Therefore, it is virtually impossible to find potassium deficits through the diet. Fruits and vegetables, especially bananas, citrus, apricots, melons, tomatoes, potatoes have a high K+ content. Polished rice and wheat flour are poor sources of potassium. In general, meat and fish have a higher K+ content than nuts and cereals. The daily intake in a mixed diet is approximately 4 g (102 mEq.). This amount is similar to all the potassium present in the ECF. Absorption. Over 90% of ingested potassium is absorbed in the small intestine and colon. The mechanisms involved in K+ uptake are not known as well as those for Na+. Once in the intestinal cells, K+ diffuses into the interstitial space and blood through potassium channels. Excretion. The kidney is the main organ responsible for K+ excretion and balance modulation. A total of 90%–95% of the ingested K+ is eliminated by the kidneys in a tightly regulated manner. The rest is excreted through the feces and sweat, which is not subjected to regulation. The loss of K+ by the stool is more or less constant, usually less than 10% of the intake, but can be very large in patients with severe diarrhea. There is also significant loss in cases of severe vomiting. Renal handling of potassium. Under a standard diet, approximately 15% of the total K+ filtered in the renal glomeruli is excreted in the urine. This shows that K+ is highly reabsorbed in the

A normal adult has approximately 50 mEq. of potassium per kilogram of body weight, a total of 3500 mEq. or 136 g. A 98% of the K+ is located in the intracellular space, where it represents the most abundant cation. Its concentration in this compartment is ∼150 mEq./L. In blood plasma and ECF its concentration ranges from 4.0 to 5.5 mEq./L. The wide difference for K+ across

 

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tubules. If the diet contains very little or no K+, less K+ appears in urine; however, there is always some K+ present in urine (at least 1% of the amount filtered). Therefore, an individual with a diet low in K+ could develop hypokalemia. The amount of potassium excreted in urine can be greater than that filtered, which indicates that K+ is also secreted by the kidneys. Plasma potassium concentration (or kalemia) and aldosterone are the main factors that regulate K+ secretion, ADH has a lesser effect. Increased extracellular [K+] (hyperkalemia) stimulates aldosterone production and secretion to the bloodstream, which activates K+ secretion in the renal collecting ducts. The hormone increases the number and activity of Na+,K+ATPase molecules in the basolateral membrane of the renal tubular cells, increasing the intracellular K+. The passage of K+ to the tubular lumen is favored by the action of aldosterone in stimulating the activity of K+ channels in the apical membrane of renal tubular cells. Regulation of K+ intracellular and extracellular concentrations. After its intake, the changes in K+ in blood are quickly compensated by its movement to the cells. The total amount of K+ in ICF is so large compared to that in ECF, that the cation displacement from the IC compartment can correct changes in plasma [K+] with insignificant modification of the intracellular concentration. The uptake of K+ by cells is controlled by several hormones. Insulin promotes K+ entry, particularly in skeletal muscle and liver. It produces stimulation of Na+,K+-ATPase. This action depends on the transfer of previously synthesized Na+,K+-ATPase from intracellular stores to the cell plasma membrane. Also, insulin action is secondary to the activation of the Na+/H+ exchanger in the target cells; Na+ entrance into the cells is an important activator of the activity of Na+,K+-ATPase. Catecholamines exert different effects, depending on their action in β2 or α adrenergic receptors. β2 favor K+ entry into cells by

 

activating Na+,K+-ATPase activity. The mechanism involves the increase in cyclic AMP, activation of protein kinase A, and phosphorylation of Na+,K+-ATPase. By stimulating the adrenergic α receptors, epinephrine promotes K+ efflux from cells. Catecholamines also have an indirect action; by stimulating glycogenolysis, they produce a rise in blood glucose and insulin release, which activates K+ entry into cells through the mechanisms listed previously. Aldosterone favors K+ entry into the cells when there is hyperkalemia. It has little or no effect if plasma K+ concentration is normal. Alterations of K+ homeostasis. Maintenance of + K homeostasis is critical since variations in this cation significantly influences heart, skeletal, and smooth muscle cell contractility, and affects nervous system excitability. It is also important in electrolyte and hydrogen ion balance. In general, K+ excess occurs when there is failure in its renal excretion, produced by hypoaldosteronism or renal failure. Also, increase in plasma K+ is usually observed in metabolic acidosis (diabetic keto acidosis), in which there is K+ leakage from the cells into the ECF. The increase of K+ in blood enhances its filtration and secretion in the nephron, which augments urine K+ output. In contrast to acidosis, alkalosis activates the movement of K+ from the ECF to the cells. Potassium deficiency is common during severe diarrhea. Changes in plasma K+ concentration do not solely occur due to changes in the total K+ content of the body; they can be caused by K+ shifts between intracellular and extracellular compartments. In diabetic keto acidosis, for example, hyperkalemia may appear even when total K+ is decreased. Given the large concentration difference between IC and EC spaces, a relatively small shift of intracellular K+ markedly increases serum K+. Hypokalemia causes alterations in ventricular repolarization, which is manifested by changes in heart rate and a characteristic trace in



Macrominerals

the electrocardiogram. Cell membrane potential tends to increase in hypokalemia and decrease in hyperkalemia. Hyperkalemia is manifested by neuromuscular symptoms, such as muscle weakness, mental confusion, numbness, and even paralysis. Arrhythmias and electrocardiographic abnormality appear when K plasma concentration is higher than 5.5 mEq./L. Above 6 mEq./L levels, K+ can cause cardiac arrest. Recommended K+ intake. It is almost impossible to produce hyperkalemia by administration of K+ with the diet in a normal individual; this is due to the effective body control mechanisms for K+. Nutritional hypokalemia is also rare, except when the ingestion of food is suppressed; the abundance of K+ in foods ensures an adequate intake even with poor diets. In any case, ingestion of 3.5 g/day, which is easily provided by a well-balanced diet, is advised. Potassium and high blood pressure. Numerous studies have shown that a diet rich in K+ lowers blood pressure. Eating fruits and vegetables provides good amounts of potassium and is recommended in the prevention and control of hypertension. An increase of 40 mEq./day of K+ in the diet reduces blood pressure more than a decrease of 60–80 mEq./day in sodium intake. Probably the mechanism of this action of K+ on blood pressure is due to stimulation of diuresis.

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Chloride (Cl−)

intake of Cl− in an adult varies between 100 and 200 mEq. Absorption. The intake of Cl− parallels that of Na+, mostly because it enters as NaCl. Chloride is almost entirely absorbed in the small intestine, coupled to Na+, via the Na+/Cl− symporter. Cl− enters the cell against its electrochemical gradient, driven by the energy derived from the Na+ gradient and in exchange for HCO −3 through the C1− /HCO −3 exchanger. From the enterocytes, Cl− is transferred to the ECF via Cl− selective channels and the K+/Cl− symporter driven by the K+ gradient. In addition, Cl− crosses the intestinal epithelium via the paracellular pathway, between the cells. In the gastric mucosa Cl− is secreted into the lumen via specific channels and the activity of a H+,K+-ATPase. Chloride in plasma. Plasma Cl− concentration is 102 mEq./L (365 mg/dL). This value is dependent on the hydration state of the body. Cl− content may be decreased and yet its plasma concentration be normal or even higher if there is an imbalance in chloride and water loss. Due to the Gibbs–Donnan equilibrium, and opposite to what occurs for Na+ and K+, Cl− level in the interstitial fluid is higher than in plasma. Excretion. Cl− is excreted in urine, skin, and feces, with the kidney being the main organ for its elimination. Renal handling of chloride. Under normal conditions, the renal tubules reabsorb nearly all the chloride present in the glomerular filtrate. Cl− reabsorption is mostly associated with Na+ throughout the nephron; the excretion rate is usually similar for both ions and is influenced by the same factors. Chloride balance disorders. Variations in body chloride content follow those of sodium. Generally, Na+ excesses or deficits are accompanied by similar changes in Cl−. Metabolic alkalosis may be an exception, since in this disorder, Cl− loss is greater than that of Na+ (i.e., alkalosis caused by vomiting). Chloride deficiencies can cause seizures.

The main anion in the ECF is chloride. A normal adult has approximately 30 mEq. Cl− per kilogram of body weight (a total of 2.100 mEq. or 75 g). About 88% of Cl− is in the ECF and the rest is in the ICF. The differences in electrical potential across the plasma membrane (cell interior electronegative with respect to the outside) restrict Cl− entry to the cells. Natural sources. Most of the Cl− ingested with food is associated with sodium. Chloride is also found in eggs and meats. The average daily

 

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Calcium (Ca) Calcium is the fifth element in order of abundance in the body, after O, C, H, and N and is the major divalent cation in the ECF. A normal 70-kg adult male has approximately 1.4 kg of calcium; a 60-kg woman, around 1.1 kg; and a newborn at term close to 25 g. Calcium (99%) is found in bone; 1% is distributed in the intravascular, interstitial, and intracellular fluids. Calcium plays an essential physiological role in the body. Its salts are the minerals that constitute bone. In addition, Ca2+ dissolved in the body fluids is essential to many biochemical processes, including nerve excitability, muscle contraction, hormone secretion, regulation of enzymes, and blood clotting. The Ca2+ level in plasma is maintained very constant at 10 mg/dL (2.5 mM or 5 mEq./L). Normal daily Ca2+ fluctuations in serum are less than 3%, even when calcium intake varies significantly. Calcium concentration remains unchanged throughout life; only higher values are observed in fetal cord blood (11.6 mg/dL or 2.9 mM). Plasma calcium is found in three different forms: (1) as ion (Ca2+), which represents approximately 50% of the total calcium. (2) Bound to proteins, primarily albumin (∼40% of the total), which is in dynamic equilibrium with the plasma Ca2+. (3) Nonionic (or diffusible), associated with anions, such as citrate or lactate. Ionized calcium is the physiologically active form of Ca2+; its level varies between 4.6 and 5.2 mg/dL (1.25 and 1.3 mM). The balance between ionic and protein-bound calcium is affected by changes in blood pH. When the pH in blood increases (alkalemia), Ca2+ decreases and the opposite occurs when plasma pH decreases. For every 0.1 unit of pH increase, calcium ion level is reduced by 0.4%. Obviously, the fraction of Ca2+ bound to protein is related to the amount of protein present, therefore, in alterations that affect protein levels

(increased in dehydration; decreased in chronic renal disease, liver failure, and severe protein malnutrition) there are changes in the amount of protein-bound calcium. An albumin decrease of 1 g/dL in plasma, produces a 0.8-mg/dL decrease in plasma calcium. Determinations of plasma total calcium do not provide direct information on the amount of free Ca2+, which is the physiologically relevant form of calcium. Especially when there are changes in blood pH or proteinemia, a patient can be hyper- or hypocalcemic, with a total calcium (free plus bound) concentration within the normal range (9.5–10.5 mg/dL). Direct measurement of ionic calcium can be performed by electrometric methods. The constancy of calcium concentration in ECF indicates the existence of a remarkably efficient homeostatic mechanism; parathyroid hormone, calcitriol and probably calcitonin, are factors involved in its regulation. Furthermore, bone is a vast reservoir of calcium, which stores it or releases it to the ECF as needed. Natural sources. Milk and dairy products, especially cheese and yogurt, are the richest in calcium. A liter of cow’s milk provides more than 1 g. Other good sources of calcium are salmon, sardines, clams, and oysters and among plants, broccoli, cauliflower, turnip, and cabbage. Meats, grains (beans), and nuts are low in calcium. The bioavailability of calcium in a standard diet is approximately 30% of the total calcium contained in the ingested food. Intestinal absorption. Calcium intake depends on intestinal absorption. With a normal diet, an adult absorbs around 30% of the 800–900 mg of calcium that come in the diet per day. Calcium absorption in the intestine is carried out by two different mechanisms: active and saturable transcellular transport, and paracellular passive diffusion. The main active site of absorption is the duodenum; paracellular diffusion occurs throughout the small intestine. Although absorption is more efficient in the duodenum and jejunum, the amount absorbed is

 



Macrominerals

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Calcemia. The Ca2+ absorbed reaches the plasma, where its concentration is maintained, with little variation, in 10 mg/dL. Calcium circulates in blood in different forms: (1) nondialyzable or bound to proteins (4.5 mg/dL), (2) as free ion, with high filterability (5.0 mg/dL), and nondissociable, combined with citrate, phosphate, and bicarbonate (0.5 mg/dL). Excretion. Calcium is excreted in urine, feces and, to a lesser degree, in sweat. Total excretion in an adult is approximately 300 mg/day. A high protein intake contributes to increased calcium output in urine. During lactation, there is a considerable amount of calcium that is secreted through the mammary gland. The calcium eliminated in feces (∼100 mg/ day) corresponds to that unabsorbed plus the Ca2+ that comes from the mucosal cells that are released in the intestine and from the digestive secretions. The loss of Ca2+ in sweat is approximately 25 mg/day. It is also eliminated through recycled skin cells, hair, and nails. Renal handling of calcium. Most of the Ca2+ is excreted by the kidneys. A 55%–60% of the total calcium in plasma is diffusible and filters in the glomeruli. The remaining 40% is bound to proteins and cannot pass the glomerular membrane. Normally, almost 10 g of calcium per day (500 mEq. or 250 moles) reach the renal tubules; 98% of this amount is reabsorbed and only 2% is excreted in urine (∼200 mg/day). Transcellular movement of Ca2+ through the apical membrane of the renal tubular cells is driven by the large electrochemical gradient (intracellular calcium concentration [Ca2+]i is about 10,000 times lower than the concentration in the tubular fluid). In the cells, a 28-kDa calbindin (Ca28k), different from the intestinal Ca9k binds Ca2+. The transport of Ca2+ from the renal epithelial cells to the interstitial space is carried out in the basolateral membrane by active processes: a Ca2+-ATPase and the 3Na+/Ca2+ exchanger, similar to that present in the intestine. The distal tubules and collecting ducts receive approximately 12% of the total calcium filtered

higher in the ileum, where the intestinal content stays for a longer time. When calcium in the intestinal lumen is high and the active transport system is saturated, an increasing proportion of Ca2+ is taken up by passive diffusion. The transcellular transport of Ca2+ comprises its passage through the apical membrane via Ca2+ channels, following the electrochemical gradient. Once in the cell, calcium binds calbindin, a 9-kDa protein in mammals (Ca9k), which can attach two calcium ions per molecule, serving as an intracellular carrier for Ca2+. Also by binding Ca2+ calbindin protects the cell from the effects of high free Ca2+. In the basolateral membrane, Ca2+ is moved into the extracellular space, against its electrochemical gradient, by two active mechanisms, the Ca2+-ATPase that uses adenosine triphosphate (ATP) and the Na+/Ca2+ exchanger, which uses the electrochemical Na+ gradient maintained by the Na+,K+-ATPase. The Na+/Ca2+ exchanger countertransports one Ca2+ out of the cell for every three Na+ that are brought in, in an electrogenic fashion. The paracellular diffusion of Ca2+ takes place through tight junctions between mucosal cells. This is a passive process that is not saturable. Ca2+ absorption is regulated according to body needs and it depends on the amounts of Ca2+ in the diet. A diet low in calcium increases the uptake efficiency. There are additional dietary factors that influence calcium influx. Lactose, other sugars, and alcohols derived from monosaccharides, such as xylitol, favor Ca2+ absorption. Phytate (myoinositol hexaphosphate) present in legumes, nuts, and grains binds Ca2+ and reduces its bioavailability. Oxalates found in spinach, beet, eggplant, strawberry, walnut, peanut, tea, and chocolate form insoluble, nonabsorbable calcium salts that are excreted with the feces. When free fatty acids are abundant in intestine, they form insoluble calcium soaps, which prevents Ca2+ uptake. This becomes important in cases of steatorrhea.

 

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FIGURE 29.1  Factors controlling calcium homeostasis. PTH, Parathyroid hormone.

in the glomeruli and reabsorb over two-thirds of that amount. In these and all nephron sections, calcium is reabsorbed through the transcellular pathway. The mechanisms that regulate Ca2+ reabsorption and excretion take place in the distal nephron. Calcium homeostasis. Calcium homeostasis is controlled by endocrine factors, mainly PTH and 1,25-(OH)2-D3 (Fig. 29.1). Parathyroid hormone (PTH) is secreted when calcium concentration in the EC fluid drops below its normal limits. PTH exerts direct action on bone and kidney, and has indirect effect on intestine. The skeleton is the main reservoir for Ca2+ and this store is used when there is little or no exogenous calcium from the diet. PTH promotes rapid mobilization of calcium from bone

 

tissue by activation of osteolysis, with calcium release into the ECF. In the kidney, PTH stimulates Ca2+ reabsorption and decreases phosphate uptake (stimulates phosphaturia). In the intestine, PTH has no direct action. It induces 1αhydroxylase in the kidney, which is involved in the synthesis of 1,25-(OH)2-D3. This active form of vitamin D stimulates calcium absorption in the intestine and increases calcium in the ECF. The overall effect of PTH is the increase in calcemia without elevation of phosphatemia. Vitamin D exerts its main actions after conversion to 1,25-(OH)2-D3 or calcitriol. Vitamin D increases Ca2+ absorption in the intestine activating all the mechanisms for the transport of this cation. In bone, vitamin D metabolites stimulate both mineralization and resorption. The absorption of



Macrominerals

calcium and its release into the ECF requires the joint action of 1,25-(OH)2-D3 and PTH. Calcitonin. The role of this hormone is not entirely clarified in humans. When administered pharmacologically it inhibits bone resorption and decreases renal calcium and phosphate reabsorption. This reduces the level of calcium and inorganic phosphate in plasma. Fig. 29.1 summarizes the factors involved in Ca2+ homeostasis. Other hormones. Growth hormones, thyroid hormones, glucocorticoids, and androgens are also involved in bone formation, and therefore exert effects on calcium homeostasis. Estrogens inhibit bone resorption mediated by PTH and depress the secretion of cytokines (interleukins 1 and 6) (p. 773) and prostaglandin E2, factors that favor Ca2+ resorption. The decline in estrogen production contributes to osteoporosis, frequently observed in postmenopausal women. Calcium balance. The overall balance of calcium in the body is positive during periods of bone formation and growth. When development is completed, a balance is reached and, although there is continuous remodeling of bone, calcium entry and exit remain equal. After 45 years of age, Ca2+ balance begins to be negative, there is decrease in the mineral matrix of bone, at a rate of ∼5% of the total every 10 years. In postmenopausal women, the rate of demineralization is faster than in men. Osteoporosis is a consequence of prolonged calcium loss. Alterations in Ca2+ homeostasis. Hypocalcemia. The reduction in plasma calcium may be due to various causes: (1) hypoparathyroidism (congenital or acquired due to resistance of the effector organs), (2) vitamin D deficiency (or alterations of its metabolism), (3) renal tubular defects (with decreased renal reabsorption), and (4) severe and prolonged dietary deficiencies. When the plasma level falls below normal, Ca2+ is mobilized from bone to normalize calcemia, which compromises bone formation. The fall of extracellular Ca2+ below 3.5 mg per 100 mL (∼0.83 mM) causes neuromuscular

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hyperexcitability and can lead to tetany (sustained muscle contraction). Hypercalcemia occurs in hyperparathyroidism, vitamin D intoxication, sarcoidosis, and some cancers. High Ca2+ in the body affects the neuromuscular system, increasing the threshold for depolarization. In the heart, it has inotropic and chronotropic effect, with changes in the ECG, and it could even lead to cardiac arrest. The excess Ca2+ can deposit in different tissues, especially in kidney, leading to kidney stones and nephrocalcinosis. The increase in Ca2+ can also result in psychiatric alterations. Regulation of intracellular calcium. Calcium, in addition to being an important component of bone and teeth, plays a variety of functions related to the nervous system activity, muscle contraction, cell motility, and it is involved in hormonal actions. While homeostatic mechanisms ensure the maintenance of calcium levels in the ECF, the multiple functions that Ca2+ exerts depend on rapid variations in its concentration, which require close monitoring and fast regulation. The calcium concentration in cytoplasm is approximately 0.1 µM, about 10,000 times lower than that in ECF. The large gradient across the plasma membrane, facilitates the production of sudden changes in the cation intracellular concentration. The cytoplasmic Ca2+ concentration can be increased 10 or more times in just milliseconds by rapid uptake from the extracellular space, or by release of the cation from intracellular stores, such as the endoplasmic (or sarcoplasmic) reticulum, mitochondria, and other organelles. This increase is the signal for a multitude of physiological actions. Ca2+ entrance. Different stimuli acting on plasma membrane receptors promote Ca2+ entry and sharply raise its concentration in the cytosol. This raise in Ca2+ functions as a “messenger” of signaling systems used by hormones and other agents. Ca2+ entry from the ECF is driven by the electrochemical gradient that favors its uptake into the cell. Several Ca2+ channel types are involved in moving this cation into the cells: (1) voltage-operated channels (VOC), which are found

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29.  Essential Minerals

mainly in excitable cells, generate rapid Ca2+ influx and activate processes, such as muscle contraction and cell exocytosis; (2) receptor-operated channels (ROC), which respond to different agents coming from the extracellular medium (i.e., neurotransmitters) or from the cell cytosol (i.e., second messengers); and (3) store-operated channels (SOC), which are controlled by the Ca2+ levels in cell intracellular stores. Ca2+ exit. To maintain the IC calcium concentration [Ca2+]i constant, cytosolic Ca2+ entering the cell must be rapidly extruded. The main system responsible for this function is the cell plasma membrane Ca2+-ATPase which, due to its high affinity for Ca2+, becomes activated at small elevations in [Ca+]i. Also, the plasma membrane Na+/Ca+ exchanger contributes to Ca2+ extrusion from the cell. Calcium movement from intracellular deposits. Ca2+ is stored by active processes into organelles from which it is released to the cytosol by ligand-activated channels. Sarcoplasmic or endoplasmic reticulum (ER). A Ca2+-ATPase operates (sarcoplasmic/ endoplasmic Ca2+-ATPase, or SERCA) that introduces Ca2+ in the ER lumen. Calcium release from the ER takes place through two channels that are both sensitive to [Ca2+]. One, called inositol 1,4,5-trisphosphate receptor (I-1,4,5-P3R), is activated by Ca2+ and by inositol 1,4,5-trisphosphate. The other, designated ryanodine receptor (RyR) opens in the presence of low concentrations of cytosolic Ca2+ and cyclic adenylribose (ADPc). RYR is inhibited by calmodulin and β adrenergic stimulation. Mitochondria. These organelles import calcium from the cytosol through a uniporter driven by the negative potential of the mitochondrial matrix. The release of Ca2+ from mitochondria is mediated by the Na+/Ca2+ exchanger. Mitochondria can minimize changes in [Ca2+]i. When there is a cytosolic raise in Ca2+, the Ca2+ uniporter is activated and Ca2+ is accumulated in the matrix. When [Ca2+] in the cytosol diminishes, mitochondria calcium is released to maintain [Ca2+]i

FIGURE 29.2  Intracellular Ca2+ regulation. IP3R, Inositol 1,4,5-trisphosphate receptor; ROC, receptor-operated channel; RyR, ryanodine receptor; SOC, store-operated channel; U, uniporter; VOC, voltage-operated channel; X, Na+/Ca2+ exchanger; ~, Ca2+-ATPase.

 

at basal levels. Fig. 29.2 schematically summarizes the buffering action that mitochondria exert on Ca2+. Golgi apparatus. A Ca2+-ATPase imports Ca2+ and the I-1,4,5-P3R-activated channel releases it from the Golgi cisternae. Ca2+ binding to specific proteins. Approximately 200 proteins have been recognized that specifically bind Ca2+ in cells. These proteins can be distinguished into those that play a calcium buffer role, and those that function as effectors. While the Ca2+ buffer proteins regulate the calcium signal, Ca2+ effectors undergo conformational changes upon Ca2+ binding, which enable them to act on a substrate, sometimes with catalytic action. One of the most widely distributed Ca2+ effector proteins is calmodulin, which contains four Ca2+-binding sites (p. 567). Fig. 29.2 shows the factors that regulate intracellular Ca2+.



Macrominerals

Ca2+ requirement. Ca2+ needs vary at different times of life. In the first 2 years, 120 mg of calcium per day are required to maintain normal growth. Breast-fed children require an intake of 300 mg/day, which is the Ca2+ content in the average daily secretion from the mammary gland. As the bioavailability of Ca2+ from cow’s milk is lower, 400 mg must be provided when mother’s milk is replaced by cow’s milk. At years 2–9, the recommended daily intake of Ca2+ is 220 mg, which requires an intake of 600 mg from the diet. In adolescents (10–17 years of age), the marked increase in bone mineralization, which occurs earlier in girls than in boys requires approximately 440 mg of Ca2+ per day, which can be met with an intake of 1300 mg. In adults, the Ca2+ requirements are approximately 320 mg, provided by an intake of 1000 mg daily. Adults over age 45 have reduced absorption, which is why the intake should be of 1300 mg. In menopausal women there is increased Ca2+ loss in urine, which requires additional dietary calcium. During pregnancy, the Ca2+ needs increase, especially in the last quarter; during this period, the fetus retains about 240 mg/day. Pregnant women absorb calcium more efficiently; the recommended intake is 1200 mg/day. Women who are breastfeeding secrete approximately 36 mg of Ca2+ per 100 mL of milk; considering a daily production of 750 mL, this represents a total of 270 mg of Ca2+ per day. If urinary and other losses are added, with maximum absorption efficiency, the daily requirement is 1040 mg and the recommended intake is 1300 mg. An intake of up to 2.5 g of calcium per day does not cause harmful effects and are considered the tolerable limit. The use of larger amounts may cause hypercalcemia and Ca2+ deposits in soft tissues. In patients with hypercalciuria, excessive Ca intake increases the risk of kidney stone formation. Ca2+ deficiency may be due to inadequate Ca2+ absorption or excessive Ca2+ loss. The risks of deficiency are higher in the first 2 years of life, during puberty and adolescence; in pregnant

725

women, especially in their third trimester; and in lactating and postmenopausal women. Males over 65 years are another population group at risk. Decreased levels of plasma ionized calcium (hypocalcemia) may cause muscle pain, paresthesia, and tetany, characterized by sustained muscle contraction, especially in hands, arms, and legs. Calcium deficiency in children can produce clinical manifestations similar to those of rickets (Chapter 26). In adults, osteoporosis occurs, with loss of bone mass. This increases bone fragility and the risk of fractures.

Phosphorus (P)

 

Phosphorus integrates a series of body compounds that are essential for the formation of cellular structures and are involved in numerous metabolic processes in the body. An average male adult contains approximately 700 g of phosphorus (∼1% of body weight), an amount that is slightly lower in women. From this, 85% of phosphorus is found in bone, primarily in the form of hydroxyapatite [Ca10(PO4)6(OH)2], the crystal structure that constitutes the mineral portion of bone. The remaining 15% is found in soft tissues and only a 0.3% is present in ECFs as phosphates. The phosphate in cells and in the ECF, exists as organic phosphate esters, or integrating nucleic acids, phospholipids, and phosphoproteins. At the pH of the body, inorganic phosphate (Pi) forms di- and monovalent anions HPO 24 − , H 2 PO −4 . Natural sources. Foods rich in phosphate include meat, poultry, fish, eggs, milk, and milk derivatives. Nuts, legumes, and grains contain phosphorus, but its bioavailability is higher in animal products. Coffee and tea contain some phosphate. Cola drinks also contain phosphorus as phosphoric acid. Phosphate from foods is not found free, but forming organic and inorganic compounds. In its organic form phosphate is bound to proteins, sugars, and lipids. The relative amount

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29.  Essential Minerals

of organic and inorganic phosphorus varies depending on the diet. In milk, for example, onethird of the total phosphate is inorganic phosphate (Pi). More than 80% of the phosphorus in the diet is in cereals (wheat, maize, and rice). In legumes and nuts, it is found as phytate (inositol hexaphosphate). Absorption. Due to its binding to organic molecules, phosphate needs to be separated before it can be absorbed by the intestine. Phospholipase C catalyzes the separation of phosphorus from glycerophosphate of phospholipids, while alkaline phosphatase in the brush border of enterocytes, stimulated by calcitriol, releases phosphate from organic compounds. The bioavailability of phosphorus from the diet varies between 50% and 70%. Inorganic phosphate is absorbed throughout the small intestine, particularly duodenum and jejunum, by passive diffusion and by saturable transport. The passive paracellular absorption is performed when the luminal concentration of phosphorus exceeds 1.5 mM, which is the usual amount after a meal. The transport across the apical membrane of the enterocytes is mediated by a Na+/Pi symporter driven by the sodium gradient, and stimulated by calcitriol. The movement of Pi to the interstitial space is carried out by a Na+independent transporter, driven by the Pi electrochemical gradient. The proper absorption of Pi is linked to that of calcium and a ratio of 2:1 Ca:Pi ratio is optimal for absorption. If Pi exceeds Ca, it tends to form Ca phosphate compounds that are insoluble and are eliminated with the feces. Phosphatemia. Phosphate appears in blood 1 h after ingestion. Plasma Pi (70%) is bound to organic compounds, such as phospholipids in lipoproteins. Most of the remaining 30% Pi circulates as HPO 24 − and H 2 PO −4 ; at normal plasma pH, the relationship HPO 24 − :H 2 PO −4 is 4:1. The plasma level of phosphorus (expressed as weight of elemental phosphorus) is 2.5–4.8 mg/ dL (1.45–2.78 mEq./L) in adults and 4.0–7.0 mg/

 

dL (2.37–4.06 mEq./L) in children during the first year of life. Excretion. Phosphorus (70%–90%) is excreted in urine in its inorganic form. The remaining 10–30% is eliminated with the feces. Renal handling of phosphate. The renal proximal tubule reabsorb ∼85% of the phosphate filtered in the glomeruli, less than 5% is reabsorbed in the thick ascending limb of Henle’s loop, the distal convoluted tubules, and collecting ducts. Approximately 10% of the total phosphate filtered is excreted in urine. Phosphate renal reabsorption takes place by the transcellular pathway. In the luminal membrane there is a 2Na+ /HPO 24 − symporter system that transports phosphate from the lumen. The transfer to the interstitial space is performed by an anion/phosphate basolateral exchanger. Calcitriol, growth hormone, insulin-like growth factor I, insulin and thyroid hormones stimulate phosphate reabsorption in the renal tubules. In contrast, calcitonin, at high doses, reduces it. Parathyroid hormone stimulates renal excretion. Homeostasis. In a normal adult, the balance between intake and loss of Pi is zero. Phosphate levels in the body are controlled at different levels, including intestinal absorption, kidney reabsorption, and bone exchange. Moreover, these processes are regulated by several factors, such as parathyroid hormone, 1,25-(OH)2D3, glucocorticoids, dopamine, and insulin. The existence of several peptides generically called phosphaturic phosphatonins has been demonstrated. The best one studied is the fibroblast growth factor 23 (FGF-23), produced in bone tissue and released when the level of phosphate in the ECF increases. FGF-23 inhibits the expression of the Na+/Pi transporter in the renal tubules, reduces phosphate reabsorption and increases phosphaturia. Also, FGF-23 inhibits 1α-hydroxylase activity in the kidney, decreasing the production of calcitriol, and therefore, the absorption of phosphate in the intestine and kidney tubules.



Macrominerals

Function of phosphate in the body. Most of the functions of phosphate are exerted in bone, where it contributes to the structural and functional characteristics of this tissue. In cells and in the extracellular spaces in general, it is an essential component of many different molecules. Some of the processes in which Pi participates are the following:

727

Bone structure. The role of Pi in bone is to constitute the hydroxyapatite deposited on collagen for bone mineralization. Nucleic acids. Phosphate is an important component of DNA and RNA. As part of free nucleotides it participates in the intermediary metabolism, storage, and energy transfer compounds, such as adenosine triphosphate (ATP), creatine phosphate, and UTP and UDP, which have a role in different metabolic reactions. Intracellular second messengers. As a constituent of cyclic AMP (cAMP) and inositol trisphosphate (IP3), Pi is involved in intracellular signaling systems. Phosphoproteins. Pi plays a major role in regulation of protein function. Thus, activation of protein kinases promotes the phosphorylation of specific proteins (enzymes and others), modifying their activity. Membrane structure. Phospholipids are essential components of cell membranes. Their amphiphilic properties allow them to form the double lipid layer, which is essential to form the basic structure and support functionality of cell membranes. Acid–base balance. Within cells, phosphate is part of body buffers. In the kidney, Na2HPO4 from the filtrate binds H+ and releases sodium, contributing to the elimination of hydrogen ions by urine. Transport of O2 by hemoglobin. In erythrocytes, Pi is part of 2,3-bisphosphoglycerate, which binds to and decreases the affinity of hemoglobin for oxygen. This promotes O2 release to the tissues.

Recommended Intake. The dietary amounts of Pi are approximately the same as those of calcium. For an adult, 800 mg/day is recommended. Children require 200–800 mg/day with a progressive increase until 9 years of age. Adolescents, pregnant women, and lactating mothers need 1250 mg/day. Drinking approximately 500 mL of milk per day for adults and 1 L for teens and women during pregnancy and lactation meets the dietary needs of Pi, as well as Ca2+. Deficiency. Hypophosphatemia is a relatively rare condition, since the usual diet provides adequate amounts of Pi. Deficits can be found when the renal excretion of phosphate is increased, the intestinal absorption is decreased, or there is an important loss via the digestive tract. Pathological conditions that lead to acidosis and stimulation of phosphate excretion can cause hypophosphatemia. Low phosphate is also found in individuals who ingest large amounts of antacids containing Al, Mg, or Ca, which reduce the intestinal absorption of Pi. Starved or malnourished patients and those subjected to refeeding by oral gavage or parenterally, can become hypophosphatemic if Pi is not provided in adequate amounts. This condition is usually known as “refeeding syndrome.” As Pi is involved in numerous biological processes, its deficiency affects all cells. Clinical symptoms become evident when phosphatemia falls below 1.5 mg/dL and include anorexia, bone mineral loss, muscle weakness, neurological disorders (ataxia, paresthesia). These symptoms are the expression of a generalized metabolic disorder, with low ATP levels in cells. The decrease in 2,3-bisphosphoglycerate in erythrocytes alters the release of oxygen from Hb and this leads to hypoxia. Hypophosphatemia is a potentially lethal condition.

Magnesium (Mg)

 

Magnesium is found in all cells and body fluids. It is the second most abundant cation in the intracellular fluid (after potassium) and

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29.  Essential Minerals

the fourth most abundant one, when all body cations are considered (after Na, K, and Ca). A 70 kg adult contains between 25 and 30 g of magnesium; more than half of this amount is found in bone, combined with calcium and phosphate. Mg that is not part of bone (∼25%) is distributed in soft tissues, mainly muscle, liver, and kidney. Magnesium is an essential element in many enzymatic reactions, especially in those in which ATP, GTP, or UTP are involved, and in those catalyzed by pyrophosphatase. In some cases, Mg2+ can be replaced by Mn2+. Magnesium is predominantly an intracellular cation (only 1% of total body magnesium is extracellular); the concentration inside the cell is 10 or more times greater than in plasma. The intracellular/extracellular relationship between Mg+2 and Ca+2 is somewhat similar to that of K+ and Na+. Natural sources. Whole grains and legumes (beans, soy) are rich in Mg2+. Ca2+ forms part of chlorophyll; therefore, it is present in all green leaf vegetables. It is also found in nuts, fruits, meats, dairy products, chocolate, coffee, and tea. The processing and preparation of food, as well as grinding grain with bran removal, reduces 80% of the original Mg. Absorption. Mg is absorbed in the small intestine, mainly in jejunum and ileum, and part also in colon. In normal adults, Mg bioavailability is 30%–70% of the total Mg present in food. The percentage of Mg absorbed is inversely related to the amount offered; it increases when Mg2+ in the diet is low. Several factors influence intestinal absorption; phytate and oxalate interfere with intestinal Mg2+ uptake. Unabsorbed fatty acids (steatorrhea) form insoluble soaps with Mg, which are excreted with the feces. Calcium, phosphate, and other minerals, such as zinc, reduce Mg absorption. In contrast, some carbohydrates (fructose and lactose) enhance Mg absorption. Active vitamin D [1,25-(OH)2-D3] has no effect at physiological doses, but activates intestinal Mg absorption at high doses. Mg2+ absorption in the intestinal epithelium occurs through Mg2+channels.

 

Magnesemia. Mg from the diet appears in blood 1 h after its ingestion. Normal blood plasma concentration of Mg2+ is 0.625–1.25 mM or 1.25–2.5 mEq./L (1.5–3.0 mg/dL); 30% of this amount is bound to protein, primarily albumin, 55% is free, in ionic state, and the rest forms complexes with different anions. Excretion. The kidney is the main organ for Mg excretion. Other routes for Mg elimination are the intestine and skin (15 mg/day). Renal handling of Mg2+. One-third of the ingested Mg is eliminated in urine. A 70% of total plasma Mg, including ionic and constituting diffusible complexes, filter in the glomeruli (∼100 mmol or 2.400 mg/day), a large proportion is reabsorbed in the tubules. The reabsorption in the distal tubules and collecting ducts (5%–10% of total filtered) is carried out through Mg2+ channels, following the Mg electrochemical gradient. Homeostasis. The balance of Mg in the body is regulated by different actions on intestinal absorption, renal reabsorption, and bone exchange. Parathyroid hormone stimulates Mg2+ reabsorption in the loop of Henle. Also, aldosterone is involved in regulating Mg renal reabsorption. Bone is an important Mg reservoir, containing approximately 55% of the body Mg. A 70% of that amount is associated with phosphate and calcium in the bone mineral matrix. The rest is on the bone surface, in an amorphous form, which can be easily mobilized and exchanged with plasma Mg. Functions. Mg is associated with phospholipids of the plasma and organelles’ membranes. It also forms part of proteins; Mg is involved in more than 300 reactions, either as a structural cofactor, or an allosteric activator of enzymes. Mg constitutes nucleic acids; up to 90% of Mg is bound to nucleotides, especially ADP and ATP, forming complexes, such as Mg2+ATP3− or Mg2+ADP2− in which Mg assists in the transfer of the phosphate group. Some of the pathways in which Mg participates are: (1) glycolytic pathway (hexokinase and phosphofructokinase); (2) pentose



Macrominerals

729

Iron (Fe)

phosphate pathway (transketolase); (3) citric acid cycle (oxidative decarboxylation); (4) formation of creatine (creatine kinase); (5) initiation of β-oxidation of fatty acids (acyl-CoA synthetase); (6) synthesis of nucleic acids; (7) DNA transcription; (8) protein synthesis; (9) amino acid activation; (10) contractility and excitability of skeletal, cardiac, and smooth muscles; (11) reactions catalyzed by alkaline phosphatase and pyrophosphatase; (12) cyclic AMP formation (adenylate cyclase); (13) blood clotting; (14) regulation of ion channels, especially K channels; (15) vitamin D hydroxylation in the liver; and (16) calcium homeostasis (secretion and actions of PTH in bone, kidney, and intestine, and activation of Ca2+-ATPase). Recommended intake levels. The dietary requirement of Mg is estimated in 400 mg/day for males 19–30 years in age, and 420 mg for those over 30 years of age. Women 19–30 years of age need 310 mg/day and over 30, 320 mg/ day. During pregnancy and lactation, an intake of 350 mg/day is recommended. Normally, the excess Mg is rapidly eliminated in the urine, so that no significant increases in plasma are observed. A high intake of Mg is not toxic, except in patients with renal insufficiency. Homeostasis alterations. Magnesium deficiency is rare in the general population because of its abundance in foods. Mg deficits can be seen during postoperative complications, after massive transfusions (chelating effect of the added citrate), refeeding syndrome in patients with starvation, diabetic ketoacidosis, extensive burns, and in a high percentage of alcoholics. Hypomagnesemia is asymptomatic unless the levels are lower than 0.5 mmol/L (1.2 mg/dL). With these levels, symptoms, such as nausea, vomiting, anorexia, muscle weakness, personality changes, hallucinations, spasms, tremors, and even tetany can occur. Another effect associated with low Mg is hypocalcemia, which may cause hyperexcitability, arrhythmias, and cardiac arrest. Hypermagnesemia has depressant effects on the central nervous system.

 

Iron represents a very small proportion of the total mass of the body (∼0.0057% of body weight in an adult human). Most authors include it among the trace elements. Despite its low amount, iron is a component of great importance. In adult women the total Fe content is approximately 3 g; in men, 4 g. Quantitative variations are observed with body weight, age, and physiological conditions, such as pregnancy. Distribution. Iron has a key role in the body as part of molecules that play vital activities. This Fe has been called functional Fe and represents ∼80% of the total Fe. A large part (65%, 2.0 g in women and 2.6 g in men) is found in hemoglobin, where it is involved in the transport of oxygen in blood; 10% (0.3 g in women and 0.4 g in men) is found in myoglobin, which carries and stores oxygen in muscle; 2.5% (0.075 and 0.10 g in female and male, respectively) corresponds to cytochromes of the mitochondrial respiratory chain, the cytochrome P450 enzymes, and numerous oxygenases, such as catalase, peroxidases, and others involved in redox reactions. All the mentioned proteins are hemoproteins; they contain a heme as the prosthetic group. In heme, the Fe is at the center of a tetrapyrrole protoporphyrin IX and is the key element for the functional properties of hemoproteins (Fig. 3.26). There are other proteins associated with nonheme iron. They represent approximately 2.0% (0.06–0.08 g) of the total Fe. Some of these molecules have iron–sulfur clusters (Fe–S, 2Fe–2S, 3Fe–3S, and 4Fe–4S) including the I, II, and III complexes of the mitochondrial respiratory chain, and metalloenzymes, such as aconitase (enzyme of the Krebs, cycle), ferrochelatase (enzyme of heme synthesis last step), oxidases (ribonucleotide reductase), and glycerolphosphate dehydrogenase. Approximately 20% of the total Fe is found in body reserves (iron deposits). These reserves, present in all cells, contain Fe complexed with proteins (ferritin and hemosiderin). These stores

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29.  Essential Minerals

are dynamic and they accumulate Fe when it is in excess and release it when required. Finally, 1% of Fe is found in blood, bound to transferrin. Fe toxicity. Body iron is found in two oxidation states, ferrous (Fe2+) and ferric (Fe3+). Free Fe, especially Fe2+, can cause tissue damage; for this reason, it is always associated to cell and plasma proteins. The toxicity of free iron is due to its ability to form free radicals. Natural sources. Foods rich in iron include liver, heart, meat of any kind, seafood, tomatoes, beans, cauliflower. Although in lesser amounts, it is also found in green vegetables, cereals, legumes, and nuts. Milk and dairy products are very poor in iron. In foods of animal origin, approximately 60% of the iron is in hemoproteins and the rest in nonheme proteins. All iron in vegetables is associated with nonheme proteins. Iron balance. The normal organism is very efficient in handling iron. Fe is constantly recycled with very little loss; an example is Fe in hemoglobin: red blood cells, after 120 days, reach the end of their useful life, are lysed, and their hemoglobin is degraded in the spleen. A total of 8–9 g of Hb are catabolized per day, which represents 25 mg of iron. From this, approximately 24 mg is reused for the synthesis of new hemoglobin. This Fe recycling is very active; only 12 h after erythrocytes lysis, 60% of their Fe content is already incorporated into new Hb. A normal adult loses an average of 1 mg of iron per day, via epithelial cells desquamated from the gastrointestinal mucosa, skin, and urinary tract; and the small amount of blood that eventually is eliminated with stool (occult blood, less than 0.35 mg Fe per day), negligible amounts are excreted in the bile, urine, or normal perspiration. Women during reproductive age have the additional loss caused by menstrual bleeding, which represents an average loss of approximately 40 mL of blood or more than 20 mg of Fe per month; there are individual variations, in some women the loss can reach up to 100 mL of blood per month.

A normal diet contains between 10 and 20 mg of Fe (per day); the intestine absorbs 8%–10% of this amount per day (1.0–1.5 mg/day). The amount absorbed varies according to the organism needs. Digestion. Foods of animal origin contain iron predominantly associated with heme proteins. Fe associated to heme is more bioavailable than nonheme Fe. The protein portion of hemoproteins is degraded by digestive proteases, releasing heme, which is soluble in the intestinal environment, especially in the presence of protein digestion products (amino acids and small peptides). For proteins containing nonheme Fe, which is mostly in ferric state, the acid medium of the stomach (pH 1.5) maintains both Fe2+ and Fe3+ in soluble form. Some of the Fe3+ can be converted into Fe2+, especially if there is ascorbic acid (vitamin C) in the lumen. In the duodenum and jejunum, where the pH is higher, Fe2+ remains in solution at a pH of 7.5–8.0, but at a pH above 5.0, Fe3+ forms ferric hydroxide [Fe(OH)3], which precipitates and is eliminated in the stool. Absorption. Both, heme and nonheme iron, are absorbed in the proximal small intestine, the first one is more efficiently absorbed than the latter. Intestinal absorption of Fe can be divided into several stages: (1) uptake in the brush border of enterocytes, and transport across the apical membrane, (2) transport in the enterocyte cytoplasm to the basolateral membrane, and (3) transfer to the circulation after crossing the basolateral membrane of the enterocytes.

 

1. Fe absorption in the enterocyte brush border. Heme is uptaken by the enterocytes at the apical membrane through the heme transport protein 1, which transfers heme intact into the cytoplasm. A hemoxigenase associated to the cell membrane separates free iron from heme; protoporphyrin continues its catabolism independently to form bilirubin. The iron separated from nonheme proteins is mostly Fe3+, poorly soluble and not readily available



Macrominerals

to the cell. Fe transport in the cell requires that specific transporters and enzymes change its oxidation state from Fe3+ to Fe2+. The amount of Fe present in the diet influences its absorption; Fe uptake increases when dietary Fe increases; however, the overall efficiency of transport diminishes. Another factor that influences intestinal Fe absorption is the diet composition. Fe bioavailability can be greatly reduced by the presence of agents that interfere with its intestinal uptake, such as phytate in legumes, nuts, and cereals and some polyphenols as tannins in tea. A mixed diet provides factors that counteract the action of these agents and favor Fe absorption. Lack of meat in the diet is usually one of the main causes of iron deficiency. Once inside the enterocyte, Fe from heme and nonheme proteins, becomes part of the same Fe pool from which Fe can be transferred to the bloodstream, stored, or used for the synthesis of iron-containing molecules. 2. Fe transport to the basolateral membrane and circulation is performed by binding it to a protein called mobilferrin (56 kDa). This complexation with proteins avoids the potentially harmful effects of free Fe. The movement of Fe from the enterocytes to the blood, and across the basolateral membrane, is mediated by the transmembrane transport protein, ferroportin. Before transport, Fe must be oxidized from Fe2+ to Fe3+. This is catalyzed by the ferroxidase hephaestin, a protein associated to ferroportin. This same action is exerted by plasma ceruloplasmin, another ferroxidase, which, similar to hephaestin, contains copper in its structure. 3. Storage in cells. Iron can remain in cells bound to apoferritin, a large protein of 480 kDa and 24 subunits that form a hollow sphere whose central cavity can accommodate up to 4500 Fe atoms. By capturing Fe, apoferritin

731

becomes ferritin (holoferritin), the main form of iron storage, not only in the intestine, but also in other cells, particularly liver and the mononuclear phagocyte system. Iron absorption in intestine is regulated and all factors involved in Fe absorption are upregulated when Fe reserves decrease. In cases of increased demand (increased erythropoiesis subsequent to bleeding, severe hemolysis, hypoxic conditions) Fe uptake and transfer to the blood are incremented. Fig. 29.3 shows a scheme of the process of Fe uptake in enterocytes. Blood transport. In the normal adult (both male and female), Fe concentration in plasma is 60– 150 µg/dL (10–30 µmol/L). Serum Fe is higher in the newborn and rapidly decreases after the fourth month of life. There is a significant circadian variation of plasma Fe, the highest values are found in the early morning and the lowest occur late in the afternoon.

 

FIGURE 29.3  Fe absorption in enterocytes.

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29.  Essential Minerals

The Fe transferred to the plasma is transported by apotransferrin, also called siderofilin. This is a glycosylated carrier protein of 80 kDa, which is synthesized primarily in liver. It can bind two ferric atoms per molecule and becomes transferrin (Tf) (holotransferrin). The presence of Tf in plasma and ferritin in cells maintain almost all Fe in a complexed state, preventing the toxic effects of free inorganic iron. Not all plasma transferrin is saturated with Fe. Less than one-third is bound to two Fe3+ atoms (diferric Tf), the rest contains one atom (monoferric Tf) or has no Fe (apotransferrin). An indirect measure of the amount of Tf in plasma can be obtained by measuring the plasma total iron-binding capacity. Normal values range between 250 and 410 µg/dL. The difference between total iron-binding capacity and serum Fe is known as unsaturated iron-binding capacity, the normal range is 140–280 µg/dL. The total iron-binding capacity is elevated in pregnancy and chronic Fe deficiency, it decreases in liver failure (liver synthesizes Tf) and during protein malnutrition. Transfer to the tissues. Transferrin binds to receptors located in the plasma membrane of cells. All cells, except mature red blood cells, have transferrin receptors. Erythrocyte precursor cells are the richest in these receptors. The transferrin–receptor complex at the cell surface is introduced into the cells by endocytosis. The decrease in pH within the endosome promotes release of Fe from Tf. This is accompanied by the reduction of Fe3+ to Fe2+, which is transported to the cytosol through the endosomal membrane by a carrier identical to that in intestinal mucosa. Apotransferrin remains bound to the receptor in the membrane of the endosome and it is returned to the cell plasma membrane. The apotransferrin–receptor complex, exposed to the extracellular space where the pH is 7.4, dissociates and apotransferrin is released. Once in plasma, apotransferrin binds Fe again repeating the cycle. Haptoglobin. Cells can capture Fe by mechanisms different from that involving the

 

transferrin receptor. One is by direct uptake of hemoglobin or heme from plasma. Normally, lysis of erythrocytes releases a small amount of hemoglobin in the bloodstream. This free hemoglobin filters in the renal glomerulus and it would be eliminated. However, hemoglobin is bound by plasma haptoglobin, the macromolecule formed cannot pass the glomerular barrier and it is retained. Hemopexin. When there is free heme is in plasma, it is bound by another protein called hemopexin. The Fe released into the cell cytosol can be stored in ferritin, exported to the circulation by ferroportin, or used for the synthesis of compounds containing Fe. One of the main destinations of Fe in cells, especially in the erythroblastic progeny, is the mitochondrion, which contains many enzymes associated with Fe. Macrophages. Another mechanism for Fe uptake operates in macrophages of the mononuclear phagocyte system, particularly in the spleen. This system is in charge of lysing erythrocytes that have completed their life cycle. Old or damaged red blood cells are lysed and phagocytosed by macrophages, hemoglobin is degraded, and iron, in part, is stored in the macrophage as ferritin. A significant portion of Fe is exported via ferroportin to reload the circulating apotransferrin. Erythroblasts. Erythrocyte precursor cells have a high affinity for binding Fe and have many transferrin receptors in their outer membrane. One of the main destinations of Fe is the mitochondria, where the last step of heme synthesis takes place. Storage. Most of the iron in the cells (particularly in liver, bone marrow, and spleen) binds to apoferritin and is stored as ferritin. The liver contains approximately 60% of the iron deposited in the body. The rest is mainly divided into cells of the mononuclear phagocyte system of spleen, bone marrow, and enterocytes. Plasma ferritin. A small portion of ferritin passes to plasma, where its concentration is related to the amount of stored Fe.



Macrominerals

Hemosiderin. When there is too much iron, ferritin is partially denatured by lysosomal action, and forms granules containing ferritin aggregates, in which iron comprises a total of up to 50% of its mass. Ferritin and hemosiderin are storage forms usable when the body requires Fe. When the body needs iron in larger amounts than usual, for example, after a hemorrhage, deposits in liver and spleen are mobilized. After these reserves are consumed, the iron deposited as ferritin in cells of the intestinal mucosa is used. This decreases the Fe saturated apoferritin in the intestine, and Fe absorption is activated. Fe release from cells. In a normal adult, the amount of iron coming into the cells is balanced by that released. The Fe is exported from the cells through ferroportin. Ceruloplasmin. Fe2+ that reaches the circulation is oxidized to Fe3+ by the ferroxidase ceruloplasmin. Ceruloplasmin, as enterocyte basolateral membrane hephaestin, is a metalloenzyme with copper as the electron acceptor. Fig. 29.4 summarizes these processes. Iron homeostasis. Since Fe excretion cannot be regulated, Fe homeostasis depends on the modulation of its absorption in the intestine. Bone marrow erythrocyte precursor cells, which actively synthesize hemoglobin, consume the largest amounts of Fe. Macrophages of the mononuclear phagocyte system are the main Fe suppliers. In addition, hepatocytes have great capacity to store Fe and transfer it as needed. There is a tight coordination between all these tissues to ensure that the requirements are satisfied and that excessive accumulation of Fe does not occur. Hepcidin, a 25 amino acid peptide hormone, is the main regulator of all tissues involved in Fe homeostasis. It is synthesized primarily in the liver and released into the circulation when Fe reserves in hepatocytes are high. Its action is mainly exerted on enterocytes and macrophages. In the intestine, hepcidin decreases Fe absorption. In macrophages, it depresses Fe

733

FIGURE 29.4  Different routes for Fe in cells with ac-

 

tive iron metabolism. CD123 and DMT1, Carriers; Cer, ceruloplasmin; Fp, ferroportin; Ft, ferritin; Hptg, Haptoglobin; Tf, transferrin; TfR, transferrrin receptor.

734

29.  Essential Minerals

recycling, which favors accumulation of Fe as ferritin. Excretion. Fe is removed from the body via the intestine in a nonregulated manner. In feces, Fe is released from the desquamated epithelial cells of the gastrointestinal tract, eventually from small amounts of blood lost, and from the unabsorbed Fe from food. Due to the association of Fe in macromolecular complexes (transferrin or hemoglobin–haptoglobin), it is hardly excreted in urine. Requirements. Only a small proportion, about 10% of the Fe in the diet is absorbed and reaches the circulation, the remainder is excreted in the feces. That percentage may increase or decrease depending on the body needs; 10 mg/ day of Fe are recommended for an adult male. During growth, needs are greater; in children 3 months to 3 years of age, 15 mg/day must be provided. The normal newborn has a reserve for 3–6 months, which were stored in the liver during fetal development. Fe supplementation is needed in infants, since milk is very low in this element. Adolescents require 18 mg/day, women 12–50 years of age need 18 mg/day, to compensate for menstrual losses, pregnant women should receive more than 18 mg/day. Deficiency. Reduced Fe amounts is a common medical problem and the most frequent nutritional deficiency. The number of people who suffer it in the world is estimated to reach over one billion, and includes individuals of lower economic class. The most common cause is inadequate dietary intake of Fe for extended periods of time. As heme iron is absorbed the best, when the meat is absent in ordinary food, the availability of Fe is significantly reduced. Other factors that lead to Fe deficiency include parasitic diseases that produce continuous blood loss, such as hookworm and schistosomiasis, common in some countries. There are stages of life and physiological conditions in which Fe requirements are significantly increased and in these the risk for Fe deficiency increases. For example, during pregnancy there is an increase

 

in the volume of plasma and erythrocyte dilution with a relative reduction in the concentration of Fe in blood. In addition, Fe is transferred from mother to fetus in amounts that can reach 3 or 4 mg/day in the third quarter. Premature infants and very low–weight newborns, who have poor reserves, are prone to Fe deficiency if supplements are not administered. In women, menstrual blood loss can cause deficiency if the iron is not replaced with adequate food or supplements. There are pathological conditions that determine alterations in Fe intestinal absorption and Fe deficiency, as for example: lack of hydrochloric acid in the gastric secretion (achlorhydria), gastrectomy, excessive consumption of antacids, intestinal malabsorption syndromes, accelerated intestinal transit, and avitaminosis C. Important hemorrhage, or small amounts of blood loss, maintained for a long time, as occurs in chronic infections and in parasitic diseases, chronic infectious or inflammatory processes (lasting more than 2 months), Helicobacter pylori infections, associated with gastric ulcers, neoplasias, and lead poisoning. Anemia due to iron deficiency. When Fe is reduced and its stores are depleted, hemoglobin synthesis and erythropoiesis is impaired, leading to anemia. The concentration of hemoglobin in blood decreases (values under 12 g/dL in women and 13 g/dL in men are considered abnormal). The hematocrit and mean corpuscular volume of RBCs is reduced. Erythrocytes are smaller than normal and poor in hemoglobin (hypochromic microcytic anemia). Patients are pale, their capacity for work is reduced, and they experience fatigue at the slightest effort. Lack of Fe during the first 2 years of life produces irreversible alterations in the central nervous system that do not improve with later supplementation treatments. These children suffer from behavioral problems, learning difficulties and reduced cognitive ability. Iron overload. Excessive accumulation of Fe results from excessive Fe absorption in the



Trace elements

intestine, hematological conditions requiring repeated transfusions (i.e., thalassemia), impaired heme synthesis that prevents the use of iron, genetic faults affecting factors involved in income regulatory processes. Initially, the Fe accumulation is as ferritin, if the overload persists, hemosiderin is formed and deposited in liver, pancreas, skin, and joints (hemosiderosis). These deposits alter the function of the organs where Fe accumulates and are the cause of a condition called hemochromatosis. Also, several genetic syndromes that cause iron overload have been described.

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TRACE ELEMENTS

present in the gastrointestinal tract. Pancreatic secretions are rich in Zn. Zn is absorbed through the small intestine, mainly in the duodenum. It is transported through the apical membrane of the cells as free Zn2+ by a saturable active carrier. Zn absorption is influenced by various factors; it is favored by small ligands, such as citrus juice acids, picolinic acid (intermediate of the pathway from tryptophan to niacin), prostaglandins, glutathione, and free amino acids (principally histidine, cysteine, and glycine). In contrast, phytates from whole grains; oxalate from spinach, chocolate, and tea and polyphenols (i.e., tannins) from whole grains, fruits, tea, and vegetable fiber, form nonabsorbable complexes with Zn. The presence of animal foods lowers the inhibitory action of these products. Other divalent cations (Fe2+, Cu2+, and Ca2+) compete with Zn for binding to its carrier, reducing Zn absorption. Usually, Zn absorption transports 35% of the total Zn contained in the intestinal lumen and reaches 3 or 4 mg (45–60 µmoles)/day; this amount is adjusted to the organism needs. Within the enterocyte, Zn has several destinations; it can be used by the same cell, it can be transported to the basolateral membrane to be released in plasma, or stored bound to proteins. Thionein is a small protein (10 kDa) rich in cysteine residues, which serves as the main ligand for Zn and other minerals, such as copper, forming metallothionein. Zn bound to metallothionein is lost when cells are shed from the villi in the intestinal lumen. Diets that are rich in Zn induce the synthesis of metallothionein. Transport. In the portal vein, Zn binds mainly to albumin; it is captured by the liver and it is sent back to the circulation bound to albumin, α2-microglobulin, and immunoglobulin G. Albumin carries approximately 70% of the total Zn present in plasma, where its concentration is maintained within narrow limits, at 12 µg/dL (10  µM). In whole blood, 70%–80% remains in the intracellular space, with higher amount in leukocytes than in erythrocytes.

These constitute a group of elements (also called oligoelements) that present in the body in concentrations ranging from picograms to nanograms per gram of wet tissue. Although found as traces, they are essential for maintaining normal metabolism. They are described in the following sections.

Zinc (Zn) Zinc is an essential element present in all body tissues. A normal adult contains approximately 2.5 g of zinc, mainly as divalent ion (Zn2+). Zinc forms part of proteins and enzymes and participates in catalytic, structural, and regulatory functions. Natural sources. Zn present in foods is associated with proteins, peptides, and nucleic acids. Beef, chicken, and fish meats are the richest sources. Lower amounts are found in milk and dairy products. Whole grain cereals, legumes, and vegetables, contain Zn, but the presence of phytate in them reduces Zn bioavailability. Fruits and refined grains are very poor in Zn. Animal foods provide 40%–70% of Zn in a mixed diet. Absorption. Zn is released from proteins and nucleic acids by the hydrochloric acid in the stomach and the proteases and nucleases

 

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Storage. There is no specific organ where Zn is deposited, it is found in all tissues, especially liver, kidney, muscle, skin, blood, and in prostate secretions. Excretion. Feces are the main routes for Zn elimination. The Zn unabsorbed from food, and that contained in pancreatic secretions and cells that shed from the gastrointestinal mucosa, are the sources for the Zn that is lost. The amount of Zn released through the urine is very small (less than 1 mg/day). Functions. Zinc is an essential component of many enzymes (at least 200), more than any other trace mineral. In many of these enzymes, Zn forms part of the catalytic site; in others, it ensures the structural stability of the enzyme. Some of the enzymes containing Zn are: carbonic anhydrase, superoxide dismutase, alcohol dehydrogenase, alkaline phosphatase, aminopeptidase, carboxypeptidase, δ-aminolevulinic acid dehydratase, collagenase, phospholipase C, polyglutamate hydrolase, transcriptases. Other functions. Zn is also important as a structural component of transcription factors that contain “zinc finger” domains, which bind to response elements in the promoter of a series of genes, activating or repressing their activity. Particularly relevant are the steroid, thyroid, calcitriol, and retinoid hormone receptors. Redox functions. Zn is involved in redox reactions mainly catalyzed by superoxide dismutase. Regulation of apoptosis. Zn influences some of the steps that trigger the process of programmed cell death (Chapter 32). Control of cell proliferation. Zn has direct effect on hormones, receptors, and genes responsible for cell growth. Membrane stabilization. Zn functions in stabilizing the structure of membrane proteins and enzymes. Immune system. Zn improves the body defense against infections. Pancreas. Zn is associated with insulin deposits in the pancreatic β cells and also promotes insulin secretion.

In saliva, a zinc metalloprotein, called gustin, is related to taste sensations. Deficiency. Insufficient intake, intestinal malabsorption, loss or disturbances in utilization are causes of Zn insufficiency. It is estimated that approximately half of the world’s population is at risk of deficiency. Among the groups at highest risk are those that require higher amounts, such as children, adolescents, pregnant, and lactating women. Alcoholics with liver cirrhosis often excrete high amounts of Zn in urine and have decreased plasma levels of Zn. Diabetic and patients with infections are also at risk of Zn deficiency. Reduction of Zn in the body is a condition that develops slowly due to the effectiveness of the adaptive mechanisms that regulate homeostasis and control income and loss. Zn deficiency in human presents with skin lesions, decreased appetite, altered taste and smell, growth defects, delayed puberty, hypogonadism that can be explained by the lack of Zn in the androgen and estrogen receptors, which reduces sensitivity of target tissues to these hormones. In addition, Zn deficiency causes increased susceptibility to infections.

Copper (Cu)

 

Copper is a widely distributed element in nature. It has great functional importance, mainly as a component of metalloenzymes, in which copper functions as an electron acceptor changing from Cu2+ to Cu+. A normal adult contains approximately 150 mg of copper, distributed mainly in liver, muscle, red cells, and plasma. Dietary deficiency of Cu is rare; however, some studies have shown that marginal copper deficiency is a relatively common condition. Natural sources. Liver, seafood, whole grain cereals, nuts, raisins, potatoes, fruits, and meats are foods rich in Cu. Lower concentrations are found in vegetables, poultry, and fish. Milk and dairy products have very small amount. The average diet provides 2.5–5.0 mg/day. Most of the



Trace elements

Cu present in food is bound to proteins, primarily as Cu2+. Absorption. Generally, the bioavailability of Cu is 50% of that coming in the diet. The percentage absorbed increases when the intake is less than 1 mg/day. Pepsin and hydrochloric acid in the stomach facilitate Cu release from proteins and the action of the proteases of the small intestine facilitates Cu absorption. The main region of the intestine involved in Cu absorption is the duodenum, which uptakes it through a saturable active transport system. Cu absorption is influenced by various dietary factors. It is favored by free amino acids, which bind to Cu and carry it along as they are transported across the intestinal epithelium by different amino acid transport systems. Some organic acids (citric, lactic, malic, acetic, and gluconic) enhance Cu absorption. Phytates hinder the entry of Cu, and also inhibit Fe, Ca, and Zn absorption. Cu absorption is regulated; when the uptake by enterocytes is high, the excess is stored and eliminated with cells that shed from the mucosa. Once inside the enterocyte, Cu can follow different routes: (1) it can be used by the same cell to synthesize cuproproteins, (2) it can be transferred to blood by active transport systems, and (3) can be bound to thionein, a metal-fixing apoprotein that becomes metallothionein. Binding of Cu to proteins, amino acids, or glutathione prevents the generation of free Cu radicals that can cause cell damage. Transport. Cu circulates in blood bound to albumin; it can also be linked to free amino acids, histidine, and the transport protein transcuprein. From blood, Cu moves into tissues, mainly liver, where it is incorporated into cuproproteins. One of these proteins is ceruloplasmin, a α2-globulin of ∼160 kDa that binds six Cu atoms per molecule. From the liver, ceruloplasmin passes to the general circulation. More than 80% of the Cu present in plasma is bound to ceruloplasmin, which is also involved in the metabolism of iron catalyzing the oxidation of Fe2+ to Fe3+. The rest of plasma Cu is attached to albumin, transcuprein, and histidine.

737

Excretion. Copper is excreted in the bile and eliminated with the feces. This is the main route for Cu elimination and helps to regulate the body Cu content. The amount being excreted in urine is very small (∼30 µg/day) as well as its elimination through sweat and desquamated skin cells. Functions. Copper is an essential cofactor for many enzyme reactions, acting as an intermediary compound in electron transfer. In several proteins and enzymes it also is a structural component. Among the most important molecules containing Cu are: ceruloplasmin, superoxide dismutase, cytochrome c oxidase, monoamine oxidase, p-OH-phenylpyruvate hydroxylase, dopamine monooxygenase, lysyl oxidase, tyrosinase, α-amidating peptidylglycine monooxygenase. Other proteins containing Cu include prion proteins (p. 536), important for normal function of the nervous system and factors V and VIII, which are involved in the process of blood clotting (Chapter 31). Deficiency. Dietary copper deficiency is rare, but it can be observed in prematures, malnourished children, patients under chronic parenteral nutrition, intestinal malabsorption, and people consuming high amounts of antacids. The most frequent symptoms of Cu deficit are: hypochromic microcytic anemia similar to that of iron deficiency, skin and hair depigmentation, bone demineralization, impaired immune function, poor myelination. In these patients, the synthesis and degradation of serotonin is decreased, which can compromise nerve excitability. There are genetic defects related to alteration of copper metabolism, such as Wilson’s disease or hepatolenticular degeneration and Menkes’ disease.

Iodine (I)

 

Iodine is required for the synthesis of thyroid hormone. A normal adult has 20–50 mg of iodine distributed in the thyroid gland, muscle,

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29.  Essential Minerals

and other tissues. In thyroid gland the concentration is much higher than that present in muscle and blood plasma. Molecular iodine presents as I2, in nature it is often found as iodides (I−) and iodates IO −3 . Natural sources. The concentration of iodine in foods is variable because it depends on its amounts in the soil of the particular geographic region considered. Sea water is relatively rich in iodine. Salt water fish and seaweed contain it in significant quantity. Absorption. Iodine from foods comes mostly as iodides or iodates, linked to free amino acids. The amount in a standard diet is 100–200 µg/day. In the digestive tract, iodate is reduced to iodide in reactions in which glutathione is usually involved. Iodide is readily absorbed through the digestive tract, including the stomach. The bioavailability of iodide is virtually 100%. Thyroxine (T4) and triiodothyronine (T3) are absorbed without change in the intestinal mucosa with a bioavailability of 75%. Therefore, it is possible to treat hypothyroidism with thyroid hormone administered orally. Transport. Iodide enters the circulation by the portal vein system and is distributed throughout the body. Blood plasma contains 4–8 µg of iodide per deciliter, predominantly bound to plasma proteins (proteic iodine). Approximately one-third of the total iodide absorbed is taken up and concentrated by the thyroid gland. Iodide excess is eliminated mainly by urine. The iodide thyroid/plasma ratio is normally 30–40. In the thyroid, iodides pass from the cell to the lumen of the gland’s follicles. Metabolism. Iodide metabolism is considered in p. 588. Functions. So far, the only known physiological role of iodine is to form part of thyroid hormones. Deficiency. Since iodine is essential for the synthesis of triiodothyronine and thyroxine, chronic deficiency of this element in the diet results in reduced production of these hormones and causes hypothyroidism. Iodine deficiency

 

affects all ages. However, the groups most at risk are pregnant women, infants, and children under 3 years of age. Iodide deficiency results in a reduction of iodide reserves in the thyroid gland and in T3 and T4 synthesis. The reduction of T4 in plasma increases, through a positive feedback mechanism, the secretion of TSH and its releasing hormone, which results in thyroid hyperstimulation and simple goiter. This is commonly due to insufficient iodine intake and is characterized by an enlarged thyroid gland. Ocean water contains iodine; therefore, areas close to the coasts have adequate iodine levels in the soil, water, and foods. In contrast, regions far from the sea or surrounded by mountains that block the winds coming from the ocean, are poor in iodine and the incidence of simple goiter with deficient production of thyroid hormones and hypertrophy of the gland is high (greater than 10%); this is known as endemic goiter. The deficiency can be compensated by adding iodine to the diet; the most practical method to do this is the addition of iodine to table salt in a ratio of 1 part in 100,000. In many countries iodide addition to salt is required by law. Deficiency of iodide in the fetus results in cretinism, which is characterized by growth failure (dwarfism) and serious neurological damage, mental retardation, hearing loss, and motor disorders (spasticity and muscle rigidity). Failure of the thyroid gland (hypothyroidism) is manifested by various symptoms: decreased basal metabolism, reduced synthesis and degradation of proteins and lipids, increased serum cholesterol, decreased glycolysis and glycogenolysis, decreased amplitude of electrocardiogram waves. Early treatment with iodine improves these symptoms, although prenatal brain damage is irreversible. If hypothyroidism begins in adulthood, one of the striking symptoms is myxedema, due to accumulation of glycosaminoglycans and water in the subcutaneous tissue, with thickening and “pasty” skin appearance.



Trace elements

There are also congenital forms of hypothyroidism caused by genetic alterations affecting enzymes involved in the biosynthesis of thyroid hormones. Early diagnosis is important because the lack of T4 and T3 in the newborn produces severe developmental disorders, especially of the nervous system.

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Manganese (Mn)

Functions. The functional relevance of Mn is related to its role in the activation of enzymes or as a constituent of metalloenzymes. Enzymes associated to Mn include: oxidoreductases, hydrolases, mutases, transferases, lyases, and ligases. The activation of enzymes by Mn is not specific and it can be replaced by other divalent cations, such as Mg2+. The only enzymes that specifically depend on Mn are glycosyl transferases, glutamine synthetase, and farnesyl pyrophosphate synthetase. Mn metalloenzymes are mitochondrial superoxide dismutase, arginase, and pyruvate carboxylase. Deficiency. The deficit in Mn is rarely seen and only occurs when there is malnutrition. Low Mn can cause nausea, vomiting, dermatitis, decreased growth of hair and nails, change in hair pigmentation. Alterations in the reproductive functions, glucose tolerance, lipid metabolism, and plasma cholesterol levels have also been described. Also, failures in the synthesis of oligosaccharides, glycoproteins, and proteoglycans produced by reduced activity of the glucosyl transferase activity can occur.

Manganese is essential to many animal species, including humans. It is important for the activity of various enzymes and is a component of several metalloenzymes. A normal adult contains approximately 20 mg of Mn. Natural sources. Mn is supplied in the diet mainly through plant foods. Nuts, whole grains, vegetables, cereals, and tea are good sources; white flour has much less than whole wheat. Meat, fish, and dairy products contain lower amounts. The average diet provides 2–9 mg of Mn per day, which covers the normal requirements of an adult. Absorption. Mn is absorbed throughout the small intestine. Low molecular weight ligands, (histidine and citrate) increase its absorption. Fiber, phytates, and oxalate form nonabsorbable manganese precipitates. Transport. From the intestine Mn passes to the portal vein, where it can remain free as Mn2+ or can be bound to α2-macroglobulin and albumin and be taken up by the liver. In hepatocytes, Mn can be excreted in the bile, incorporated to enzymes, or secreted back to the circulation. Little is known about the mechanism by which Mn enters the cells. Mn is not stored in the body, but its concentration is higher in bone, which contains about 25% of the total body Mn, mainly associated with hydroxyapatite. Other organs containing Mn are liver, kidney, pancreas, and hair. Excretion. Almost all of the excess Mn is eliminated with the feces. This includes the Mn excreted in the bile or that not absorbed in the intestine.

Selenium (Se)

 

Selenium is an essential trace element in humans. Due to its similarity with sulfur, it can replace sulfur in methionine, cysteine, and cystine and form seleno-amino acids. These can be used for the synthesis of various proteins, including enzymes. The normal adult contains from 3 to 15 mg, depending on the geographic area of residence. Natural sources. Se content in food depends on the existing in the soil and varies greatly in different regions. In general, products of animal origin have more Se than plants. Se is present in organic compounds, mainly proteins, either as selenocysteine, which predominates in foods from animals, or as selenomethionine, more abundant in plants. It is also in inorganic compounds, including selenite SeO 23 − or selenate SeO 24 − . The best sources of Se are salt water fish, shellfish, and Brazil nuts (cashew).

740

29.  Essential Minerals

Absorption. After digestion of proteins containing seleno-amino acids, Se is transported into the enterocytes by the same carriers that transport the corresponding sulfur amino acids. Transport. Se is transported in circulation bound to plasma low and very low density lipoproteins (LDL and VLDL). Most of it (60%–80%) is bound to selenoprotein P. The liver contains over 30% of the total body Se, muscle has 30%, kidneys 15%, and 10% circulates in the plasma. Metabolism. The seleno-amino acids may remain in the cell as part of the general amino acid pool. Selenomethionine, mainly from vegetables, is not distinguished from its sulfur analog by mammals; it is metabolized and incorporated into protein by the same ways as methionine. Free selenium is converted to hydrogen selenide (H2Se) with H donated by glutathione, and seleno-phosphate by the seleno-phosphate synthetase, which transfers phosphate from ATP. Seleno-phosphate is intermediate in the biosynthesis of selenoproteins, containing predominantly selenocysteine in animals. Selenoprotein biosynthesis uses a special tRNA that initially binds serine. By a process that requires seleno-phosphate, the serine bound to tRNA is converted to selenocysteine. The UGA codon, which usually indicates termination of protein synthesis, when it coexists with a specific mRNA sequence on the 3′ untranslated side, induces insertion of tRNA loaded with selenocysteine. Excretion. Se is excreted in urine and feces. Urinary excretion is the major mechanism for the homeostatic control of Se. Functions. Se is a component of proteins, many of them with enzymatic activity. Twentyfive selenoprotein genes have been identified in the human genome, but only 15 of them have been characterized. The concentration of selenoproteins in endocrine glands (thyroid, adrenal, pituitary, testis, and ovary) is higher than in other organs. The best known selenoproteins are: (1) glutathione peroxidase (GSPx), which presents five isozymes that catalyze the removal of

hydrogen peroxide and other peroxides from different compounds; GSPx forms part of the antioxidant system of the body (see Chapter 10); (2) thioredoxin reductase, a NADPH-dependent flavoenzyme with selenocysteine in its catalytic site; and (3) iodothyronine deiodinases, which are selenoenzymes involved in the metabolism of thyroid hormones (p. 588). In addition, selenophosphate synthetase, selenoprotein P and sperm selenoprotein that results from the transformation of one of the glutathione peroxidases. Deficiency. The deficit has been described in patients maintained with parenteral nutrition for prolonged periods of time. Symptoms of Se deficiency are pain and muscle weakness, loss of hair, and skin pigmentation. In children, growth retardation and development are due to failures in thyroid hormone metabolism. Some studies have shown that selenium deficiency is correlated with an increased incidence of neoplasias, especially prostate cancer.

Molybdenum (Mo)

 

Molybdenum is a transition element that in the body is usually linked to S or O in two oxidation states, Mo4+ and Mo6+. Mo is an essential element; it is biologically inactive unless attached to a pterin core forming a cofactor similar to folic acid, molybdopterin, indispensable for the activity of several enzymes. Natural sources. Mo is widely distributed in common foods, but its content varies according to the Mo concentration in the soil. Legumes, whole grains, cereals, chicken, liver, and kidney are good sources of Mo. The content in beef depends on the diet that cattle are fed with. Absorption. Mo is absorbed throughout the gastrointestinal tract, in higher amounts in the proximal portions of the small intestine. Transport. From enterocytes Mo enters the circulation, where it is transported as molybdate (MoO 24 −) bound to albumin and α2-macroglobulin, and also loosely bound to erythrocytes. Liver and kidneys are the organs that concentrate Mo



741

Summary

at the highest amounts. Livestock, grazing on soil contaminated with Mo from industrial or mining areas, shows copper deficiency. Excretion. Most Mo is excreted in the urine as molybdate in quantities that are directly related to the intake. It is also eliminated with the bile. Mo homeostasis depends on the regulation of its excretion more than its absorption. Functions. Mo in molybdopterin, binds to the active site of three hydroxylases: sulfite oxidase, xanthine oxidase/xanthine dehydrogenase, and aldehyde oxidase and it is important for their activity. Deficiency. Mo deficit is very rare in man, it could be produced by prolonged ingestion of diets containing high concentrations of sulfate, copper, or tungsten. For people living in areas with very low content of Mo in soil, increased incidence of esophageal cancer has been described.

Fluorine (F)

incorporated into bone hydroxyapatite. The protein in the bone matrix has a high affinity for fluoride. Osteoporosis, bone decalcification common in older individuals, improves with consumption of moderate amounts of F. Fluorohydroxyapatite, which is less acid soluble than hydroxyapatite, makes teeth more resistant to decay. Moreover, it has inhibitory action of bacteria that proliferate in the dental plaque. Water fluoridation, at a concentration of 1 part per million, has a preventive effect on tooth decay, favoring the mineralization of the dental enamel. Toxicity. Chronic ingestion of larger amounts of F than those indicated previously, produces fluorosis. In some areas, drinking water contains more than 4 mg/L of fluoride, which can cause toxic effects. Fluorosis is characterized by alterations in bone, kidney, muscles, the nervous system, and skin, where it leads to lesions that could favor skin cancer. In children, fluorosis causes white spots and brown streaks in newly formed teeth, which become brittle. F has inhibitory action on various enzymes, such as enolase, which results in inhibition of glycolysis.

Although fluorine is not an essential element in humans, it has, at very low concentrations, beneficial effects, protecting against demineralization of calcified tissues. At present there is no evidence to include it as an essential factor in the diet. It is harmful if its intake exceeds 10 mg/ day. Natural sources. F is present in small amounts in foods, in concentrations that vary depending on the geographical region they come from. It is commonly found as fluorides bound to metals, nonmetals, or organic compounds, including proteins. Saltwater fish, consumed with its bone, and tea are rich sources of F. In some countries, fluoridation of tap water is performed, with addition of 37–63 mM (0.7–1.2 mg/L) of F. In this case, the daily intake of F can reach 1.4–3.4 mg/day. Absorption. F is absorbed throughout the gastrointestinal tract. Functions. F contributes to the mineralization of bones and teeth. F promotes the precipitation of calcium and phosphate and becomes itself

Cobalt (Co) Cobalt is not an essential element in humans, it is a component of cobalamin or vitamin B12 (p. 677), and is provided preformed in the food. Free Co is not used by the organism.

SUMMARY

 

Sodium is the main cation of the ECF (55% of the total Na+ is in the ECF); the rest is located mainly in bone (40%). Plasma Na+ concentration is 135–145 mEq./L, while inside the cells, it only reaches 10 mEq./L. Na+ contributes to half of the osmolarity of ECF and drives fluid movement between different body compartments. The major route for Na+ excretion is the kidney. Aldosterone, the main Na+ regulator, activates Na+ reabsorption in the renal tubules. Atrial natriuretic peptide also contributes to Na+ homeostasis by favoring its urine excretion. Potassium is the main cation of the intracellular space (90% of the total K+ is in the ICF), with a concentration of

742

29.  Essential Minerals

∼150 mEq./L. In plasma, K+ circulates in concentrations of 4–5.5 mEq./L. The uneven distribution of K+ and Na+ between intra- and extracellular compartments is due to the activity of the Na+,K+-ATPase of the cell plasma membrane. K+ amounts are regulated by its elimination in the urine, via aldosterone-induced secretion in the renal distal tubules. Chloride is the main anion in ECF, corresponding to 88% of the total body Cl−. Plasma Cl− concentration is 102 mEq./L. Since Cl− is Na+ main attending anion, its amounts follow those of Na+. Cl− contributes importantly to plasma osmolarity. Its regulation in the body follows that of Na+. Calcium is abundant in bone, which contains 99% of the total body Ca2+. The plasma concentration of Ca2+ is 10 mg/dL (2.5 mM or 5 mEq./L), 50% of which exists as free Ca2+ and the rest is bound to proteins or forms nonionizable compounds. Ca2+ is the physiologically active form. When the pH increases (alkalosis) Ca2+ decreases and the opposite occurs in acidosis. Adults and children 1–10 years of age need to ingest ∼800 mg of Ca2+ per day; infants require 350–550 mg/day; and women during pregnancy and lactation, 1200 mg/day. Milk and dairy products are the best sources of Ca2+. Ca2+ homeostasis is primarily under the control of parathyroid hormone and 1,25-(OH)2-D3. The intracellular Ca2+ concentration is very low (0.1 µM). Various stimuli acting via membrane receptors promote Ca2+ entrance into the cell, via Ca2+ channels opening. This increase in Ca2+ serves as a signal to regulate many cell processes. Ca2+-ATPase and Na+/Ca2+ exchanger in the plasma membrane extrude Ca2+ from the cell, maintaining its cytoplasmic levels low. Cytosolic Ca2+ also varies by movement of this cation from intracellular stores (endoplasmic reticulum and mitochondria). Reduction of extracellular Ca2+ (below 3.5 mg/dL) causes increase in neuromuscular excitability (tetany). Prolonged loss of Ca2+ causes osteoporosis. Phosphorus is mainly located in bone (over 80% of the total P) forming part of hydroxyapatite. In the ECF, P exists partly as phosphate anions HPO 24− /H 2 PO −4; the plasma concentration of P is 2.5–4.8 mEq./L. P is absorbed in the jejunum and ileum, regulated by 1,25-(OH)2-D3. Phosphate levels are also maintained by controlling reabsorption in the kidney tubules, by mechanisms that are activated by calcitriol and inhibited by parathyroid hormone. Magnesium is an essential cation, involved in many enzymatic reactions, neuromuscular excitability. It forms complexes with ATP and other triphosphate nucleotides. The plasma concentration of Mg is 1.5–3.0 mg/dL (0.625– 1.25 mM or 1.25–2.5 mEq./L), of which 30% is bound to proteins. Iron is mainly bound to proteins in the body. An adult contains a total of 4.0–4.5 g; 2.6–3.0 of which are in Hb and 1.0–1.5 g bound to ferritin and hemosiderin in intracellular stores. A normal adult man loses ∼1 mg Fe per day; women have a

 

higher loss, due to menstrual bleeding. Animal foods contain heme proteins whose Fe is more easily absorbed than Fe from plants. The presence of HCl and ascorbic acid in gastric juice is important for Fe absorption. The recommended amounts of Fe for an adult are 10 mg/day; higher amounts are required for pregnant women, children, and adolescents. Fe is absorbed in the intestine in its ferrous state. Fe transport across the intestinal mucosa is proportional to the body needs. Once in the enterocyte, Fe is transferred to the basolateral membrane and to the circulation, or stored in the cell as ferritin. Passage of Fe to blood is mediated by ferroportin; this requires the prior oxidation of Fe2+ to Fe3+, which is catalyzed by hephaestin and ceruloplasmin. In plasma, Fe is carried by transferrin. The normal plasma level of Fe is 60–150 µg/dL. Transferrin transfers Fe to cells by binding to cell membrane receptors, which are internalized by cells via endocytosis. Fe is released in the cytosol, stored as ferritin, and the transferrin receptor is recycled after secretion from the cell. Fe is being continuously recycled in the body, mainly by the lysis and production of erythrocytes and Hb. Fe is eliminated mainly by the intestine. An overload of Fe results in formation of hemosiderin granules and hemosiderosis. Lack of Fe in the diet produces hypochromic microcytic anemia. Trace elements include the following: Zinc is present in foods of animal origin. It is absorbed mainly in the jejunum. In the enterocyte it is linked to metallothionein and in plasma, it is transported bound to albumin. When in excess, Zn is excreted in pancreatic juice. Zn is a constituent of many enzymes. Its deficiency causes delayed development, anemia, and hypogonadism. Copper amounts in the body reach a total of 150 mg; 50% of Cu is found in muscle and bone, 10% is found in liver. Cu is part of enzymes, such as cytochrome oxidase, superoxide dismutase, monoamine oxidase, tyrosinase, and ceruloplasmin. Cu deficiency is mainly characterized by anemia. Iodine is almost exclusively required for the synthesis of thyroid hormones. It is absorbed in the intestine as iodide. Thyroid captures a third of the total iodide absorbed, peroxidase oxidizes it and incorporates it in tyrosine residues into thyroglobulin, from which the T3 and T4 hormones are released. Chronic iodine deficiency causes hypothyroidism (endemic goiter). Manganese is mainly provided by vegetables in the diet. It is required as a cofactor for some enzymes. Molybdenum is an important component of several metalloenzymes. Selenium is associated to several amino acids. Selenomethionine and selenocysteine form part of different proteins, such as glutathione peroxidase, iodotyrosine deiodinases, thioredoxin reductase, and synthetase selenophosphate.



BIBLIOGRAPHY

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