ACTA FAC. MED. NAISS. 2003; 20 (4): 189-202

Review article

TRACE ELEMENTS

Dušica Simić¹, Ivana Budić²

¹University Children's  Hospital Belgrade Clinic for Pediatric Surgery and
²Orthopedics, Clinical Center, Nić

INTRODUCTION

The trace elements have been shown to influence a number of biochemical and physiological processes. The two major recognized functions are to act as cofactors for metal-ion-activated enzymes or to form such a tight complex with the protein that the two are isolated together as a unit called metalloenzyme. Trace elements play a part in the synthesis and structural stabilization of both proteins and nucleic acids. They are also constituents of proteins and hormones (1). In addition, they are involved in the function of sub cellular systems such as mitochondria, as well as in membrane transport, nerve conduction, and muscle contraction. Some of them (Cu, Zn, Mn, and Se) act as antioxidants.

A free radical is simply defined as any species capable of independent existence that contains one or more unpaired electrons, an unpaired electron being one that is alone in an orbital. Oxidative stress is a condition of imbalance between pro-oxidants and antioxidants. Tissue injury occurs due to enhanced formation of free radicals or other reactive species, in one hand, and because of reduced protective mechanisms in the other.

Gene expression is changed, especially of these genes that control antibodies and cytokines  biosynthesis. It is necessary to understand very complex molecularly mechanism involved in immunomodulatory activity of trace elements.

Nowadays it is well known that two subpopulations of T-helper lymphocytes (Th1 and Th2) exist. Th1 lymphocytes cytokines, Interleukin (IL) 2, Interferon gamma (IFN-g) and Tumor necrosis factor beta (TNF-ß) are necessary in development of the phagocyte dependent immunity, while Th2 cytokines, IL -4, IL-5, IL-6, IL-9, IL-10, IL-13 are important for humoral immunity (2).

Presence or absence of different trace elements influence on Th1 and Th2 response (3). Immune function could be damaged in patients with trace elements deficiency, e.g. in elderly (4), critically ill (trauma, burns), but the patient condition could be improved after the supplementation (5).

CLINICAL DEFICIENCY SYNDROMES AND SUB-CLINICAL STATES 

It is, however, now clear that as an individual develops progressively more severe depletion of trace elements status, he/shi will pass through a series of stages with biochemical or physiological consequences. The metabolic or physiological penalty of such a sub-optimal nutritional status is usually not clear, but the assumption remains that this impaired metabolism is likely to result in detrimental effects. Similarly, specific and localized tissue deficiencies can occur which can lead to pathological changes. Such situations can be defined as sub-clinical deficiency. The time course for development of a sub-clinical deficiency state varies for each individual trace element, and depends upon the nature and amount of tissue or body stores. The consequences of an inadequate intake are more clearly delineated in figure 1.

Optimal tissue function with body stores (if any) replete
                        ß
Mobilization of stores (if any)
                        ß
Initial depletion         Þ        Compensation (if possible)
                                        -         increased absorption from gut
                                        -         reduced renal excretion
                                        -         reduced growth velocity (zinc)   

ß                                       

Intracelular content reduced

                   ß

impaired biochemical functions Þ    reduced intracellular

                                                                                         enzyme activity

 -      metabolic effects

 -    antioxidant systems

                                                   gene expression/regulation

                        ß

non-specific functional effects Þ  short term:

                                                                               - cognitive effects

                                                                               - fatigue/work capacity

                                                                               -  immunological function

                                                                                  long term:

                                                                                 -  free radical damage to

                                                                                       dna/cell membranes

                        ß

clinical disease        Þ      typical for each trace element or

                                                                        vitamine

                                                -    complicated if multiple deficiencies

                        ß

                        death      

Figure 1. Consequences of inadequate micronutrient intake
 

Sub-clinical deficiency state can be either absolute or relative. Thus an intake less than the requirement in normal health will lead to sub-clinical deficiency, or to a typical clinical deficiency state. However, certain patents have significantly increased requirements as a result of their disease process, and hence an intake normally regarded as adequate may be relatively insufficient and lead to a sub-clinical deficiency state. Trace elements deficiency is a result of:

- reduced intake or abnormal absorption
- increased needs
- increased losses

Sometimes several factors could cause trace element deficiency. It could be fended especially in alcoholics, in patients who suffer from celiac disease and inflammatory bowel diseases ets. If the patient is younger he/she is on greater risk to develop trace elements deficit -because of the faster metabolism and smaller depots (6).

Disturbance of complex interaction between trace elements could provoke nutritive deficit. E.g. increased exposition to cadmium as a result of the pollution lead to increased requirements for zinc.  Premature infants have low level of Cu, Cr and Fe. Term newborn accumulates Cu and Cr during the last 8-12 weeks of gestation. Total body Zn increase during this time. Premature infants could hardly achieve positive Zn balance during the early postnatal period and have higher risk to develop Cu, Zn, Se, Mg and Mo deficit.

The extent of whole body depletion of one or more essential inorganic micronutrients, will depend on a number of factors:

1. The nutritional state of the patient on admission to hospital. The pre-existing illness may have caused a period of anorexia, or inadequate digestion or absorption of nutrients.

2. The duration and severity of inadequate nutritional intake whilst in hospital, as a result of surgery or other treatment.

3. Any increased losses through small bowel fistula/aspirate (rich in zinc), biliary fluid (rich in copper) or burn exudate fluid (rich in zinc/copper/selenium).

4. Moreover, some individuals will have an increased daily requirement, partly to keep up with increased losses, and partly to meet metabolic requirements - these are particularly important when patients become anabolic after a period of catabolism or when normal growth occurs in a child.

In patients on  total parenteral nutrition (TPN) without trace elements supplementation, symptoms appear after 4 weeks (3). In order to prevent this deficiency it is important to  provide trace elements. It is interesting that fresh frozen plasma contains high amount of Zn and physiological amounts of Cu and Se (14). Hence, in the past, trace elements have been supplemented by the administration of fresh frozen plasma once a week. Commercial preparations are convenient  and easy to use. Multi-elements solutions are better for clinical practice because all trace elements are compensated at the same time  by one dosage. Disadvantage of this approach is that it is impossible to individualize administration. This could lead to overprovision.

PROVISION OF TRACE ELEMENTS 

Defining the optimal intake of trace elements is far from ideal. It is possible to make a reasonable assessment of the requirements of an individual, based upon the requirements in health, the likely underlying nutrition state of the patient at the time of presentation, and the ongoing effects of the disease process. Such a level of provision has been proved to be adequate in most cases to prevent the development of a deficiency state. The increasing number of patients dependent on life-long TPN makes the long-term provision of adequate amounts of trace elements an important part of nutritional therapy.

It is very difficult to measure trace elements quantity in the body. Identification of the trace element deficiency should be included in the nutritional assessment in every patent. Biochemical level interpretation is difficult, so deficiency is rarely recognized on time.

The biggest problem in trace elements estimation emerges from the fact that tests of plasma concentration are a poor reflection of tissue status, biological activity or nutrients balance. Plasma concentration of Zn, Fe, Se all fall during an acute phase response (APR) whereas Cu increases (Table 1.). Plasma concentration may be of value in stable patients without an active APR. It  may be also helpful in identifying over-provision.

Table 1.Effects of the acute phase reaction on plasma micronutrients

In order to prevent toxic accumulation, doses are decreased during the first week of life, particularly in premature (kidney function is not completely developed).

Zn and Cr should be avoided or reduced in kidney diseases, Cu and Mn should be avoided or reduced in biliary obstruction (excreted in the bile). Fe requirements in children on PN are high (growth and development). These patients need "top up" transfusions. Zn and Mg losses are increased during the increased intestinal losses.

Excess trace elements may be provided inadvertently as contaminants of other nutrients in TPN e.g. Al in Ca/P supplements, Cr in amino acids. Some older commercial trace element supplements contain excess manganese which has been shown to be related to toxicity condition in some patients.

To comprehend how the trace elements changes  influence the body, it is necessary to understand some key features of their deficiency (Table 2).

Table 2. Metabolism of Selected  Trace Elements in Adults

ZINC (Zn)
Good Zn sources are: liver, fish, meat, eggs, legumes, walnut, coconut, and even water in some regions. Active transportation in the small bowel is the mode of Zn absorption. Phytates and fibres decrease Zn absorption. The major route of excretion is by the stool.

A false increase in levels occurs with external contamination, hemolysis, and prolonged fasting; a false decrease occurs with corticosteroid use, infection and inflammation, and postprandial sampling.

 A progressive fall in Zn concentration usually reflects inadequate intake of the nutrient.  Decline in serum alkaline phosphatase activity often signals the onset of zinc deficiency.

Zn levels in blood and urine provide only partial information about the Zn status. Hair or erythrocyte analysis is more reliable. Impaired taste perception could also be investigated. Zn level in plasma lower than 50 mg/dl is considered to be a deficit.

Zn in an essential component of more than 70 metalloenzymes (18), including carbonic anhydrase (involved in carbon dioxide metabolism), alkaline phosphatase, lactic acid dehydrogenase (important for the inter conversions between pyruvate and lactate) and some peptidases (important in protein digestion). These metalloenzymes are involved in the metabolism of lipids, carbohydrates, proteins and nucleic acids (RNK and DNK). Other zinc-containing proteins include nerve growth factor and gustin, a salivary protein that is thought to play an important role in taste perception.

Human zinc deficiency occurs with:

1. Inadequate dietary intake

2. Malabsorption syndromes associated with steatorrhea

3. Acrodermatitis enteropathica, a genetic defect in zinc absorption

4. Dietary factors such as excess phytate and fiber, which may impair zinc absorption

5. Prematurity since about two thirds of the zinc in the fetal body at term is accumulated during the last 10-12 weeks of gestation

6. Increased needs in catabolic patients

7. Patients maintained on prolonged PN without adequate zinc supplementation.

Zinc is crucial to growth and development. It is important in wound healing, and as an oxidant that plays major role as a superoxide-dismutase cofactor.

More recent works have shown an action Zn-specific on monocytes by inducing monokine secretion (IL-1b, TNF-a) and a subsequent indirect stimulation of T cels. These facts may explain the high sensitivity of cell-mediated immunity response to Zn deficiency. It has recently been shown that a Zn deficiency can lead to a Th2 dependent humoral immune response, which may be determinant for the outcome of different diseases (7). Zn supplementation may be beneficial in treatment of gram negative septicemia (8) and HIV+ adults probably by enhancing immune function (9).

Moderate Zn deficit cause immunological changes such as: thymus involution, thymocytes count depletion and late hypersensitivity type reaction reduction (skin tests). Clinical manifestations of Zn deficiency are: growth failure, diarrhea, perineal and perioral skin lesions, alopecia, increased susceptibility to infections, delayed sexual maturation, severe anorexia, impaired taste perception, lethargy, irritability, mental depression, behavioral disturbances, adynamic intestinal motility a night blindness.

In patients maintained on prolonged PN without adequate zinc supplementation Zn deficit symptoms could appear after just 2 weeks. Clinical manifestations could be very prompt if the losses are big (diarrhea, fistulae). It has been calculated that every kg of stool or ileostomic contents contains 17,1 mg Zn. Every kg of small bowel fistula content contains 12,2 mg Zn.

Although the Zn level is low in patients with cardiopulmonary by-pass, trauma and sepsis, Zn must be supplemented very carefully during the acute phase response because it could elevate cytokines level(10). High doses of Zn in elderly could cause  immunity disturbance(11). Zn supplementation is particularly important during the anabolic phase of illness. Average Zn requirements are (mg/kg/day): premature 100-500, infant 50-100, child 50-80. Recommended doses in adults are 10-15 mg (orally) and 2,5-4,0 (i.v.). During the acute catabolism phase the dose is increased for 2 mg (12). Chronic intake in doses larger than 15 mg/day could alternate Cu metabolism making its absorption difficult. As a consequence immune disturbances occurs (Table 3). 

Table 3. Zinc (Zn)

*The amount in the commonly used adult trace element preparation Addamel (Fresenius Kabi)
¹ Recommended Dietary Allowances 10^th Ed. National Acad Press, Washington 1989
² Dietary Reference Value for Food energy and nutrients in the United Kingdom, HMSO 1991
³ Population reference intakes. In Commission of the European Community. Reports of the Scientific Committee for Food. (31^st Series) Chapter 37 1992

SELENIUM (Se)
Nutrients that contain Se are: leguminosae, cereals and milk products.

Glutathione peroxidase (GSH-Px) in erythrocytes is a selenium containing enzyme. This enzyme catalyzes the reduction of hydrogen peroxide to water, thereby protecting the cell membrane, macromolecules (DNK) and hemoglobin from oxidative damage (lipid peroxidation) and hemolysis. Eleven selenium proteins have been identified. The actions of selenium are linked closely to those of vitamin E and have a sparing effect on vitamin E requirements.

Se is an essential nutritional factor with important effects on both cell-mediated and humoral immune responses. Se deficiency leads to a depressed delayed-type hypersensitivity and reduced phagocytic killing, response of T and B cells to mitogens, and  activity of cytotoxic T and Natural killer (NK) cells. Probably, cells of the immune system do not respond normally to antigens or cytokines and exhibit abnormal phagocytolysis because of increased oxidative stress. Se supplementation leads to an improvement of the immune function enhancing phagocytosis, cytotoxic T and Nk cells activity, and the expression IL-2 receptors on T lymphocytes. This may explain the stimulatory effect of Se on B-cell antibody production.

Increased Se requirements are in inflammatory intestinal diseases and in burns. At the same time, an increase in activity of GSH-Px is achieved in Se supplementation. This is important because, GSH-Px is one of the antioxidants that are involved in the down regulation of Nuclear Factor-kB (NFkB) modulating inflammatory response in critically ill patients.

Se deficiency could cause muscle pain and muscle tenderness, liver necrosis and cardiomyopathy (secondary to prolonged TPN). Selenium deficiency is more severe in the case of vitamin E deficiency (vitamin   E is free radical scavenger that has synergistic antioxidant action with Se in membrane protection (14)).

Low levels of selenium in the soil have been associated with a high incidence of some forms of cancer in humans. Keshan disease is an endemic disease (a fatal cardiomyopathy) in children who live in a region of China where selenium levels are low in staple foods.

Se is excreted by the kidneys (kidney diseases could impair this process). Se requirements are (mg/kg/day): neonatesd 2-5, children 2. In adults, daily oral requirement is 50-200 mg or 1mg intravenously.  In PN < 2 weeks Se deficiency doesn't occur. In a patient on long-term PN Se must be added to the preparation (Table 4).

Table 4. Selenium (Se)

*The amount in the commonly used adult trace element preparation Addamel (Fresenius Kabi)
¹ Recommended Dietary Allowances 10^th Ed. National Acad Press, Washington 1989
² Dietary Reference Value for Food energy and nutrients in the United Kingdom, HMSO 1991
³ Population reference intakes. In Commission of the European Community. Reports of the Scientific Committee for Food. (31^st Series) Chapter 37 1992

COPPER (Cu)
Food rich in copper is consisted of: oysters, meat, walnut, liver, kidney, oil, margarine and dried legumes. Approximately 40% of ingested Cu is resorbed  in stomach and upper parts of small intestine. Absorbed Cu is attached to albumin in portal circulation and forms ceruloplasmin in the liver. Copper is an essential component of a number of metalloenzymes (Table 5, 6). Ceruloplasmin, a glycoprotein that contains eight Cu atoms per molecule, accounts for more than 95% of the Cu present in the blood plasma. This cuproprotein plays a major role in the Cu transport and has ferroxidase activity. Ceruloplasmin is necessary for the optimal rate of oxidation of Fe2+ from body stores in the liver and bone marrow to Fe3+; this is necessary step before iron can attach to transferrin for transport to and uptake by the erythrocyte precursors in the bone marrow. In copper deficiency, lack of ferroxidases contributes to the microcyte hypochromic anemia which is unresponsive to oral iron therapy. This anemia is accompanied by neutropenia; bone marrow exam reveals vascularization of the red cells series as well as a noticeable maturation arrest of the white cell series.

Table 5. Copper (Cu)

*The amount in the commonly used adult trace element preparation Addamel (Fresenius Kabi)
¹ Recommended Dietary Allowances 10^th Ed. National Acad Press, Washington 1989
² Dietary Reference Value for Food energy and nutrients in the United Kingdom, HMSO 1991
³ Population reference intakes. In Commission of the European Community. Reports of the Scientific Committee for Food. (31^st Series) Chapter 37 1992

Table 6. Metalloenzymes Containing Copper as an Essential Component

Approximately 80% of the absorbed Cu is excreted by the biliary system.

Mother's milk contains 0,6 nmol/100ml, and this value is decreased during the lactation. Cow milk contains 0,13 nmol/100ml. Newborn should intake 0,95 nmol/100ml, and premature infant requires considerable higher dose.

Cu is very important for CNS and its deficiency could cause CNS abnormalities. The others clinical manifestations of Cu depletion are: anorexia, failure to grow, diarrhea, pallor, depigmentation of hair and skin, dilated superficial veins, defective elastin formation (aneurysm), hypothermia, osteoporosis, periosteal reactions, cupping and flaring of long bones, flaring of anterior ribs, sub metaphyseal fractures.  It is a component of Cu-Zn superoxide dismutase (the crucial plasma antioxidant), citoxrom c-oxidase, and tyrosinase and monoamino oxidase.

It has immunomodulatory properties.

Human copper deficiency has been reported:

1. In association with generalized malnutrition and prolonged diarrhea in older infants and children.

2. In association with intestinal malabsorption syndromes.

3. In jejunostomy and biliary losses.

4. In Menke's kinky hair syndrome - as a result of a genetic defect in copper absorption.

5. In premature infants since the majority of fetal copper stores are accumulated during the last 3 month of gestation, and therefore, the premature infant is born with decreased copper stores as compared to term infants.

6. In patients maintained on prolonged parenteral nutrition (PN) without copper supplements.

Requirements (µg/kg/day) are: premature 30-60, newborns 20-50 and children 20. The adults should take 1,2-3,0 mg/day orally or 0,5-1,5 mg/day intravenously. Deficiency could be treated also with Cu sulfate (2-3 mg/day). Because of its route of elimination, Cu intake should be decreased in patients with hepatobiliary diseases.

IRON (Fe)
Liver, eggs, meat and green vegetables are rich in iron. Iron absorption is the best from the animal food which contains Fe in ferrous form (Fe++). Fe  in vegetables is in ferric form (Fe+++). In acidic stomach environment dissociate in ferrous form. This conversion is facilitates when meat is consumed together with vegetables, or when the juice is drunk during the meal. Phytates from the flour and exaggerated milk intake interfere Fe absorption. Less than 10% of Fe from the food is resorbed, mainly in the duodenum and upper part of the jejunum. It is further transported in a ferric form banded to the transferrin (transferrin content is decreased in infection and other toxic conditions). Fe is stored as a ferritin (in bone marrow) or hemosiderin (in liver). Its absorption is also hindered by fiber and steatorrhea.

Iron is a constituent of hemoglobin, myoglobin, the cytochromes, and a number of other proteins that function in the transport, storage, and utilization of oxygen (Table 7). It is absorbed in ferrous form according to body need.

Table 7. Iron (Fe)

*The amount in the commonly used adult trace element preparation Addamel (Fresenius Kabi)
¹ Recommended Dietary Allowances 10^th Ed. National Acad Press, Washington 1989
² Dietary Reference Value for Food energy and nutrients in the United Kingdom, HMSO 1991
³ Population reference intakes. In Commission of the European Community. Reports of the Scientific Committee for Food. (31^st Series) Chapter 37 1992

Cellular Fe homeostasis is a central element in the regulation of immune function. Free Fe is necessary for bacterial or tumor growth: removal of Fe limits multiplication of pathogens and an environmental Fe depletion is a part of the antimicrobial and cytocidal strategies of immunocompetent cells. But at the same time, Fe is also crucial for NK cells, neutrophils, macrophages and lymphocytes for optimal function. Moreover, Fe catalyses the formation of hydroxyl radicals, which is essential for monocytes/macrophages to kill intracellular pathogens. Small environmental Fe concentrations up-regulate cytokine-induced effects in macrophages. The relation between cell mediated immunity and Fe metabolism constitute a complex network of interactions. The Th1 cytokines favour an increased uptake of Fe into monocytes/macrophages but and increased Fe in macrophages may have a deleterious effect on the host immune response by interfering with INF-g  stimulation of these cells. Fe overload affect negatively the release of NO and IL-12 by neutrophils and macrophages, and CD4 Th1 development because Fe directs the immune response towards a Th-2 response making difficult the fight against infection.

Iron deficiency occurred during nutrition deficit, chronic bleeding, after the gastrectomy, during the malabsorption and many chronic diseases. Iron deficiency causes: fatigue, headache, pallor, irritability, anorexia, poor weight gain, atrophy of the papillae of the tongue, hypochromic microcytic anemia.

Iron overprovision causes hemosiderosis or hemochromatosis and has been associated with an increased risk of human cancer.

Iron provision in critically ill or malnourished patients is sometimes difficult because bone marrow poorly reacts. Severe infections in malnourished patients could be provoked by the high level of circulating Fe (28). Stead (29) has found normal Fe depots but alternated Fe mobilization in malnourished patients with malign or chronic inflammatory diseases. He noticed improvement in Fe metabolism after the usage of the solutions without Fe. Other authors suggested Fe administration until Fe depots are not fulfilled. Iron nutritional support is controversial. There are some disagreements about the requirements. Daily looses are round 1 mg in man and 1,5 mg in women. Body depots are bigger in man (1000mg) than in women (300 mg). New commercial preparations don't contain Fe , although there is some evidence that low birth infants have lower reserves and that in them Fe supplement could be useful. There is agreement that term infant and older children shouldn't be given Fe during parenteral nutrition because of possible overprovision which could disturb intestine homeostasis. Average requirements  (µg/kg/day) are: premature 100-200, infants 20-100, and children 100. Daily oral dosage for adult man and woman after menopause is 10 mg, women during the reproductive period should take 15-18 mg/day. Intravenous dosage during PN is 1,0-12,5 mg/day.

CHROMIUM (Cr)
Chromium is insulin cofactor and it is very important in lipoprotein metabolism (Table 8).  Cr deficiency state causes: glucose intolerance, peripheral neuropathy, ataxia, metabolic encephalopathy and increased susceptibility to cardiovascular disease. Symptoms withdraw after a two-week course of intravenous administration  (150-250 µg/day). Diagnostic test could be glucose tolerance improvement and determination of Cr in the hair. Cr is excreted in the urine, and intake should be reduced in kidney diseases.

Tissue content is very low and absorption is poor (it makes some difficulties in requirement determination). Daily requirements are 50-290 µg/day orally or 0,2 µg/day i.v.

Table 8. Chromium (Cr)

NA Not available

*The amount in the commonly used adult trace element preparation Addamel (Fresenius Kabi)
¹ Recommended Dietary Allowances 10^th Ed. National Acad Press, Washington 1989
² Dietary Reference Value for Food energy and nutrients in the United Kingdom, HMSO 1991
³ Population reference intakes. In Commission of the European Community. Reports of the Scientific Committee for Food. (31^st Series) Chapter 37 1992

MANGANESE (Mn)
Manganese is poorly absorbed from the intestine and is excreted primarily in the bile.

Mn is important cofactor for several enzymatic system such as: mitochondrial superoxide dismutase, pyruvate decarboxylase, arginase, lucin aminopeptidase and alcal phosphatases (Table 9). It participates in protein and energetic metabolism, particularly in glucose usage during the aerobic metabolism. Balanced daily intake is necessary for proper mucopolysacharides metabolism, growth, skeletal definition and reproduction.

Table 9. Manganese (Mn)

*The amount in the commonly used adult trace element preparation Addamel (Fresenius Kabi)
¹ Recommended Dietary Allowances 10^th Ed. National Acad Press, Washington 1989
² Dietary Reference Value for Food energy and nutrients in the United Kingdom, HMSO 1991
³ Population reference intakes. In Commission of the European Community. Reports of the Scientific Committee for Food. (31^st Series) Chapter 37 1992

Extensive skeletal abnormalities, dermatitis, lack of appetite, nausea, vomiting, increased body temperature, hair pigmentation changes, lipid disturbances (hypercholesterolemia), ataxia, abnormal development of middle ear, diminished coagulation factors dependent on the vitamin K and anemia have been reported in manganese deficiency.

Manganese is excreted in bile, hence dosage must be modified in the case of biliary tract obstruction. In children with liver function disturbances on a long-term PN overprovision and accumulation of Mn could occur, that might lead to deposit formations in basal ganglia. Daily requirement is 0,7-5 mg/day orally and 1 µg/kg/day i.v.

IODINE (J)
Iodine is absorbed in the intestine and excreted in the urine. Intrauterine iodine deficiency cause cretinism ( infantile hypothyroidism), if it is occurred lately decelerate growth and metabolism but there is no evidence of mental retardation.
Daily requirements are (µg/kg/day): Premature and newborn 0,04, children 0,02-0,04. Adults should take orally 150 µg/day or intravenously 1-2 µg/day J (Table 10).

Table 10. Iodine (J)

*The amount in the commonly used adult trace element preparation Addamel (Fresenius Kabi)
¹ Recommended Dietary Allowances 10^th Ed. National Acad Press, Washington 1989
² Dietary Reference Value for Food energy and nutrients in the United Kingdom, HMSO 1991
³ Population reference intakes. In Commission of the European Community. Reports of the Scientific Committee for Food. (31^st Series) Chapter 37 1992

FLUORIDE (F)
The most important role of F is to reduce the incidence of dental decay and to provide skeleton firmness. Daily requirements (µg/kg/day) are: premature and newborn 1-3, children 0,7-1,5 (Table 11). In high dose F can cause stain teeth.

Table 11. Fluoride (F)

NA  Not available

*The amount in the commonly used adult trace element preparation Addamel (Fresenius Kabi)
¹ Recommended Dietary Allowances 10^th Ed. National Acad Press, Washington 1989
² Dietary Reference Value for Food energy and nutrients in the United Kingdom, HMSO 1991
³ Population reference intakes. In Commission of the European Community. Reports of the Scientific Committee for Food. (31^st Series) Chapter 37 1992

MOLYBDENUM  (Mo)

Molybdenum is a component of enzymes participating in oxido-reduction reactions involving organic sulfur (sulfite oxidase) and metabolites of degraded nucleic acid (xanthine oxidase). Molybdenum is readily absorbed from the intestinal tract and excreted chiefly in urine.
Molybdenum deficiency, which is not confirmed in humans, could cause  growth failure, tachycardia, tachypnea, headache, night blindness, central scotomas, lethargy, disorientation and coma, elevated levels of plasma methionine and low serum uric acid levels.  Molybdenum excess alternates purine metabolism. Daily requirements are calculated as µg/kg/day: < 1 year 0,12, in children > 1 year 0,12 -0,003 (Table 12). There is no evidence that molybdenum must be added to PN preparations.

Table 12. Molybdenum (Mo)

*The amount in the commonly used adult trace element preparation Addamel (Fresenius Kabi)
¹ Recommended Dietary Allowances 10^th Ed. National Acad Press, Washington 1989
² Dietary Reference Value for Food energy and nutrients in the United Kingdom, HMSO 1991
³ Population reference intakes. In Commission of the European Community. Reports of the Scientific Committee for Food. (31^st Series) Chapter 37 1992

COBALT (Co)

Co is a component of vitamin B12.

A growing number of  trace elements have been recognized to be of nutritional importance. In very small quantities human body contains nickel, tin, silicium and vanadium.  Until now, their physiological importance has not been established entirely.
As it was mentioned before, concentration of many trace elements changes significantly during the acute phase response to trauma or infection. Interpretation of this hypothesis is limited and therefore (especially for the patients on TPN) the  Zn, Cu, Se and Fe status estimation is performed on a regular basis. The further laboratory testing is used only when some clinical dilemma occurred - when it is necessary to confirm trace elements deficit. When this testing is not available, and a deficiency is suspected, the therapeutic trial is made. In patients receiving EN or TPN where some intestinal absorptive capacity may still be present, an oral or enteral multi-mineral supplement may also be provided. A two-week course of a well balanced multi-mineral supplement is unlikely to cause any harm, and may occasionally be beneficial (Table 13, 14, 15).

Table 13. Daily trace elements requirements:

basal values = Addamel N 1 ampulla

Table 14. Trace elements products for i.v. usage (Fresenius Kabi):

Table 15. Others trace elements sources:

Alternatively, an increase in intravenous supply can be given for a limited period, with careful clinical monitoring (15). In such cases a blood/plasma sample at the beginning of supplementation should be stored for possible analysis at a later date.

Some papers reports that trace elements compensation improves immune function simultaneously with clinical recovery. Se, Cu and Zn reduce infection incidence after the extensive burns. This results point out to synergistic and complementary trace elements function.

Trace element stability in "all in one" system is not investigated entirely. The most common precipitations are: Fe phosphate and  Cu cysteinate formation, or selenite reduction in insoluble Se.

CONCLUSION

The provision of an adequate amount of essential trace elements is an integral part of all nutrition support regimens by both parenteral and enteral routes. Defining the optimal intake of trace elements is far from ideal.  It is possible to make a reasonable assessment of the requirements of an individual, based upon the requirements in health, the likely underlying nutritional state of the patient at the time of presentation, and the ongoing effects of the disease process.

Care must be taken to minimize overprovision of trace elements.

It is to be expected that in the next few years, well controlled clinical trials will help to clarify the situations where increased provision of trace elements is or is not helpful, both in reducing the biochemical effects of free radicals, and also in altering complication rates and outcome in serious illness.

REFERENCES

1. Shenkin A. Micronutrients in clinical nutrition. Enteral and Tube feeding 3rd Ed. Ed J L Rombeau, R H Rolandelli. W B Saunders 1997, p. 96.
2. Cunningham-Rundles S, Lin DH. Nutrition and immune system of the gut. Nutrition 1998;14:573-579.
3. Long KZ, Santos JI. Vitamins and the regulation of the immune response. Pediatr Infect Dis J 1999;18:283-290.
4. Ravaglia G, Forti P, Maioli F, et al. Effect of micronutrient status on natural killer cell immune function in healthy free-living subjects aged > 90y. Am J Clin Nutr 2000;71:590-598.
5. Berger MM, Spertini F, Shenkin A, et al. Trace element supplementation modulates pulmonary infection rates after major burns: a double blind, placebo controlled trial. Am J Clin Nutr 1998;68:365-371.
6. Radlović N. Parenteral nutrition. In: Stepanović R, Nestorović B et al. Nutrition in pediatrics 1991:164-181.
7. Shenkin A. Mikronutrients in the severely injured patient. Proceedings of the Nutrition Society 2000.
8. Driessen C, Hir K et all. Divergent effects on zinc on different bacterial pathogenic agents. J Infect Dis 1995;171: 486-89.
9. Cunningham-Rundles S, Kim SH et al. Micronutrient and cytokine interaction in congenital pediatric HIV infection. J Nutr 1996; 126:267 4S-9S.
10. Fortes C, Forastiere F et al. The effect of zinc and vitamin A supplementation on immune response in an older population. J Am Geriatr Soc 1998; 46:19-26.
11. Braunschweig CL, Sowers M et al. Parenteral zinc supplementation in adult humans during the acute phase response increases the febrile response. J Nutr 1997;127:70-74.
12. Shenkin A. Trace elements and vitamin in parenteral and enteral nutrition. In Sobotca Subject:L. et all:Basics in clinical nutrition. 2nd Ed. ESPEN. 2000. 62-70.
13. Guidelines for essential trace elements preparation for parenteral use: A statement by an expert panel, AMA Department of Foods and Nutrition. JAMA 241: 2051-2054, 1979.
14. Stead NW et al. Enhanced mobilization of iron from body stores in malnourished patients during intravenous nutritional support. Surg Gynecol Obstet 154:321-325, 1982.
15. Velasco PDJ. Micronutrients. Book of lectures. 22nd ESPEN Congress. Madrid. 2000;74-77.