Mineral Status Evaluation

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Chapter 24 Mineral Status Evaluation

L. Charles Masur, MD

Chapter Contents

Introduction

Minerals and Disease

Essential Minerals

Calcium, 
Chloride, 
Cobalt, 
Copper, 
Iodine, 
Iron, 
Magnesium, 
Manganese, 
Molybdenum, 
Nickel, 
Phosphorus, 
Potassium, 
Selenium, 
Sodium, 
Sulfur, 
Zinc, 

Conclusion

image Introduction

Studies assessing the bioavailability of minerals in humans first appeared in the scientific literature in the 1960s,1–3 and over the ensuing years it became clear that minerals play an important role in the biochemistry of the human body.4,5 Abnormal levels of minerals can have deleterious effects on multiple enzyme systems, neuronal structures, and organs, including the brain, heart, thyroid, liver, kidneys, and skin.4 Thus, mineral analysis can be an important health assessment tool for many patients. Opinions vary considerably as to which tissue or body fluid may be “best” for the assessment of any or all nutritional element(s).

In general, nutritional elements are better evaluated in blood or in urine. Blood mineral status can be assessed from an intracellular (e.g., potassium in erythrocytes, zinc in leukocytes) or extracellular (e.g., copper in serum) perspective, or overall in whole blood (total cellular components and serum). Levels of elements in serum will vary day-to-day depending on dietary intake. Many factors, such as specific protein carriers and the ionic charge of an element and its capacity to be in equilibrium, may affect the usefulness and reproducibility of a specific assay method and the appropriateness of a chosen tissue. The life span of the cellular components of blood is about 3 to 4 months, so any analysis using these cellular components must be interpreted with this time frame in mind; reported values will reflect exposure and absorption that occurred during that period.

When mineral analyses involve the cellular components of blood, the clinician must ensure that samples are spun down immediately after collection, thereby separating the cells from the serum. If whole blood is allowed to sit for an extended period or is shipped without such separation, some of the cellular components will break down, allowing their contained elements to disperse into the liquid component of the sample. Subsequent centrifugation will remove all of the liquid component, leaving the remaining intact cells to be analyzed for their elements. In that scenario, erroneously low levels of intracellular elements would be reported.

Although hair analysis (see Chapter 17) does have the benefit of convenience and low cost, interpretation is made difficult by the ease with which hair can be contaminated from external sources of exposure. With that proviso, hair analysis can accurately reflect exposure to, and absorption of, a limited number of elements (e.g., chromium) or deficiencies of others (e.g., copper). The most appropriate use of hair analysis appears to be in the assessment of toxic metal exposure but even then, its utility remains highly controversial (“an unproven practice” according to the American Medical Association).6

Most clinicians employ whole blood or urine analysis in the evaluation of mineral status since these fluids are the simplest and most economical to collect and transport. Whole blood requires no centrifugation and, like urine, requires no special treatment, other than collection and shipping in approved containers. Red blood cell (RBC) analysis might best be utilized in the assessment of elements that are more commonly represented intracellularly (e.g., iron, potassium). Reputable laboratories use current technology (e.g., induction-coupled plasma mass spectroscopy) operated by highly trained personnel to perform these tests and to produce accurate and precise results. Excellent reference range data are available to allow appropriate interpretation of analytic findings.

image Minerals and Disease

Serum levels of various minerals have been implicated as clinical markers of disease.4 Patients with cirrhosis have demonstrated low serum selenium,7 calcium,8 magnesium,9 and zinc.10 Those with emphysema and cancer have shown elevated serum copper concentrations; copper and manganese levels are often elevated in congestive heart failure, infection, and psychoses.11 Other associations have been observed between trace minerals and breast cancer,12 gastrointestinal malignancy,13 and malignant ascites,14 although in other studies, selenium, copper, zinc, and magnesium seemed to have no diagnostic value for distinguishing malignant from nonmalignant effusions15 or cervical cancer.16 Heart tissue levels of selenium, iron, copper, zinc, and phosphorus have been associated with ejection fraction and cardiac index.17 In men infected with human immunodeficiency virus, helper T-type 4 cells seemed closely correlated with serum magnesium concentration.18

The ratios of trace elements may be indicators for various disease states. The concentrations of copper, zinc, and selenium, and their relative levels in whole blood and thyroid tissue, follow specific patterns for various thyroid disorders, including thyroid cancer. Further, and although the mechanisms are unclear, the copper-to-zinc ratio was found to be significantly increased in patients with breast cancer but not in patients with benign breast diseases.19 In one study, serum copper-to-zinc ratios were shown to be of diagnostic and prognostic value in head, face, and neck cancer, with alterations in copper, zinc, and copper-to-zinc ratio related to the stage of the disease.20 Other studies identified distinct differences in copper/zinc ratios among various levels of skin disease severity.21

image Essential Minerals

There are a number of minerals that are common to all living organisms, in that they support biochemical processes in structural and functional roles. These essential elements are calcium, chloride, copper, iodine, iron, magnesium, manganese, molybdenum, phosphorus, potassium, selenium, sodium, and zinc (and perhaps, boron, cobalt, nickel, and sulfur). Other minerals, although not discussed here, have also been described as “essential,” including chromium,22 fluoride,23 and vanadium.24

Calcium

Dietary sources of calcium include dairy products, canned fish with bones (e.g., salmon, sardines), green leafy vegetables, nuts, and seeds. Assessment of dietary intake of calcium is confounded by multiple factors that affect absorption, such as the quantity of fiber and other natural chelators in the diet; gastric acidity; the ratio of dietary calcium to phosphorus (and dietary magnesium); as well as gut transit time and other factors.

Serum calcium is so closely regulated (by the parathyroid gland) that its use as an indicator of calcium balance is not reliable when considered in isolation. Measurement of ionized calcium may be useful in evaluation of calcium status. Urinary calcium is of value in a patient with a known low total calcium intake and persistent calciuria. Hair calcium levels are subject to considerable variability and should not be taken as a quantitative determination of calcium status (although a relationship between hair calcium level and coronary disease has been reported).25,26 In patients with high phosphorus and low calcium intakes, hair calcium level was consistently reported as much as three times higher than normal. Hair calcium returned to normal with proper supplementation and dietary changes.27

In one study that evaluated intracellular, plasma, and membranous levels of calcium and magnesium in hypertensive patients, there were no differences between controls and patients. However, the absolute levels of calcium and magnesium were lower, and the calcium/magnesium ratio in membranes was significantly higher in patients with essential hypertension than in healthy subjects.28

The best test to evaluate body calcium sufficiency may well be whole blood analysis, since this will assess calcium present in serum, intracellularly, and in the cell membranes.

Chloride

Chloride is necessary for the production of hydrochloric acid in the stomach and is also essential in cellular pump functions. The main dietary source of chloride is table salt. Chloride is readily assessed in serum and in urine.

Increased serum chloride may be associated with dehydration but could be present with either a metabolic acidosis or a respiratory alkalosis. High chloride can also be present along with elevated sodium in conditions such as Cushing disease. Urine chloride analysis, and often the analysis of urine sodium as well, may be important when considering alkalosis or acidosis or when assessing high or low serum chloride levels. Low serum chloride accompanies low serum sodium; low chloride may be associated with metabolic alkalosis and is often seen with prolonged emesis or in conditions causing respiratory acidosis, such as chronic obstructive pulmonary disease.

Body chloride levels are best evaluated in serum along with other electrolytes such as sodium. Urine chloride is a necessary component of a full electrolyte assessment and/or a metabolic panel.

Cobalt

Cobalt is essential in the production of vitamin B12, which is synthesized by bacteria. Cobalt metabolism and testing is better discussed elsewhere, especially in the context of vitamin B12 deficiency.

Copper

Under normal conditions, far more copper is absorbed than is needed by the body. Dietary sources include beans, eggs, fish, fresh fruits, liver, milk, mushrooms, nuts, oysters, peas, poultry, and whole grains. Nearly all dietary copper is stored initially in the liver, leaving only a small percentage in the blood. The principal mechanism for the control of copper homeostasis is excretion through the biliary system.

Because 95% of copper in serum is bound to the protein ceruloplasmin, there is almost no ionic copper so urinary copper output usually is minimal. At present, analysis of copper in serum may be the best indicator of body copper levels, provided that clinical conditions known to cause abnormal copper metabolism (e.g., Wilson’s disease, cirrhosis of the liver) have been ruled out.27 Some studies have shown hair copper measurement to be an acceptable method of assessing copper status29,30 with the same provisos as mentioned previously regarding the ruling out of other illnesses known to affect copper metabolism and retention. When high copper levels are seen on hair analysis, external copper contamination (e.g., exposure to swimming pool and hot tub water, which are often disinfected with copper-containing chemicals) always should be considered.

Iodine

Iodine is necessary for the synthesis of thyroid hormones; iodine deficiency may lead to enlargement of the thyroid gland (goiter). Although iodine is readily measurable in urine, levels are highly variable31; thus, evaluation of urine iodine is not a reliable method to assess body iodine status. In contrast, it has been suggested that whole body sufficiency of iodine may be assessed in urine using an “iodine loading test.”32 Interpretation of the results of this test presupposes specific receptor/storage sites that take up and store iodine/iodide. When body storage of iodine/iodide is optimal, the percentage excretion of an oral loading dose of iodine/iodide excreted in urine is maximal; some authors purport that body stores are optimal when excretion is 90% or more.33 An emerging assessment of iodine status is serum thyroglobulin, which appears to be a better measure of iodine status over weeks and months.34

Iron

Iron is essential for the function of many enzymes and has a role in the production of proteins (e.g., hemoglobin). Dietary sources include beans, dark green leafy vegetables, dates and figs, dried fruits, egg yolk, fish, molasses, nuts, organ meats, red meat, shellfish, as well as whole and enriched grains. Serum iron concentration has long been used as an indicator of iron deficiency. In practice it is not of much value when taken in isolation because there is considerable variation in serum iron levels, even when samples are taken from the same person at the same time each day. Serum iron measurement is much more reliable when combined with other indicators, such as serum transferrin or ferritin.

Ferritin is an iron storage protein accounting for 20% of the total body iron in normal adults. It is found principally in the cytoplasm of reticuloendothelial and liver cells, and, to some degree, in developing red cell precursors in bone marrow. This protein is involved in both absorption and recycling of iron and is a convenient and generally reliable indicator of total body iron stores.

A decrease in serum ferritin level (normal 12 to 300 ng/mL) is an early sign that body iron stores are low. As iron deficiency progresses, anemia (normal hemoglobin 13 to 15 g/100 mL), decreased serum iron concentration (normal 75 to 150 mcg/100 mL), and elevated iron-binding capacity (normal 300 to 400 mcg/100 mL) become apparent.35,36 Serum ferritin may not be completely reliable in several common conditions, including cancer, infections, inflammation, and acute and chronic liver diseases, where it might be elevated. When iron overload is associated with hemochromatosis, hemosiderosis, or thalassemia, serum ferritin is also elevated.

The best way to evaluate body iron stores may well be with RBC analysis coupled with serum iron, serum ferritin, and total iron binding capacity.

Magnesium

Magnesium is essential for adenosine triphosphate (ATP) production and as a structural component of bones. Good dietary sources include nuts, soy beans, and cocoa mass. Measurement of magnesium status presents some difficulties, but the magnesium retention test is probably the most accurate, though cumbersome, method of assessment.37 However, analysis of white blood cell magnesium content may be nearly as accurate as the magnesium retention test.38

Serum magnesium concentration may be influenced by many factors; it constitutes about only 1% to 3% of total body magnesium and does not reflect magnesium levels in other tissues.39 The level of binding, complexing, or chelating of magnesium to serum proteins and other fractions is subject to many uncontrollable variables. Serum magnesium levels as low as 1.2 mEq/L have been measured in patients with normal total body magnesium.40

Erythrocyte membrane tests may also be useful in testing magnesium status (see previous discussion of calcium) and may be more clinically relevant than either plasma or intracellular studies.19 Although the calcium/magnesium ratio in erythrocyte membranes was shown to be high in essential hypertension patients, it is unclear whether this finding is a cause or an effect of hypertension. However, it has been suggested that magnesium levels are low in hypertensive patients.40

The best test to evaluate body magnesium sufficiency may well be whole blood analysis since this will assess total magnesium in serum, intracellularly, and in the cell membranes of both red and white blood cells.

Manganese

Manganese is a trace element. It serves as a cofactor in enzyme functions (e.g., superoxide dismutase) and is essential in carbohydrate metabolism and production of skeletal and connective tissue development, and is a catalyst in fatty acid and cholesterol production. Dietary sources include dark green leafy vegetables, dried fruits, dried legumes, nuts, and whole grains. Assessment of body status for manganese is difficult as it is normally present in trace amounts (1% of the level of copper or zinc in blood).

Whole blood manganese concentration is a valid indicator of body manganese and soft tissue levels.41 Proper technique is essential in the collection procedure as well as the actual analysis. Hair manganese level may be a rough indicator, especially in chronic toxicity, but whole blood manganese is the most reliable measurement tool.

Molybdenum

Dietary sources of molybdenum include beans, peas, red meats, and whole grains. It is a trace element important in xanthine, aldehyde, and sulfite oxidase (metabolism of sulfur-containing amino acids) systems. Xanthine oxidase catalyses oxidative hydroxylation of purines and pyridines; aldehyde oxidase oxidizes purines, pyrimidines, and pteridines and is involved in nicotinic acid metabolism. Sulfite oxidase deficiency or absence leads to neurologic symptoms and early death. Reduced dietary intake may result in low urinary molybdenum excretion, low serum uric acid, and excessive urinary xanthine excretion.6 Molybdenum deficiency has been reported as occurring in in-born errors of metabolism and in patients receiving total parenteral nutrition.42 Body sufficiency of molybdenum is best assessed by erythrocyte or whole blood analysis.

Nickel

Nickel is generally accepted as being a trace element in animals,43 but its importance in humans requires further study.44 Food sources of nickel are limited except perhaps in the case of high-acid prepared foods. It has been reported to be involved in iron metabolism and in stabilizing the structures of nucleic acids and proteins,45 and it may be a cofactor of some enzymes.46 Recent nickel exposure is best assessed by whole blood analysis. Nickel is rapidly cleared by urinary excretion, so acute exposure to excessive nickel can be readily assessed by urine element analysis.

Phosphorus

Phosphorus serves a multiplicity of roles in human metabolism. Phosphorus is readily available in most foods, even in fast foods and especially in soft drinks. It is used as a structural component of bones (hydroxyapatite is a combination of ionic calcium and phosphorus). It is important in DNA, RNA, and energy production (ATP); in cell membrane structure (phophoslipids); and in most second messenger signaling pathways. It is involved in the renal production and serum concentration of 1,25-dihydroxy vitamin D.47 High serum phosphorus is a predictable component of end-stage renal disease where no dietary restriction or other mitigating treatment is provided.48 Intracellular phosphorus levels can be assessed with RBC analysis. Serum analysis provides an excellent evaluation of extracellular phosphorus levels, and whole blood element analysis provides a simple and straight forward method of assessing overall body phosphorus status.

Potassium

Potassium is an electrolyte and, along with sodium, essential to the regulation of ATP and the triggering of nerve and muscle activity. Dietary sources include bananas, legumes, potatoes (skins), and tomatoes. Consumption of a diet high in sodium (e.g., fast food items) can predispose to a potassium deficiency. Potassium is primarily an intracellular ion, and so serum measurements may not accurately reflect body stores. A low serum potassium level usually indicates an advanced intracellular deficit; however, an intracellular deficit may also occur with normal or high serum potassium concentrations.

RBC potassium content has been shown to mirror the potassium content of other tissue cells.43,49 Although RBCs do not have nuclei, the sodium–potassium membrane pump that maintains the proper influx and efflux of these ions is intact. Whole blood potassium concentration is almost as accurate as the RBC potassium level because 98% of potassium is intracellular. The validity of intracellular potassium levels was demonstrated in a study where the electrocardiographic repolarization phase in elderly subjects was measured; alterations of repolarization correlated well with intracellular potassium levels but showed no correlation with serum levels.50

Selenium

Selenium is a trace element. Dietary sources of selenium include red meat, seafood, Brazil nuts, and whole grains. It is a cofactor essential to the activity of antioxidant enzymes such as glutathione peroxidase. Selenium may replace sulfur in cysteine to produce selenocysteine. Polypeptides containing selenocysteine include such selenoproteins as glutathione peroxidases and thioredoxin reductases (increases metallothionein redox capacity; supports vitamin E regeneration). Selenium deficiency may be associated with metal toxicity symptoms (due to lack of reduced metallothionein capacity).

After absorption, selenium is distributed throughout the tissues but does not seem to equilibrate with blood selenium levels. Blood selenium levels do not correlate with selenium intake, except at extremes.51 Furthermore, serum levels of selenium do not appear to be associated with mortality and morbidity in relationship to infectious disease,52 although one study found low serum levels of selenium and zinc to be associated with advanced gastrointestinal cancer.6

RBCs are high in glutathione peroxidase and could provide a means of assessing selenium levels, but may not give a good picture of total body status. Whole blood is generally the choice for assessment of selenium sufficiency.

Sodium

Sodium is an electrolyte and is essential, along with potassium, in the regulation of ATP. Sodium and chloride ions are the major electrolytes of the body. Dietary sources include table salt, sea vegetables (e.g., kelp, seaweed), milk, and spinach. Sodium and water depletion (e.g., dehydration, heat stroke, prolonged and excessive diarrhea or vomiting) can lead to hypotension; excessive long-term sodium intake (e.g., diets high in fast foods, prepared foods) is associated with hypertension. Sodium status is best assessed in serum.

Sulfur

Sulfur is essential for amino acid production and is obtained from cysteine and methionine contained in dietary protein sources. Sulfur sufficiency is best assessed with analysis of urine for essential elements. High urine sulfur may be seen in dehydration, recent use of thiol-containing complexing agents (e.g., dimercaptosuccinic acid, 2,3-dimercapto-1-propanesulfonic acid), high intake of sulfur-containing foods, and/or nutritional supplements (e.g., N-acetylcysteine, lipoic acid), and if there is impaired capacity to reabsorb cysteine (cystinuria). The possibility of cystinuria can be evaluated through urine amino acid analysis.

Zinc

Zinc is essential to the production and function of many enzymes, such as carboxypeptidase, alcohol dehydrogenase, and carbonic anhydrase. It is an intracellular ion, and some research shows that serum zinc concentrations are not sensitive indicators of depletion.53 Urinary zinc level is also not a good indicator. Low hair zinc levels may indicate depletion, but normal values do not rule out low body stores.24,54,55 Leukocyte zinc level has been investigated and found to be an accurate index of body stores.56 In one investigation, 16 young women were given high and then low zinc dietary intake for specified periods. Low zinc intake status was not correlated with plasma zinc levels. Plasma zinc concentration was not significantly lower during the low dietary intake period than during the high dietary intake period. However, there was no significant change in fractional zinc absorption or urinary zinc excretion.57

The best test to evaluate body zinc sufficiency may well be whole blood analysis, since this will assess zinc present in serum, intracellularly, and in the cell membranes of both red and white blood cells.

image Conclusion

The increasing availability of reliable laboratory methods for mineral analysis undoubtedly will better assist clinicians in evaluating disease status, progression, and prognosis as well in helping to make better treatment decisions. However, no analytic test is better than the laboratory performing it. Proper collection and analytic procedures must be used, and each step in the preparation and processing of a sample must be carefully performed and monitored. In hair analysis, proper sample preparation and the use of ultrahigh purity digesting acid and distilled water are extremely important. In blood and urine analysis, collection tubes specially designed for the specific tissues being sampled and the minerals being collected must be used. Where analysis of cellular components of blood is involved, care must be taken to separate these components from serum without delay and definitely before transport.

Ultimately, it is the clinician’s responsibility to verify the validity of an analytic procedure and to choose a reputable laboratory well known for its expertise, accuracy, and precision of its results. These steps will allow the clinician to confidently interpret and apply the results of any analysis. Finally, and most importantly, treat the patient, not the laboratory work!

It should be noted that many of the articles listed in the Reference section are reviews, and thus can serve as sources of additional information.

References

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6. Hair analysis. A potential for medical abuse. Policy number H-175.995 (Sub. Res. 67, I-84; Reaffirmed by CLRPD Rep. 3-I-94). Chicago: American Medical Association; 1994.

7. Burk R.F., Early D.S., Hill K.E., et al. Plasma selenium in patients with cirrhosis. Hepatology. 2003;27:794–798.

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12. Kuo H.W., Chen S.F., Wu C.C., et al. Serum and tissue trace elements in patients with breast cancer in Taiwan. Biol Trace Elem Res. 2002;89:1–11.

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14. Celik H.A., Aydin H.H., Ozsaran A., et al. Trace elements analysis of ascitic fluid in benign and malignant diseases. Clin Biochem. 2002;35:477–481.

15. Teksen F., Mungan D., Sayal A., et al. Serum and pleural fluid selenium, copper, zinc, and magnesium levels in malignant and nonmalignant pleural diseases. Respiration. 1996;63:25–27.

16. Altintas A., Vardar M.A., Gonlusen F., et al. Copper, zinc, and magnesium tissue and serum levels in patients with cervical carcinoma. Eur J Gynaecol Oncol. 1995;16:278–281.

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21. Gupta S.K., Shukla V.K., Vaidya M.P., et al. Serum trace elements and Cu/Zn ratio in breast cancer patients. J Surg Oncol. 1991;46:178–181.

22. Eastmond D.A., Macgregor J.T., Slesinski R.S. Trivalent chromium: assessing the genotoxic risk of an essential trace element and widely used human and animal nutritional supplement. Crit Rev Toxicol. 2008;38:173–190.

23. Cerklewski F.L. “Fluoride-essential or just beneficial”. Nutrition. 1998;14:475–476.

24. O’Dell B.L., Sunde R.A. Handbook of nutritionally essential mineral elements. New York: Marcel Decker, Inc. 1997:624–629.

25. Bland J. Dietary calcium, phosphorus and their relationships to bone formation and parathyroid activity. J John Bastyr Col Naturopathic Med. 1979;1:3–7.

26. MacPherson A., Balint J., Basco J. Beard calcium concentration as a marker for coronary heart disease affected by supplementation with micronutrients including selenium. Analyst. 1995;120:871–875.

27. Solomons N. Biochemical, metabolic and clinical role of copper in human nutrition. J Am Coll Nutr. 1985;4:83–105.

28. Kosch M., Hausberg M., Westermann G., et al. Alterations in calcium and magnesium content of red cell membranes in patients with primary hypertension. Am J Hypertens. 2001;14:254–258.

29. Piccinini L., Borella P., Bargellini A., et al. A case control study on selenium, zinc, and copper in plasma and hair of subjects affected by breast and lung cancer. Biol Trace Element Res. 1996;51:23–30.

30. Donma M., Donma O., Tas M.A. Hair zinc and copper concentrations and zinc: copper ratios in pediatric malignancies and healthy children from southeastern Turkey. Biol Trace Element Res. 1993;36:51–63.

31. Andersen S., Karmisholt J., Petersen K.M. Reliability of studies of iodine uptake and recommendations for number of samples in groups and in individuals. Br J Nutr. 2008;99:813–818.

32. Abraham G.E. The safe and effective implementation of orthoiodosupplementation in medical practice. Original Internist. 2004;11:17–36.

33. Flechas J.D. Orthoiodosupplementation in a primary care practice. Original Internist. 2005;12:89–96.

34. Zimmermann M.B. Methods to assess iron and iodine status. Br J Nutr. 2008;99(Suppl 3):S2–S9.

35. Cook J., Lipschitz D.A., Miles L.E., et al. Serum ferritin as a measure of iron in normal subjects. Am J Clin Nutr. 1974;27:681–687.

36. Peter F., Wang S. Serum iron and total iron binding capacity compared with serum ferritin in assessment of iron deficiency. Clin Chem. 1981;27:276–279.

37. Seelig M. Magnesium deficiency in the pathogenesis of disease. New York: Plenum Medical Books; 1980.

38. Hosseini J.M., Johnson E., Elin R.J. Comparison of two separation techniques for the determination of blood mononuclear cell magnesium content. J Am Coll Nutr. 1983;2:361–368.

39. Ryschon T.W., Rosenstein D.L., Rubinow D.R., et al. Relationship between skeletal muscle intracellular ionized magnesium and measurements of blood magnesium. J Lab Clin Med. 1996;127:207–213.

40. Kisters K., Tepel M., Spieker C., et al. Decreased membrane Mg2+ concentrations in a subgroup of hypertensives: membrane model for the pathogenesis of primary hypertension. Am J Hypertens. 1998;11:1390–1393.

41. Keen C. Whole blood manganese as an indicator of body manganese. N Engl J Med. 1983;308:1230.

42. Casey E.C., Neville M.C. Studies in human lactation 3: molybdenum and nickel in human milk during the first month of lactation. Am J Clin Nutr. 1987;45:921–926.

43. Bahemuka M., Hodkinson H. Red blood cell potassium as a practical index of potassium status in elderly patients. Age Ageing. 1976;5:24–30.

44. Anke M., Groppel B., Kronemann H. “Nickel–an essential element”. IARC Sci Publ. 1984;53):339–365.

45. Neilsen F.H. Possible future implications of nickel, arsenic, silicon, vanadium and other ultratrace elements in human nutrition. In: Prasad A.S., ed. Clinical, biochemical and nutritional aspects of trace elements. New York: Alan R Liss; 1982:379–404.

46. Nielsen F.H. Fluoride, vanadium, nickel, arsenic and silicon in total parenteral nutrition. Bull NY Acad Med. 1984;60:177–195.

47. Portale A.A., Halloran B.P., Morris R.C., Jr. Physiologic regulation of the serum concentration of 1,25-dihydroxy vitamin D by phosphorus in normal men. J Clin Invest. 1989;83:1494–1499.

48. Block G.A., Hulbert-Shearon T.E., Levin N.W. Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: A national study. Am J Kidney Dis. 1998;31:607–617.

49. Lans K., Stein I.F., Meyer K.A. The relationship of serum potassium to erythrocyte potassium in normal subjects and patients with potassium deficiency. Am J Med Sci. 1952;223:65–74.

50. Barbagallo Sangiorgi G., Costanza G., Di Sciacca A., et al. Serum potassium levels, red-blood-cell potassium and alternations of the repolarization phase of electrocardiography in old subjects. Age Ageing. 1984;13:309–312.

51. Lane H.W., Warren D.C., Taylor B.J., et al. Blood selenium and glutathione peroxidase levels and dietary selenium of free-living and institutionalized elderly subjects. Proc Soc Exp Biol Med. 1983;173:87–95.

52. Olmez A., Yalcin S., Yurdakok K., et al. Serum selenium levels in acute gastroenteritis of possible viral origin. J Trop Pediatr. 2004;50:78–81.

53. Davies S. Assessment of zinc status. Intl Clin Nutr Rev. 1984;4:122–129.

54. Hambidge K.M., Hambidge C., Jacobs M., et al. Low levels of zinc in hair, anorexia, poor growth and hypogeusia in children. Pediatr Res. 1972;6:868–874.

55. Pekarek R., Sandstead H.H., Jacob R.H., et al. Abnormal cellular immune response during acquired zinc deficiency. Am J Clin Nutr. 1979;32:1466–1471.

56. Jones R., Keeling P.W., Hilton P., et al. The relationship between leukocyte and muscle zinc in health and disease. Clin Sci. 1981;60:237–239.

57. Griffin I.J., Hicks P.D., Liang K.L., et al. Metabolic adaptations to low zinc intakes in premenarcheal girls. Am J Clin Nutr. 2004;80:385–390.

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