Chapter 24 Mineral Status Evaluation
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).
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.
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
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
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
Copper
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
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.
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
Manganese
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
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
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
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
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.
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