Mineral Status Evaluation

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Chapter 24 Mineral Status Evaluation

image Introduction

Studies assessing the bioavailability of minerals in humans first appeared in the scientific literature in the 1960s,13 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.

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.

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

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.

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