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The 2015 Dietary Guidelines Advisory Committee indicated that magnesium was a shortfall nutrient that was underconsumed relative to the Estimated Average Requirement (EAR) for many Americans. Approximately 50% of Americans consume less than the EAR for magnesium, and some age groups consume substantially less. A growing body of literature from animal, epidemiologic, and clinical studies has demonstrated a varied pathologic role for magnesium deficiency that includes electrolyte, neurologic, musculoskeletal, and inflammatory disorders; osteoporosis; hypertension; cardiovascular diseases; metabolic syndrome; and diabetes. Studies have also demonstrated that magnesium deficiency is associated with several chronic diseases and that a reduced risk of these diseases is observed with higher magnesium intake or supplementation. Subclinical magnesium deficiency can exist despite the presentation of a normal status as defined within the current serum magnesium reference interval of 0.75-0.95 mmol/L. This reference interval was derived from data from NHANES I (1974), which was based on the distribution of serum magnesium in a normal population rather than clinical outcomes. What is needed is an evidenced-based serum magnesium reference interval that reflects optimal health and the current food environment and population. We present herein data from an array of scientific studies to support the perspective that subclinical deficiencies in magnesium exist, that they contribute to several chronic diseases, and that adopting a revised serum magnesium reference interval would improve clinical care and public health., Competing Interests: 4 Author disclosures: RB Costello, RJ Elin, A Rosanoff, TC Wallace, F Guerrero-Romero, A Hruby, PL Lutsey, FH Nielsen, M Rodriguez-Moran, Y Song, and LV Van Horn, no conflicts of interest., (© 2016 American Society for Nutrition.)

Magnesium is an essential element needed for health. Even though only 1% of the total body magnesium is present in blood, the serum magnesium concentration (SMC) is the predominant test used by medicine to assess magnesium status in patients. The traditional method to establish a reference interval for the SMC is flawed by the large number of "normal" individuals who have a subtle chronic negative magnesium balance due to a significant decrease in magnesium intake over the past century. Evidence-based medicine should be used to establish the appropriate lower limit of the reference interval for health and I recommend 0.85 mmol/L based on current literature. The decrease in magnesium in the diet has led to chronic latent magnesium deficiency in a large number of people since their SMC is still within the reference interval due to primarily the bone magnesium supplementing the SMC. These individuals need adjustment of their diet or magnesium supplementation to achieve a normal magnesium status for health.

Changes in serum total and ionized magnesium (Mg and Mg2+) and calcium (Ca and Ca2+) were monitored in three patients who transiently developed severe (total Mg < 0.50 mmol/l) to profound hypomagnesemia (total Mg < 0.35 mmol/l) due to cisplatin or interleukin-2 therapies. Mg2+ and Ca2+ were measured with the Nova ion-selective electrodes at 37 degrees C and all results were normalized to pH 7.40. Independent of the etiology, the Mg2+ fraction (Mg2+/total Mg) increased as the concentration of the serum total Mg decreased in all three patients. When the total Mg was around or below 0.35 mmol/l the Mg2+ approached or exceeded total Mg, suggesting an error in the measurement of Mg2+. The findings were extended by including a group of 31 additional patients whose serum total Mg, Mg2+, total Ca, and Ca2+ concentrations varied from abnormally low to above normal. The serum total and ionized concentrations strongly correlated for both Mg (r2 = 0.88) and Ca (r2 = 0.92). The Mg2+ fraction rapidly increased with a fall in the total Mg concentration (r2 = 0.76) and total Mg/total Ca ratio (r2 = 0.71). In fact, with decreasing total Mg concentrations or total Mg/total Ca ratios, the Mg2+ fraction progressively increased to 93-128% of the total, confirming an error in the Mg2+ determinations. The Ca2+ fraction showed a slight and insignificant decrease with falling total Ca concentrations and total Mg/total Ca ratios. The Mg2+ concentration was directly related (r2 = 0.62), whereas the Ca2+ concentration showed a complex relationship to the total Mg/total Ca ratio. Whether this latter relationship represents a technical artifact or a true biological phenomenon requires further study. The apparent overestimation of Mg2+ at very low total Mg concentrations, and in the presence of a very low total Mg/total Ca ratio, could be due to improper chemometric correction of the Ca effect on the Mg electrode, non-linearity, and inadequate calibration. Whatever the mechanism, the failure of this method to correctly measure very low serum Mg2+ concentrations in the sera of patients with severe hypomagnesemia, or likely in any patient with an unusually low total Mg/total Ca ratio, erodes its diagnostic usefulness.

Magnesium-deficient mice immunized with SRBC showed a significant decrease (P less than 0.001) in the number of PFC in their spleens compared with mice on a control diet. Serum immunoglobulin concentrations (IgG1, IgG2, IgA and IgM) were determined after 3, 6, 9 and 12 days on the respective diets. The serum IgG2 and IgM concentrations of magnesium- deficient mice were decreased (P less than 0.005) by 6 days and remained at these concentrations until 12 days. The serum IgG1 and IgA concentrations of magnesium deficient animals also decreased (P less than 0.01) by 6 days but returned toward control concentrations at 12 days. Serum magnesium concentrations confirmed the magnesium deficiency of the experimental animals. Therefore, magnesium deficiency has profound immunosuppressive capabilities in mice by significantly reducing the number of antibody synthesizing cells and serum immunoglobulin concentrations.

The tenth anniversary for the determination of magnesium in MBC shows progress, but fundamental questions are still unanswered. Uniformity of the methodology for the assay and the units for reporting the result is a key factor for the validity and comparability of results. There is relatively good agreement among investigators for the mean value of magnesium in MBC expressed with three different units. The MBC magnesium results do not correlate with serum or red blood cell magnesium concentrations in humans. There may be a correlation for magnesium between MBC and muscle and between magnesium and potassium in MBC. The correlation for magnesium between MBC and muscle or other body tissues, particularly bone, needs to be defined for the clinical utility of the assay. A number of studies to date suggest a possible clinical utility for the MBC magnesium assay in several disease entities. Thus, the MBC magnesium assay has come a long way in a relatively short time. The future for the assay is uncertain but does hold hope that this relatively simple test can provide useful information about intracellular or total body magnesium status.

Rats placed on a magnesium-deficient diet show decreased erythrocyte magnesium concentration, shortened erythrocyte survival, and erythrocyte membrane ultrastructure defects and become progressively anemic. Whether these pathologic processes are due to abnormal erythropoiesis or occur in the peripheral circulation is unknown. In the present study, magnesium and hemoglobin concentrations, reticulocyte count, erythrocyte pyrophosphatase, and pyruvate kinase activities were determined at weekly intervals for 6 weeks in whole blood and age-dependent erythrocyte fractions isolated from inbred Fisher rats fed a diet deficient in magnesium or the same diet with added magnesium. Freeze-fracture electron microscopic examinations were performed on age-dependent erythrocyte fractions to evaluate the membrane defect. The youngest red cells from magnesium-deficient rats were similar to those of control animals with respect to erythrocyte magnesium concentrations, pyrophosphatase activities, and membrane morphology. The older erythrocyte fractions from magnesium-deficient rats showed significant decreases in magnesium concentrations, pyrophosphatase activity, and the presence of membrane abnormalities. Thus, new erythrocytes produced in magnesium-deficient rats appear to be normal but rapidly develop biochemical and morphologic abnormalities with aging in a magnesium-deficient plasma environment.

This study investigated the anemia of dietary magnesium deficiency in inbred Fisher white rats using freeze-fracture electron microscopy. The plasma membranes of erythrocytes from animals receiving two different magnesium-deficient and control diets were observed at weekly or biweekly intervals for 6 wk. The earliest changes were small plaques on the external surface (ES) and fracture face (PF) of erythrocyte plasma membranes, which occurred after 2 wk of either magnesium-deficient diet. These plaques persisted and increased in size with progressive magnesium deficiency. When fully developed, the plaques consisted of round or oval elevations approximately 30-50 nm in diameter outlined by a narrow raised border. The surface of the plaques was smooth and devoid of intramembranous particles. Incubation of erythrocytes from magnesium-deficient rats in a physiologic solution containing 2 meq/liter magnesium for 1 hr at 37degrees C did not alter the appearance of the plaques. Erythrocytes from control rats, obtained during the same time periods, showed no plaques. Thus, a deficiency of magnesium in rats altered erythrocyte membrane structure.

Magnesium deficiency in rats causes anemia, the mechanism of which is unknown. The effect of dietary magnesium, splenectomy, and magnesium content of erythrocytes on erythrocyte survival was studied in Fisher rats. Half of the animals were splenectomized, the remainder sham-splenectomized; each group was subdivided, and some were placed on a magnesium-deficient diet, the rest on a control diet. After 6 weeks, each of the four subgroups was divided, half were given 51Cr-labeled red cells from magnesium-deficient rats, the remainder, labeled normal red cells. The survival functions of the labeled erythrocytes were fitted to a mathematical model composed of both first-order and accelerating components. The results show that the most important factor influencing erythrocyte survival was dietary magnesium intake. The magnesium content of the transfused red cells affected erythrocyte survival only in the rats fed the control diet, whereas splenectomy affected erythrocyte survival only in rats receiving the magnesium-deficient diet. The accelerating component of the survival function was increased eightfold in the animals fed the magnesium-deficient diet, whereas much smaller changes occurred in the first-order components.