Perspective: The Case for an Evidence-Based Reference Interval for Serum Magnesium: The Time Has Come

Abstract

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.

Keywords: chronic disease; magnesium deficiency; plasma magnesium; reference interval; serum magnesium.

FIGURE 1

Age-specific distributions of serum magnesium in US adults. Data were derived from NHANES I (1971–1975). Mg, magnesium.

FIGURE 2

Data derived from urinary magnesium excretion in 93 men and 150 women participating in 27 different tightly controlled metabolic unit studies in which dietary magnesium ranged from 84 to 598 mg (3.46–246 mmol/d). Diet, dietary; Mg, magnesium.

FIGURE 3

Risk estimates and corresponding risk and reference circulating magnesium concentrations from prospective studies of incident cardiovascular diseases. Estimated risks [from published ORs, RRs, or HRs (, –162)] were derived from comparing the cutoff of circulating magnesium in cases to controls or the risk quantile compared with the reference quantile. The risk estimate at a given circulating magnesium concentration is connected to its corresponding reference magnesium concentration by a line for the following outcomes: atrial fibrillation (closed circles), coronary heart disease morbidity or mortality (closed squares), cardiovascular disease morbidity or mortality (open circles), heart failure (open squares), ischemic stroke (open diamonds), and sudden cardiac death (shaded circles). By way of example, for sudden cardiac death (shaded circle), 1 study (157) observed an RR of 0.23 at a circulating magnesium concentration >0.86 mmol/L relative to <0.78 mmol/L, which in this case was the reference concentration (RR = 1). Published and/or derived risk estimates (along with CIs) used to create this figure are shown in Supplemental Table 2. CHD, coronary heart disease; CVD, cardiovascular disease.

FIGURE 4

Associations between the risk of developing impaired glucose tolerance (A) and type 2 diabetes (B) in relation to serum magnesium concentrations in individuals followed for ≤15 y. Poisson regression models were adjusted for age, sex, family history of diabetes, waist circumference, and HOMA-IR index. Mg, magnesium.

FIGURE 5

The etiology of chronic latent magnesium deficiency. Mg, magnesium; STMC, serum total magnesium concentration. Adapted from reference with permission.

FIGURE 6

Current and proposed clinical cut-offs of the serum total magnesium concentration for assessing magnesium status. Current reference range derived from reference .

FIGURE 7

Summary of the accumulated evidence base to inform a revised serum reference interval. CRP, C-reactive protein; CVD, cardiovascular disease; Mg, magnesium; T2D, type 2 diabetes.