Introduction

Magnesium is essential for life. Although its homeostasis at the cellular, tissue, and organism levels seems to be well buffered, there is a widely distributed tendency for low magnesium status to be associated with the most common chronic diseases [1]. In the absence of a more selective, reliable, and easily testable biomarker, serum magnesium is the most frequently used laboratory test for evaluating clinical magnesium status. Researchers use serum magnesium reference ranges to designate hypo-, normo-, or hypermagnesemic status, whereas hospitals and primary care physicians use serum magnesium values in deciding whether to administer magnesium therapy. Consequently, the lower cutoff for serum magnesium reference value of a hospital or clinical laboratory determines the number of patients diagnosed as “hypomagnesemic.”

Hypomagnesemia has several clinical manifestations that vary from asymptomatic to severe. Overt symptoms present at ≤ 0.6 mmol/L [2] (Fig. 1). These clinical manifestations include metabolic issues (hypokalemia and hypocalcemia), neuromuscular-central nervous system symptoms (hyperexcitability, muscle weakness, tremors, seizures, tetany, headaches, and fatigue), cardiovascular abnormalities (tachycardia, arrhythmias such as torsade de pointes, ventricular fibrillation, mitral valve prolapse, cardiac ischemia, myocardial infarct, and hypertension), and endocrine abnormalities (insulin resistance and type 2 diabetes) [2, 3] (Table 1). Reported severe, overt symptoms of hypomagnesemia also include the mimic of acute stroke [4], life-threatening arrhythmias [3], metabolic acidosis [5], and new-onset diabetes following heart transplantation [6]. In intensive-care units, hypomagnesemia is associated with higher mortality, the need for mechanical ventilation, and increased length of stay [7].

Fig. 1
figure 1

Reproduced from Costello and Rosanoff [14], which was adapted from Costello et al. [12]

Total serum magnesium concentration for assessment of magnesium status. Conversion factor: for mg/dL to mmol/L, multiply by 0.411; for mmol/L to mg/dL, multiply by 2.43; and for mmol/L to mEq/L, divide by 0.5.

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Table 1 Clinical manifestations of hypomagnesemia.
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In addition to hypomagnesemia presenting with overt disease states, patients can present with asymptomatic hypomagnesemia or chronic latent magnesium deficit (CLMD) at serum Mg levels well above 0.6 mmol/L (Fig. 1). CLMD has been defined as a subclinical condition that renders individuals more susceptible to disease. CLMD occurs with a small chronic negative magnesium balance, which may be attributed to decreased dietary intake, decreased gastrointestinal absorption, and/or increased renal loss [8]. The most common cause of CLMD worldwide is decreased magnesium dietary intake, since processed food and fast food tend to have low magnesium content [9, 10]. However, illness and drug use must also be taken into account. Over time, this negative magnesium balance causes the serum magnesium concentration to decrease. Since this is a subtle chronic process, some magnesium is depleted in bone to support the circulating serum magnesium pool [11]. Thus, patients with CLMD appear to have “normal” magnesium status, because their serum magnesium value falls within the traditionally normal reference ranges, but these patients are not in sufficient magnesium status for long-term health. The actual magnesium deficiency of the patient is latent—a fallacy of the reference interval as serum magnesium reference intervals have been established with “healthy” individuals, including many who unknowingly have CLMD [11]. This is the basis for updating the lower limit reference interval for the serum magnesium concentration.

Two groups of magnesium researchers, one in the United States [12] and one in Germany [13], have independently agreed on a serum magnesium value of 0.85 mmol/L as the low cut-off point to define hypomagnesemia, since serum magnesium values < 0.85 mmol/L (2.07 mg/dL or 1.7 mEq/L) have been associated with an increased risk of various diseases (e.g., cardiovascular disease [CVD], metabolic), obesity, and aging.

In response to the COVID-19 pandemic, our international group of magnesium researchers (Magnesium Global Network [MaGNet]) began meeting in September 2020 to discuss the research. In these meetings, we discussed the serum magnesium reference ranges used by our institutions’ hospitals and laboratory service providers, and we discovered that they were far from uniform. We decided to gather these values to compare them with the suggested evidence-based serum magnesium reference for hypomagnesemia of 0.85 mmol/L [1213], and we present those findings here.

Materials and methods

We collected and evaluated the various serum magnesium reference range values of our institutions, including the laboratory methodology used to obtain those values when available. To expand our indicative database, we also gathered serum magnesium reference range values from colleagues around the world. Institutions were coded by country, and all contributed values were calculated to express commonly used alternate units of serum magnesium—milligrams per deciliter (mg/dL), millimoles per liter (mmol/L), and milliequivalents per liter (mEq/L)—for each reported value. GraphPad Prism version 9 was used to tabulate data and create Fig. 2. The independently suggested evidence-based serum magnesium reference range of 0.85–0.95 mmol/L (2.07–2.3 mg/dL or 1.7–1.9 mEq/L) was added to Figure 2 for comparison.

Fig. 2
figure 2

Serum magnesium reference ranges from several institutions and laboratory service providers, gathered by magnesium researchers for the MaGNet Global Magnesium Project. Assessment methods are indicated with lowercase letters as follows: colorimetric (a), colorimetric/xylidyl blue (b), enzymatic assay (c), atomic absorption spectroscopy (d), and not reported (e). Colorimetric, photometric, and spectrophometric designations of methodology are all classified under colorimetry. See Table 2 for full details

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Results

As shown in Fig. 2 and Table 2, the level of serum magnesium designating a patient as hypomagnesemic differs worldwide. Forty-three values were gathered from institutions in 16 different countries, including China, Germany, India, Iran, Israel, Italy, Japan, Korea, Mexico, Poland, Romania, Slovakia, Switzerland, Taiwan, the United Kingdom, and the United States. Of those 43 values, only 2 (5%) designated a low serum magnesium reference range cut-off value of 0.85 mmol/L. Forty-one values of the 43 institutions (95%) designated their low cutoff for definition of hypomagnesemia below and even well below this suggested standard, from 0.58 mmol/L for IT4 to 0.78 mmol/L for IL1. Most of the collected values (29 of 43; 67%) used colorimetric methodology, with 9 specifying xylidyl blue and 1 indicating calmagite as the colorimetric agent. Of the 43 values, 1 (2%) used atomic absorption spectroscopy and 3 (7%) used enzymatic methodology. Ten values (21%) did not report methodology. Figure 1 summarizes the definition of low and high magnesemia as proposed by previous works on magnesium reference range [14] and highlights how CLMD is currently included in the normal serum magnesium range (see Discussion).

Table 2 Working table of serum magnesium reference ranges for various hospitals and institutions
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Discussion

Such different serum magnesium reference range values render our current use of this medical tool imprecise, causing many hypomagnesemic patients to be deemed normomagnesemic and potentially minimizing the effects of low magnesium status in research.

When different cut-off values for hypomagnesemia are used, substantially different results can ensue. For instance, in one study at a Warsaw hospital, when a lower cut-off reference value of 0.65 mmol/L was used, 7% of 20,483 patients were deemed hypomagnesemic [15]. With the lower cut-off reference value of 0.75 mmol/L, 25% of this same patient cohort showed hypomagnesemia. Finally, with a lower cut-off reference value of 0.85 mmol/L, 60% were diagnosed as hypomagnesemic [15].

Clearly, the serum magnesium reference range used by a hospital, clinical, or research laboratory is crucial in the designation of low magnesium status. The present observational study’s wide spectrum of serum reference interval values used in hospital and clinical laboratories around the world documents an urgent need for a consensus reference interval for serum magnesium concentration, specifically on the lower cut-off limit, since low magnesium status is currently a common condition worldwide [16]. The evidence-based lower cut-off value of 0.85 mmol/L (2.07 mg/dL or 1.7 mEq/L) proposed by the US and German research groups [12, 13] specifically prevents the inclusion of individuals with CLMD [12], who usually fall into the lower half of the reference interval of < 0.85 mmol/L (see Fig. 1).

Despite the central role of magnesium in maintaining proper immune, vascular, and pulmonary function, emerging evidence indicates that magnesemia is seldom assessed in patients [17]. Additionally, an evidence-based standard for the upper range of serum magnesium to differentiate between a “safe” and “hypermagnesemic” value is yet to be determined.

Conclusion

The 43 serum magnesium reference range values we collected from 16 countries varied widely, and all but 2 (DE2 and IN1) had a hypomagnesemic cut-off point well below that of the recommended 0.85 mmol/L (2.07 mg/dL or 1.7 mEq/L). Thus, the hypomagnesemic reference values in this informal collection indicate that physicians and researchers are vastly underestimating hypomagnesemia in their patients and institutions, interpreting as “normal” serum magnesium values that fall well below that recently proposed to be safe for good health. It is critically important to appropriately identify, diagnose, and manage low magnesium status, which is often overlooked and may play a role in susceptibility to increasingly common chronic diseases (e.g., CVD, diabetes, and chronic obstructive pulmonary disease), among other conditions.

A consensus serum magnesium to define hypomagnesemia is suggested to be 0.85 mmol/L (2.07 mg/dL or 1.7 mEq/L). An evidence-based, standardized serum magnesium reference range for hypermagnesemia still needs to be determined. MaGNet researchers should continue gathering and monitoring new evidence to further update recommendations for guidelines that define the correct serum magnesium reference range to maintain health.

Disclosures

Christina West received financial support from CMER for her role in this work. She provides editorial consulting services to authors, nonprofit organizations, and publishers, but has no conflicts of interest that influenced or are relevant to this work. Anton Kraus is an employee of Verla-Pharm Arzneimittel.