In clinical settings, the evaluation of serum total Mg concentration is the primary method used to assess Mg status, with the normal reference range typically being 0.7–1.0 mmol/L (1.7–2.4 mg/dL) [1,2,23]. The normal values may differ between laboratories, and some studies have employed slightly different ranges [23]. These discrepancies in normal values may partly account for the differences in reported Mg disorders prevalence among patients with similar characteristics [1].

Unlike hypomagnesemia, few studies assessed the prevalence of hypermagnesemia in various health settings [24,25,26,27]. In a population-based prevalence study evaluating the prevalence of Mg concentrations in an urban general population (n = 1558), the overall prevalence of hypermagnesemia was 3.0% [26]. Pregnant women with eclampsia are considered to be a high-risk group due to the need for high doses of intravenous Mg to prevent eclamptic seizures [28]. However, Mg intoxication incidence was in a large systematic review involving 9556 women with Mg use due to pre-eclampsia, only 1.3–1.6% [27].

In a hospital setting, the prevalence of hypermagnesemia ranges from 5.7% to 9.3% [24,29]. The most extreme cases of elevated serum Mg concentration recorded were in a premature infant at 33 weeks gestation with a concentration of 18 mmol/L and in a 78-year-old woman who ingested water from the Dead Sea with a concentration of 13.4 mmol/L [24,25]. It has been estimated that around 10% to 15% of hospitalized patients with renal failure develop hypermagnesemia due to reduced renal excretion of Mg [30]. Hypermagnesemia was associated with poor health outcomes, including increased in-hospital mortality and 1-year mortality among hospitalized patients [4,31,32]. Moreover, hypermagnesemia strongly predicts the in-hospital mortality rate of acute myocardial infarction [33]. This may be due to Mg ions competing with the calcium ions for activation and deactivation sites located on the type II isoform ryanodine receptor channels in cardiac myocytes, damaging cardiac contraction, and relaxation [34]. Additionally, Mg can also impair the release of acetylcholine, leading to motor end-plate sensitivity depression and inducing arrhythmia, myocardial depression, and vasodilation [35].

Moreover, hypermagnesemia appears to be an indicator of disease severity among patients hospitalized with SARS-CoV-2, and hypermagnesemia was associated with prolonged hospitalization, higher rates of ICU admission, greater need for mechanical ventilation, and mortality [36].

The commonly used method is measuring total serum magnesium concentration, although it may not provide the most reliable evaluation due to potential influences from serum protein concentrations. Recent advancements in ion-selective electrodes have enabled the measurement of ionized magnesium concentration, but standardization is needed. Red cell magnesium concentration does not correlate well with overall magnesium status while assessing magnesium content in mononuclear cells is technically challenging. Muscle magnesium content assessment through invasive procedures has shown promise in predicting cardiac magnesium levels [1,35].

A 24-h urine excretion of magnesium can reflect intestinal absorption and identify renal magnesium wasting. The magnesium tolerance test accurately determines magnesium retention after intravenous administration, but its utility is limited in patients with renal magnesium loss. Intracellular free magnesium concentration can be measured using fluorescent probes or nuclear magnetic resonance [1,37].

Magnesium balance studies, isotopic analysis, hair and tooth analysis, and enzyme activation studies have been explored, but they are less reliable than serum or red cell magnesium concentration. Overall, a combination of tests, such as measuring total serum magnesium and employing the magnesium tolerance test, currently provides the most accessible assessment of magnesium status. With advancements in technology, ionized magnesium measurement may become more widely available and reliable in the future [1,38].

Patients with either acute kidney injury or chronic kidney disease (CKD) are at increased risk of hypermagnesemia due to the importance of the renal system for Mg excretion, and 10–15% of hospitalized patients with kidney injury may develop hypermagnesemia [33]. Moreover, in rare circumstances, several endocrinological conditions might cause marked rises in serum Mg concentrations, such as hyperparathyroidism, adrenal insufficiency, and hypothyroidism, by increasing Mg renal reabsorption [39,40]. Hyperparathyroidism and calcium metabolism disturbance can result in hypermagnesemia through an increased calcium-induced Mg absorption in the tubule [41]. Familial hypocalciuric hypercalcemia (FHH) is a rare autosomal dominant condition that occurs due to a variant in the calcium-sensing receptor gene (CaSR). The CaSR presents in all the kidney segments and prominently in the basolateral side of TAL, controlling the sodium chloride and divalent cation, such as Mg and calcium, transportation both transcellularly and paracellularly by enhancing various channels such as NKCC2 and ROMK [42]. As a result of CaSR gene variations, the aforementioned channels (NKCC2 and ROMK) get over-activated and create a positive activity in the lumen, which encourages the action of the paracellin, which induces the reabsorption of the Mg and calcium transcellularly and paracellularly. In hypothyroidism, it is suggested that Mg excretion is impaired due to a drop in renal blood flow and filtration rate [43,44]. Increased sodium-potassium ATPase activity in settings of hypothyroidism has been reported, which results in a high electrochemical gradient leading to reabsorption of Mg. The latter could explain the association between hyperkaliemia and hypermagnesemia [44,45,46,47]. Finally, certain drugs that act on renal endothelial vessels and the angiotensin system might cause hypermagnesemia, such as lithium, angiotensin-converting enzyme inhibitors, and non-steroidal anti-inflammatory drugs (Table 1) [41].

Hypermagnesemia might develop in individuals despite normal renal functions, especially in elderly patients with certain bowel conditions that enhance the absorption or reduce gut motility, including inflammatory bowel diseases and constipation [48]. Similarly, anticholinergics medications or laxatives might result in high serum Mg concentrations, primarily in settings of pre-existing bowel pathology [49]. Medications containing Mg can elevate serum Mg concentrations if taken continuously, particularly when renal function is impaired. Amaguchi and colleagues reported a case of symptomatic hypermagnesemia secondary to Mg supplements in an elderly with underlying constipation [48]. In order to evaluate the risk of hypermagnesemia in patients using magnesium oxide tablets, a retrospective study was conducted involving 2176 individuals who took daily magnesium oxide for laxative purposes. The study indicated a correlation between hypermagnesemia and CKD grade 4 and higher dosages of magnesium oxide. Moreover, elevated serum Mg concentration was associated with magnesium oxide dosage exceeding 1000 mg/day, CKD grade 4, and the concurrent use of stimulant laxatives [50]. Milk alkali syndrome may also cause hypermagnesemia, as reported already in 1936 by Cope, where patients developed toxic symptoms of hypercalcemia, hyperphosphatemia, hypermagnesemia, and azotemia secondary to calcium carbonate-containing alkali therapy [51,52]. In patients undergoing dialysis, increased dialysate Mg can also cause symptomatic hypermagnesemia [53]. Moreover, a case report demonstrated hypermagnesemia in a patient with post-urethral irrigation with hemiacidrin, which is utilized in the nephrolithiasis process [54]. Moreover, excessive infusion of Mg sulfate during the management of eclampsia is a well-known cause of hypermagnesemia, which can be fatal [41,55]. Hypermagnesemia resulting solely from dietary intake is not reported thus far, as the kidneys effectively eliminate excess magnesium through urine. However, patients with CKD are more susceptible to developing hypermagnesemia due to impaired renal excretion. Hence, educating these patients about minimizing their consumption of magnesium-rich foods, such as seeds, nuts (such as almonds and cashews), black beans, brown rice, bananas, and broccoli, is crucial [56].

Mg is an essential intracellular cation. Consequently, in scenarios where hemolysis occurs due to various causes, including tumor lysis syndrome, there is a potential risk of developing hypermagnesemia [57]. Other causes which can present with hypermagnesemia through the extracellular shifts include rhabdomyolysis and metabolic acidosis, including diabetic ketoacidosis [58]. Metabolic acidosis causes urinary Mg wasting as a compensatory mechanism for the rapid rise in serum Mg [59]. Hence, chronic low-grade metabolic acidosis in humans eating Western diets may contribute to decreased Mg status [60].