Hypomagnesemia and Hypermagnesemia: Comparison
Please note this is a comparison between Version 2 by Lindsay Dong and Version 1 by Steven Van Laecke.

Magnesium is an essential element with a pleiotropic role in human biology. Despite tight intestinal and renal regulation of its balance, insufficient intake can finally result in hypomagnesemia, which is a proxy of intracellular deficiency. Conditions such as diabetes, cancer, and infections are often associated with hypomagnesemia, which mostly predicts an unfavorable outcome. 

  • magnesium
  • diabetes
  • hypomagnesemia
  • CKD

1. Introduction

Magnesium is the second most abundant intracellular cation, which acts as a cofactor of >600 enzymes in human biology. It is therefore involved in many essential cellular processes, which include glycolysis, oxidative phosphorylation, transmembrane ion transport, signal transduction, and protein and deoxyribonucleic acid (DNA) synthesis and polymerization [1,2][1][2]. Almost the entire magnesium content of the body (25 g) is located in bone (60%), where it is incorporated into hydroxyapatite and, to a lesser degree, in soft tissue (38%), lessening its exchangeability. The small extracellular magnesium fraction is protein-bound (20–30%) and complexed to anions, including bicarbonate, citrate, sulfate, or phosphate (5–15%) [1,2][1][2]. Of the serum fraction of magnesium, more than half (55–70%) is ionized and thus biologically active.
The increased interest in magnesium is illustrated by an exponential rise in publications during the last decade. This is largely driven by accumulating evidence of a potential role of hypomagnesemia (mild if serum Mg < 0.7 mM and severe if serum Mg < 0.4 mM) or, more accurately, magnesium depletion in the development of cardiovascular disease [2,3][2][3]. Also, the list of etiologies of magnesium deficiency is still expanding. Novel hereditary causes of hypomagnesemia are being deciphered in tight conjunction with the exploration of the various pathways of renal tubular magnesium transport [4,5][4][5]. The causal role of commonly used drugs such as proton pump inhibitors or, more rarely, cetuximab (monoclonal antibodies against epidermal growth factor receptor) adds to the increasing list of drugs associated with decreased magnesium absorption or enhanced urinary loss. At least as important from a general population perspective is an observed deficient magnesium intake, not only in adults but also in adolescents following a high consumption of refined food with simultaneous insufficient intake of whole grains and of green leafy vegetables, with magnesium being a constituent of chlorophyll [6,7,8][6][7][8].

2. Hypomagnesemia

2.1. Pathophysiology

About 80 to 90% of the daily food intake of magnesium is absorbed via non-saturable paracellular concentration-driven passive uptake, especially in the jejunum and, to a lesser degree, the colon [1]. The potentially saturable active transcellular transport is restricted and occurs across the colonic channels transient receptor of melastatin (TRPM) 6 and 7 [1]. Both hypomagnesemia by itself and active vitamin D promote intestinal magnesium absorption, which can be upregulated from 40 to about 80% in case of magnesium deficiency. Most of the filtered magnesium load in the kidney is reabsorbed in the thick ascending limb (TAL) of Henle (70%) across an electrochemical gradient via the tight junction channels claudin-16 and -19 [1]. Next to hypervolemia, hypermagnesemia and hypercalcemia also inhibit the renal magnesium absorption at the level of the TAL of Henle via stimulation of the calcium-sensing receptor (CaSR), while hyperparathyroidism increases the renal magnesium absorption [31,32][9][10]. The remainder of the tubular absorption occurs in the proximal tubule (10–25%), while the distal convoluted tubule (DCT) is responsible for the regulation of the final urinary magnesium output via the adaptation of active absorption via TRMP6 [1]. Gastrointestinal causes of hypomagnesemia are not uncommon and include deficient intake or intestinal malabsorption of magnesium with incomplete renal compensation. In this regard, determination of fractional urinary magnesium excretion on a morning voiding sample can demonstrate urinary magnesium wasting if >2%, but only in the setting of a normal kidney function. Magnesium deficiency can occur even with normal serum magnesium concentrations, which reflects the limitations of serum magnesium as a proxy of total body magnesium content. Some authors have claimed that the biologically active ionized serum magnesium fraction is a more specific marker of magnesium status and correlates better with blood pressure measurements and other clinical assessments [40][11].

2.2. Hereditary Etiologies of Hypomagnesemia

In the last decade, transgenic murine models and the identification of their disorders have provided valuable insights into the molecular mechanisms of renal magnesium absorption [5]. The spectrum of etiologies of hereditary magnesium wasting related to monogenic mutations yielding dysfunctional transporter proteins, is still expanding [1,4,46][1][4][12]. Phenotypic traits alluding to a genetic etiology and warranting advice from the geneticist apart from family history, are features like early-onset hypomagnesemia, dysmorphic characteristics, neurosensorial hearing loss, cognitive dysfunction, epilepsy, diabetes, nephrocalcinosis and biochemical features such as hypercalciuria, metabolic alkalosis, and hypokalemia. More recently, however, mutations of other genes such as CKCNKB, KCNJ10, FXYD2, or HNF1B, which indirectly reduce NCC activity, can lead to the same clinical phenotype, explaining why the genotype in Gitelman syndrome is often unknown [49][13]. Also, four pathogenic variants in the mitochondrial genome leading to defective oxidative phosphorylation and hence NCC-mediated uptake were reported in 13 families with a Gitelman-like syndrome [50][14]. Gitelman syndrome was usually considered a benign condition despite the presence of hyperaldosteronism and hypomagnesemia. This premise has more recently been challenged by the confirmation of adverse metabolic and cardiovascular effects, including disturbed glucose metabolism, insulin resistance, and immunodeficiency due to impaired IL-17 response [51,52][15][16].

2.3. Hypomagnesemia and Glucose Metabolism

The relationship between (mild to moderate) hypomagnesemia and disturbed glucose metabolism, including diabetes mellitus, is quite well established with magnesium deficiency, which correlates inversely with glycemic control [53][17]. This relationship is, however, bidirectional. Both low dietary magnesium intake, hypomagnesemia, and single nucleotide polymorphisms in genes involved in cellular magnesium physiology, which influence serum magnesium concentration, predict the development of diabetes or prediabetes in the general population or in kidney transplant recipients [54,55,56][18][19][20]. Magnesium is an essential element for insulin secretion, which, moreover, increases the insulin-dependent glucose uptake in adipocytes, contributing to improved insulin sensitivity [57][21].

3. Symptoms

The variety of symptoms related to hypomagnesemia and their severity depend not only upon the degree of hypomagnesemia but also the (absence of) chronicity and the presence of concomitant electrolyte disturbances, including hypocalcemia and hypokalemia [61][22]. The majority of patients with moderate hypomagnesemia (0.5–0.65 mM) have chronic asymptomatic hypomagnesemia. Non-specific and therefore under-recognized symptoms are drowsiness and fatigue. Neuromuscular symptoms include the somewhat specific downbeat vertical nystagmus in severely hypomagnesiemic subjects in the absence of structural brain lesions [61][22]. The risk for choreiform movements, tetany, and seizures is amplified in patients with hypocalcemia [1,61][1][22]. Following severe hypomagnesemia (<0.5 mM), parathyroid hormone (PTH) hyposecretion and renal and skeletal resistance to PTH might aggravate hypocalcemia and ensuing neuromuscular symptoms [62][23].

3.1. Hypomagnesemia and Its Clinical Correlates

Meta-analyses of prospective studies in the general population pointed to a dismal cardiovascular outcome corresponding with hypomagnesemia [26][24]. An increased mortality risk was also observed in particular populations such as the elderly, people with variable degrees of CKD, kidney transplantation (KTR), and people with heart failure [29,30,64,65,66,67,68,69][25][26][27][28][29][30][31][32]. Hypomagnesemia also has immunotropic properties considering the extracellular magnesium regulation of the activity of CD8+ T-cells via their sensing co-stimulatory molecule LFA-1 and by increasing the cellular expression of activating NK receptors (NKG2D) [70,71][33][34]. A functional defect in MAGT1 transcellular receptors leads to the hereditary X-linked disease X-men disease, which is characterized by recurrent Epstein–Barr viremia (EBV) and a propensity to develop B-cell lymphoma [71][34]. The beneficial role of magnesium supplements, as described in the original paper, could, however, not be validated in a recent trial [72][35]. Hypomagnesemia was associated with increased infection risk and/or mortality in kidney transplant recipients and systemic lupus erythematodes (SLE) patients and higher mortality risk in patients with community-acquired pneumonia. Serum magnesium was also lower in children with increasing circulating Epstein–Barr Virus (EBV) levels and lymphoma [20,30,73,74,75,76][26][36][37][38][39][40]. Hypomagnesemia is also associated with the occurrence of cerebrovascular disease, including Alzheimer’s disease, while a higher serum magnesium concentration correlated with a higher brain volume and the absence of subclinical cerebrovascular disease according to data from the ARIC study [77,78][41][42].

3.2. When and How to Treat Hypomagnesemia?

A solid indication to treat hypomagnesemia is the presence of clinical symptoms and/or severe hypomagnesemia (<0.5 mM), which classically necessitates intravenous correction. The short-acting and thus transient effect of intravenous magnesium sulfate, of which half is renally excreted, should be taken into account as it temporarily abolishes the concentration gradient and hence the tubular magnesium reabsorption and can lead to hypotension and more sporadically hyperphosphatemia [62,88][23][43]. Oral magnesium supplements are used for the correction of mild to moderate chronic hypomagnesemia [62][23]. Meta-analyses of RCTs have demonstrated small but statistically significant effects on surrogate endpoints such as CRP and blood pressure [89][44]. SGLT2 inhibitors could theoretically become an elegant option to treat patients with hypomagnesemia, especially in patients with diabetes mellitus, renal disease, and/or cardiovascular disease. The magnesiotropic effect of these drugs seems related to the increased renal expression of TRPM6/7 and Claudin-16 (TAL Henle), which led to an increment in serum magnesium concentration of 0.05–0.2 mM in treated patients in the published large RCT [90,91,92][45][46][47]. In the CANVAS trial, the rise in serum magnesium in patients treated with canagliflozin did, however, not correlate with the better cardiovascular outcome of these treated patients [93][48]

3.3. Magnesium and Pregnancy

Intravenous magnesium sulfate is an evidence-based treatment of pre-eclampsia, but iatrogenic hypermagnesemia is rather common and should be monitored, especially in case of decreased kidney function. According to a recent retrospective study of 429 severely pre-eclamptic women, the majority (61%) developed critical hypermagnesemia, which was associated with lower gestational age, a higher uric acid concentration, and a higher baseline serum magnesium concentration [94][49].

3.4. Magnesium and Critical Illness

Although of potential use in critically ill patients, the role of correcting hypomagnesemia remains unclear, and a meta-analysis including three RCTs demonstrated lower mortality (RR 0.54 with 95%CI of 0.30–0.96) although high-quality trials are warranted to further support this [61,97][22][50]. Intravenous (IV) magnesium supplementation decreased the incidence of atrial fibrillation by 49% after cardiac surgery and has shown (in addition to standard-of-care treatment of rapid atrial fibrillation) significantly improved rate control and, to a lesser degree, the restoration of sinus rhythm [98,99][51][52]. Also, other therapeutic indications of intravenous magnesium sulfate exist, such as torsades de pointes, analgesic properties where it may reduce postoperative morphine consumption, asthma, and status asthmaticus in children, and/or chronic obstructive pulmonary disease exacerbations [100,101,102][53][54][55]. In the aforementioned placebo-controlled trials, hypomagnesemia was, interestingly, not a prerequisite for inclusion in the studies.

3.5. Efficacy of Magnesium Supplementation

The evidence to support one magnesium formulation over another is rather limited but favors the use of organic magnesium compounds, although bioavailability is also enhanced by concomitant intake with food with the exception of partly fermentable and non-fermentable fibers, phytate, and oxalate [27][56]. Also, high intestinal concentrations of minerals such as calcium lower intestinal magnesium absorption. Absorption is enhanced with lower intestinal pH in conjunction with intake of proteins, medium-chain triglycerides, and low- or non-digestible carbohydrates (and avoidance of proton pump inhibitors if feasible) [27][56].

4. Hypermagnesemia

Hypermagnesemia is defined by a serum magnesium concentration >1.2 mM (2.5 mg/dL) and is almost non-existent in patients with normal kidney function unless exposure occurs to huge concentrations of magnesium, for instance, in survivors of near-drowning in the Dead Sea [104][57]. A decline in glomerular filtrations impairs the adaptive ability to decrease renal magnesium absorption, although this does not automatically translate into hypermagnesemia, considering the prevalence of hypomagnesemia in CKD and even ESKD. This paradox is due to dietary restrictions to limit potassium exposure, generalized malnutrition, vitamin D insufficiency, use of diuretics and, of course, the development of a negative magnesium balance due to the low magnesium dialysate concentration in patients on peritoneal or hemodialysis [39,105][58][59]. Hypoalbuminemia can aggravate the negative magnesium balance in hemodialysis patients due to a higher concentration of free and dialyzable ionized fraction. Symptoms of hypermagnesemia (>1.7–2.1 mM) are mostly neurological, with typically absent deep tendon reflexes, impaired consciousness, and disturbed gait, although more vague symptoms such as nausea and vomiting can co-exist. Hypermagnesemia can result in arrhythmia, including bradycardia and malignant ventricular tachycardia. The treatment of symptomatic and/or severe hypermagnesemia (>3 mM) includes airway management, continuous cardiac monitoring, and intravenous calcium (100–200 mg over 5–10 min), which antagonizes the neuromuscular and cardiac effects of magnesium and rarely renal replacement therapy [111][60]. For mild hypermagnesemia, the removal of sources of exogenous magnesium is mostly sufficient. Controversy exists concerning the potential beneficial role of (mild) hypermagnesemia considering the pleiotropic effects of magnesium, which include anti-inflammatory, anti-oxidant, and anti-apoptotic properties [1,112,113][1][61][62]. Accumulating evidence points to a protective role of magnesium in vascular calcification supported by in vitro data, experiments in rodents with CKD but, more importantly, by RCTs in patients with CKD, where magnesium appears as one of the only treatment options where evidence was generated in favor of anti-calcification properties, although not all studies show a consistent protective effect [10,11,114][63][64][65]. The discrepancy of absent benefit despite a biological rationale could allude to the poor reflection of cellular magnesium concentration by serum magnesium levels and has led some investigators to propose an altered reference interval for normal serum magnesium [45][66]

5. Conclusions

Hypomagnesemia is becoming more and more prevalent, and this is most likely attributable to a restricted oral intake and, to a lesser extent, to the widespread use of causal drugs, which include proton pump and calcineurin inhibitors. In line with this, some authors have proposed an adaptation of the normal reference values of serum magnesium concentration to comply with an updated Gaussian distribution. The indications to correct moderate and asymptomatic hypomagnesemia remain theoretical and are based upon in vitro data, cross-sectional data, or therapeutic trials with mostly surrogate endpoints. Fortunately, trials are ongoing (NCT04079582, NCT03565913) to address the effects of increased magnesium exposure to patients with increased cardiovascular risk including CKD and dialysis patients, bearing in mind the potentially negative effects of overcorrection. Hypermagnesemia remains mostly confined to patients with ESKD and to women with pre-eclampsia treated with high-dose IV magnesium supplementation. Rather scarcely, case reports and series of hypermagnesemia upon exposure to antacids and cathartics in patients with relatively preserved kidney function have been described. The majority of recently published interventional trials demonstrated no hazardous outcome following magnesium exposure in (CKD) patients with mild hypermagnesemia.


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