Magnesium is one of the most abundant cation in the body as well as an abundant intracellular cation. It plays an important role in molecular, biochemical, physiological, and pharmacological functions in the body. The importance of magnesium is well known, but still it is the forgotten electrolyte. The reason for it not getting the needed attention is because of rare symptomatology until levels are really low and also because of a lack of proper understanding of magnesium physiology. Some studies estimate that approximately three-fourths of Americans do not take the recommended dietary allowance of magnesium [1
]. The reported incidence of hypomagnesemia is likely less than expected. The reported incidence of hypomagnesemia is approximately 2% in the general population. In hospitalized patients, the risk is the highest for intensive care unit (ICU) patients [2
]. The cause of hypomagnesemia depends primarily on alterations in intake, redistribution, and excretion. Understanding the physiological aspects is important to guiding the management of magnesium disorders.
4. Role at Cellular Level
Magnesium is an essential component of the RNA and DNA tertiary structures. It plays a role in polynucleotide chain binding, and the most studied interaction between magnesium and RNA is transfer RNA (t-RNA) where it is known to stabilize the structure. In DNA, magnesium forms hydrogen bonds to stabilize the DNA conformation [14
]. Magnesium is not only required by DNA and RNA polymerases but is also an important factor in DNA repair mechanisms. Magnesium is important in many enzymatic activities. It serves as a cofactor as well as an activator for many enzymes. Some of the enzymes requiring magnesium are topoisomerases, helicases, protein kinases, cyclases, and glycolytic pathway enzymes [14
]. One of the important enzymes is adenosine triphosphate, which provides cellular energy for several processes. Magnesium plays a role in the movement of sodium and potassium across membranes [15
5. Causes of Hypomagnesemia
The causes of hypomagnesemia can be broadly classified into three categories: decreased intake, redistribution from extracellular to intracellular, and increased losses via renal or gastrointestinal systems (Table 1
Decreased intake can result from inadequate dietary consumption, starvation, and alcohol dependence. Approximately 48% of the population in the United States have been shown to consume less than the daily magnesium requirement [16
]. Some studies estimate that approximately three-fourths of Americans do not take the recommended dietary allowance of magnesium [1
]. The recommended daily allowances for magnesium are outlined in Table 2
. Hypomagnesemia develops in people with chronic alcohol abuse who do not satisfy the definition of alcohol dependence.
Refeeding syndrome, hungry bone syndrome, treatment of diabetic ketoacidosis, and acute pancreatitis result in shifts of magnesium from extracellular to intracellular compartments, resulting in hypomagnesemia. The mechanism of hypomagnesemia associated with refeeding syndrome is not clear; it is possibly related to the intracellular movement of magnesium with carbohydrate feeding and preexisting low magnesium status [17
]. Hungry bone syndrome causes hypomagnesemia by increased uptake of magnesium by renewing bone after parathyroidectomy or thyroidectomy [18
]. Correction of diabetic ketoacidosis also causes hypomagnesemia by driving magnesium into the cells. Acute pancreatitis causes hypomagnesemia by saponification of magnesium in necrotic fat [18
Gastrointestinal causes of hypomagnesemia include losses due to diarrhea, vomiting, nasogastric suction and fistulas, malabsorption, and small bowel bypass surgery. Proton pump inhibitors (PPIs) are being widely and over-utilized these days; they rank among the top prescribed and one of the most sold drugs. The duration of treatment in most occasions is for months to years. The exact mechanism of PPIs causing hypomagnesemia is unclear but one of the hypotheses is impairment of intestinal absorption [20
]. A decrease in intestinal luminal pH with the use of PPIs may alter TRPM6/TRPM7 channel affinity for Mg and disrupt the active transport system. The U.S. Food and Drug Administration (FDA) has received reports of hypomagnesemia with prolonged PPI use [21
]. A meta-analysis done by Cheungpasitporn et al. reported the relative risk of hypomagnesemia with PPI use at 1.43 [22
]. Primary intestinal hypomagnesemia is a rare disorder and is an inborn error of metabolism. This disease is characterized by a selective defect in magnesium absorption [18
Renal losses are primarily due to defects in the magnesium excretory pathways. They can be secondary to inherited or acquired causes. A few examples of inherited disorders that result in urinary magnesium wasting are Bartter syndrome, Gitelman syndrome, and familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC). Acquired causes of renal losses include medications and alcohol dependence. Loop and thiazide diuretics inhibit net magnesium reabsorption by inhibition of the electrical gradient required for magnesium reabsorption in the thick ascending loop [2
]. On the other hand, the potassium-sparing diuretics lower magnesium excretion by increasing magnesium transport. The nephrotoxic drugs that are known to cause urinary magnesium wasting are aminoglycoside antibiotics, amphotericin B, cisplatin, pentamidine, tacrolimus, and cyclosporine. They cause hypomagnesemia by impairment of loop and distal magnesium reabsorption [18
]. Hypomagnesemia is common in alcoholic patients with a prevalence of around 30% and is mostly secondary to excess urinary excretion of magnesium due to tubular dysfunction induced by alcohol [18
]. Hypercalcemia can cause hypomagnesemia by increased filtered calcium load to the loop of Henle, resulting in decreased reabsorption of magnesium [18
7. Neuromuscular/Neurological Manifestations
The earliest manifestations of magnesium deficiency are commonly seen in the form of neuromuscular and neuropsychiatric alterations. The most common clinical manifestations result from hyper-excitability, including positive Chvostek’s and Trousseau’s signs, tremor, fasciculation, and tetany [9
]. It can also cause headaches, seizures, fatigue, generalized fatigue, and asthenia.
There may be different mechanisms which can lead to neuromuscular problems in magnesium deficiency. Magnesium is necessary for axon stabilization. The threshold for axon stimulation is decreased and there is an increase in the nerve conduction velocity with hypomagnesemia. It inhibits the entry of calcium into the presynaptic nerve terminals, influencing the release of neurotransmitters at the neuromuscular junction and thereby causing hyper-responsive neuromuscular activity. Magnesium also increases the release of calcium from the sarcoplasmic reticulum and decreases the re-uptake of calcium; these factors lead to increased contractility to a given stimulus and decreased ability to recover from the contraction [9
The type of magnesium supplementation, route of administration and aggressiveness depends on the etiology, symptomatology, severity, and other associated electrolyte abnormalities. Patients with simultaneous electrolyte abnormalities such as hypokalemia or hypocalcemia should be treated appropriately with potassium or calcium replacements, respectively, as treatment with magnesium alone will take several days to correct. In any form of magnesium replacement, renal function should be considered and appropriate renal dosing should be done to avoid hypermagnesemia in patients with chronic kidney disease. In all cases, the underlying cause of magnesium deficiency needs to be delineated and appropriately addressed to prevent recurrences [42
]. Potassium-sparing diuretics like amiloride increase magnesium reabsorption in the collecting tubule, thereby decreasing magnesium excretion, and can be beneficial especially in cases where diuretic therapy is needed [18
Patients with hypomagnesemia and on PPIs should consider discontinuing PPIs and switching to alternative medical treatments. Some cases were shown to normalize their magnesium levels after one week of discontinuation of PPIs [21
]. Proton Pump Inhibitors were added to the 2015 AGS (American Geriatrics Society) Beers Criteria as potentially inappropriate in older adults [43
]. It is suggested that healthcare professionals consider obtaining the serum magnesium level prior to the initiation of PPIs as well as performing periodic checks in patients who are expected to need long-term treatment with these agents.
Magnesium is present in plant and animal foods. Green leafy vegetables, legumes, nuts, seeds, and whole grains are examples of good sources. Food processing like refining grains can lower the magnesium content [19
]. Selected food sources of magnesium with their percent daily values are shown in Table 4
In severe and symptomatic hypomagnesemia, intravenous magnesium sulfate is the recommended treatment [42
], which should be given slowly with clinical and hemodynamic monitoring. An important physiological aspect that must be considered here is that the plasma magnesium concentration is the major regulator of magnesium reabsorption in the loop of Henle, and a rapid elevation in plasma magnesium will result in significant urinary excretion of magnesium (approximately half of the infused magnesium) [18
]. This is well illustrated in Figure 2
which shows the relation between urinary and plasma magnesium levels in a healthy subject on a magnesium-free diet [13
]. For mild to moderate forms or in asymptomatic patients, oral magnesium is the preferred choice of replacement. Therefore, it is recommended that when intravenous magnesium replacement is needed, the rate of infusion should be slow over 12–24 h.
There are very limited human data on the bioavailability of different magnesium supplementation salts. A study done in rats showed that organic salts are more bioavailable than inorganic ones, with magnesium gluconate having the highest bioavailability. Magnesium gluconate exhibited the highest Mg bioavailability of the ten Mg salts studied [45
]. There are different oral formulations with varying bioavailabilities, magnesium content, and tolerance. Table 5
shows the different magnesium salts, their magnesium contents, bioavailabilities, and tolerabilities.