Proton Pump Inhibitors and Severe Hypomagnesaemia

Tim Cundy; Jonathan Mackay

Disclosures

Curr Opin Gastroenterol. 2011;27(2):180-185. 

In This Article

Magnesium Metabolism and Homeostasis

Most magnesium is in the mineral phase of bone (~600 mmol in an adult) or within the cells of the soft tissues (~400 mmol). After potassium, it is the most abundant intracellular cation. Within cells, magnesium is a cofactor in over 300 enzymatic reactions, involving control of calcium and potassium channels, membrane stabilization and neuromuscular excitability, protein and nucleic acid synthesis and oxidative phosphorylation. It is of particular importance in energy metabolism – all enzymatic reactions involving ATP have an absolute requirement for magnesium.

Less than 0.5% of total body magnesium (~2.5 mmol) is present within the plasma. In plasma, approximately 60% of the total magnesium is in the ionized form, approximately 15% is complexed (with phosphate, citrate or bicarbonate) and the remainder (~25%) is protein-bound. The distribution within the various plasma fractions may be altered by changes in protein concentration and pH.

Magnesium is widely distributed in foods. Green vegetables are an important source, but food processing can remove much of the magnesium from cereals and carbohydrate foodstuffs. 'Hard' waters contain an appreciable amount (up to 5 mmol/l). Typical daily magnesium intakes range from 6 to 20 mmol, with a median of approximately 12 mmol.

Of the typical dietary intake of approximately 12 mmol, about half is absorbed, mainly in the small intestine. There are two separate transport systems (Figs 1 and 2). One is an active transcellular process, saturated at low intraluminal concentrations. Transport from the lumen into the epithelial cells is mediated by the transport proteins TRPM6 and TRPM7.[3] The transporter responsible for moving magnesium out of the cells into blood is not yet known. When magnesium intake is normal, this process accounts for approximately 30% of absorption, but this proportion increases at low magnesium intakes.

Figure 1.

Cartoon illustrating the active (transcellular) and passive (paracellular) pathways for the absorption of magnesium from the lumen of the small intestine into the blood
The passive pathway involves passage through the tight junctions between cells. In the active process, transport from the luminal side is believed to be mediated by the TRPM6/7 complex, but the transporter responsible for moving magnesium out of the epithelial cells into blood is not yet known. tight junction; TRPM6/7; unidentified transporter.

Figure 2.

The quantity of magnesium absorbed by passive and active mechanism is related to the magnesium content of a meal
At low luminal concentrations the active transport process is dominant. Adapted from [5].

The other transport system, typically accounting for approximately 70% of absorption, is a passive paracellular pathway through the 'tight junctions' between enterocytes that make a seal between the luminal and mucosal surfaces. The tight junctions comprise interconnected transmembrane protein strands that match strands on adjacent enterocytes. There are many integral and peripheral protein components, but among the most important are the claudins. The differing degrees of 'leakiness' of tight junctions depend mainly on the number of fixed charges. The tight junctions in the gut are relatively leaky compared with those on other epithelial surfaces.[4]

A constant fraction (~7%) of ingested magnesium is absorbed through this mechanism.[5] The rate of absorption through this process is dependent on the transepithelial electrical voltage (usually +5 mV) and the concentration gradient (typically 1–5 mmol/l in the lumen and 0.5–0.7 mmol/l nonprotein-bound magnesium in the blood).[3] Some magnesium can be absorbed from the large bowel. An estimated 2 mmol per day is secreted into the intestine; thus the net daily intestinal absorption is approximately 4 mmol, which is balanced by excretion into the urine.

The ionized and complexed magnesium fractions are ultrafilterable in the kidney. In a healthy adult, approximately 100 mmol are filtered daily. Fifteen–20% of the ultrafilterable magnesium is reabsorbed in the proximal tubules, but the majority (~70%) is reabsorbed in the thick ascending limb of the loop of Henle, by a passive paracellular process, driven by the lumen-positive electrochemical gradient. The final urinary magnesium excretion is determined by active transcellular reabsorption of Mg2+ in the distal convoluted tubule. This is a multistep process with passage of Mg2+ across the luminal membrane through the epithelial channels TRPM6 and TRPM7, cytosolic diffusion, and then active extrusion across the opposite basolateral membrane. Between 3 and 5% of the filtered magnesium finally appears in the urine. The kidney has a maximal limit for tubular reabsorption (TmMg), above which all ultrafilterable magnesium is excreted.[6]

There are clear homeostatic mechanisms for regulating magnesium status, although the magnesium 'sensor' is not known. The kidney appears to be the prime organ in the fine regulation of magnesium homeostasis. In times of magnesium deprivation, the kidney can reduce magnesium excretion to less than 1 mmol per day. There is also intestinal adaptation mediated through the active transport process. The proportion of dietary magnesium absorbed is higher (up to 75%) when the diet is magnesium-depleted, but lower when the dietary load is greater.

Magnesium can regulate parathyroid hormone (PTH) secretion in a manner similar to calcium, but is only a half to a third as potent. PTH secretion is thus stimulated by modest hypomagnesaemia and suppressed by hypermagnesaemia. Paradoxically, profound hypomagnesaemia inhibits PTH secretion.

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