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Causes of hypomagnesemia

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jun 2014. | This topic last updated: Nov 04, 2013.
INTRODUCTION — Hypomagnesemia is a common entity occurring in up to 12 percent of hospitalized
patients [1]. The incidence rises to as high as 60 to 65 percent in patients in an intensive care setting in which
nutrition, diuretics, hypoalbuminemia, and aminoglycosides may play important roles [2-5]. The kidney can,
in the presence of magnesium depletion, lower magnesium excretion to very low levels; the stimulus for this
response is a fall in the plasma magnesium concentration. (See "Regulation of magnesium balance".)

There are two major mechanisms by which hypomagnesemia can be induced: gastrointestinal or renal losses.
Regardless of the cause, hypomagnesemia begins to occur after a relatively small magnesium deficit because
there is little rapid exchange of extracellular magnesium with the much larger bone and cell stores.

Hypomagnesemia is often associated with hypokalemia (due to urinary potassium wasting) and hypocalcemia
(due both to lower parathyroid hormone secretion and end-organ resistance to its effect). (See "Clinical
manifestations of magnesium depletion".)

The major causes of hypomagnesemia will be reviewed in this topic. The regulation of magnesium balance,
the signs and symptoms of hypomagnesemia, and the evaluation and treatment of patients with
hypomagnesemia are presented elsewhere. (See "Regulation of magnesium balance" and "Clinical
manifestations of magnesium depletion" and "Evaluation and treatment of hypomagnesemia".)

GASTROINTESTINAL LOSSES — Gastrointestinal secretions contain some magnesium, and potential


losses are continuous and not regulated. Although the obligatory losses are not large, marked dietary
deprivation can lead to progressive magnesium depletion.

Magnesium losses from both the upper and lower gastrointestinal tract can induce hypomagnesemia. In
general, magnesium depletion is more commonly due to diarrhea than to vomiting [5]. This is because the
magnesium content of lower tract secretions is significantly higher (up to 15 meq/L versus approximately 1
meq/L for upper tract). Common settings in which hypomagnesemia may be seen include acute or chronic
diarrhea, malabsorption and steatorrhea, and small bowel bypass surgery.

In addition, hypomagnesemia with secondary hypocalcemia can be produced by a familial disorder


characterized by a selective defect in magnesium absorption (primary intestinal hypomagnesemia). This
disease presents in the neonatal period with hypocalcemia that is responsive to magnesium administration [6].
In some instances, the defect appears to have an X-linked recessive inheritance, but others have described
autosomally recessive inheritance with linkage to chromosome 9 [7]. The autosomal recessive form is caused
by mutations in the TRPM6 gene [8-12]. The encoded protein, which is expressed both by intestinal epithelia
and by the renal distal convoluted tubule, functions as an apical magnesium entry channel [13]. Thus, patients
with this disorder have not only decreased intestinal magnesium absorption, but also inappropriate renal
magnesium wasting.

Hypomagnesemia can also be seen in acute pancreatitis. The mechanism of hypomagnesemia is presumably
similar to the mechanism partially responsible for hypocalcemia in acute pancreatitis: saponification of
magnesium and calcium in necrotic fat [14]. The degree of hypocalcemia may be exacerbated by the
hypomagnesemia, which can both lower parathyroid hormone secretion and induce end-organ resistance to its
effect. (See "Etiology of hypocalcemia in adults" and "Clinical manifestations of magnesium depletion".)
Proton pump inhibitors — Hypomagnesemia, usually with hypocalcemia, has been described in case reports
with the chronic use of omeprazole (usually for more than one year) and other proton pump inhibitors (PPIs)
[15-18]. The association of PPIs with lower serum magnesium has also been described in population studies.
The best data come from a large cohort of 11,490 patients admitted to the intensive care unit at a single center
[19]. In this study, the relationship between PPI use and magnesium varied by whether patients concurrently
used diuretics (see "Effect of diuretics on magnesium handling by the kidney"):
●In patients taking diuretics, concurrent use of PPIs was associated with a 0.028 mg/dL (0.011 mmol/L)
lower adjusted serum magnesium. In addition, the prevalence of hypomagnesemia (defined as a serum
magnesium less than 1.6 mg/dL [0.66 mmol/L]) was significantly higher in patients taking both drugs as
compared with those who only used diuretics (15.6 versus 11 percent).
●In patients not taking diuretics, use of PPIs was not associated with the serum magnesium or the
prevalence of hypomagnesemia.

In a smaller study of 402 inpatients with hypomagnesemia and matched controls, proton pump inhibitors were
not associated with hypomagnesemia [20]. However, duration of use was not examined, and most patients
were not taking diuretics; therefore, these findings are potentially consistent with those of the larger cohort
study.

The presumed mechanism is impaired absorption of magnesium by intestinal epithelial cells caused by PPI-
induced inhibition of transient receptor potential melastatin-6 (TRPM6) and TRPM7 channels [21]. Renal
losses are not likely to be involved since urinary magnesium excretion is appropriately low in patients with
hypomagnesemia due to PPIs [17,18]. Some patients have inappropriately low serum parathyroid hormone
levels [16], a finding that is well described in patients with hypomagnesemia due to other causes. (See
"Clinical manifestations of magnesium depletion", section on 'Calcium metabolism'.)

In March 2011, the United States Food and Drug Administration (FDA) issued a safety warning suggesting
that, in patients expected to be on PPIs for long periods of time and in those taking other medications
associated with hypomagnesemia as described below (eg, diuretics), providers measure serum magnesium
levels prior to initiation of PPI therapy and periodically during treatment [22]. The hypomagnesemia can be
partially or completely corrected by high-dose oral magnesium supplementation [16-18]. Hypomagnesemia
resolves with cessation of PPI therapy [15,16,18].

RENAL LOSSES — Urinary magnesium losses can occur via a variety of either acquired or intrinsic
mechanisms. (See "Regulation of magnesium balance".)
Medications — Both loop and thiazide diuretics can inhibit net magnesium reabsorption, while potassium-
sparing diuretics may enhance magnesium transport and lower magnesium excretion. The degree of
hypomagnesemia induced by loop and thiazide diuretics is generally mild, in part because the associated
volume contraction will tend to increase proximal sodium, water, and magnesium reabsorption. A more
detailed review of how these changes might occur is discussed separately. (See "Effect of diuretics on
magnesium handling by the kidney".)

In addition to loop and thiazide diuretics, many nephrotoxic drugs can produce urinary magnesium wasting
[23], including but not limited to:

●Aminoglycoside antibiotics (see "Aminoglycosides", section on 'Nephrotoxicity').


●Amphotericin B (see "Amphotericin B nephrotoxicity").
●Cisplatin (see "Cisplatin nephrotoxicity").
●Pentamidine (see "Overview of kidney disease in HIV-infected patients", section on 'Electrolyte
disorders').
●Cyclosporine (see "Cyclosporine and tacrolimus nephrotoxicity").
●Antibodies targeting the epidermal growth factor (EGF) receptor (cetuximab, panitumumab,
matuzumab) (see "Chemotherapy-related nephrotoxicity and dose modification in patients with renal
insufficiency").

The impairment in loop and distal magnesium reabsorption may occur prior to the onset of, and may persist
after the resolution of, the acute tubular necrosis and acute kidney injury (AKI) associated with these
nephrotoxins. Studies in the rat, for example, have shown a dose-related and rapidly reversible decrease in
renal tubular reabsorption of magnesium and calcium (but not sodium and potassium) within 60 minutes of
beginning an infusion of gentamicin [24]. The hypermagnesuria in this setting can be striking, and the
resulting hypomagnesemia may be sufficient to produce hypocalcemia. With cisplatin therapy, a reduction in
gastrointestinal magnesium absorption may also contribute to the hypomagnesemia [25].

Volume expansion — Expansion of the extracellular fluid volume, by reducing reabsorption of sodium and
water, can decrease passive magnesium transport. Mild hypomagnesemia may ensue if this is sustained, as in
primary aldosteronism. (See "Pathophysiology and clinical features of primary aldosteronism".)
Alcohol — Hypomagnesemia is common in alcoholic patients admitted to the hospital; in one study, for
example, the prevalence was 30 percent [26]. Excessive urinary excretion of magnesium occurred in 18 of the
38 patients with hypomagnesemia. The defect in urinary excretion appears to reflect alcohol-induced tubular
dysfunction that is reversible within four weeks of abstinence [27]. This effect is relatively modest, and other
factors are also thought to contribute to hypomagnesemia in these patients, including dietary deficiency, acute
pancreatitis, and diarrhea.
Uncontrolled diabetes mellitus — Hypomagnesemia is not uncommon in patients with uncontrolled diabetes
mellitus; it appears to be associated with increased urinary magnesium excretion that is reversed by correction
of the hyperglycemia with insulin [5,28,29]. It has been proposed, although not proven, that hypomagnesemia
may impair glucose disposal and may play a role in the pathogenesis of some of the complications of
diabetes. As a result, the American Diabetes Association (ADA) has published a consensus statement
suggesting that diabetic patients with hypomagnesemia should receive magnesium supplementation.
Hypercalcemia — Patients with hypercalcemia due, for example, to hyperparathyroidism can develop mild
hypomagnesemia. This finding results at least in part from the fact that calcium and magnesium functionally
compete for transport in the thick ascending limb of the loop of Henle. A variety of mechanisms may
contribute to the reduction in magnesium reabsorption resulting from hypercalcemia. One well-established
mechanism is mediated by the basolateral calcium-sensing receptor (CaSR) in the thick ascending limb:
●Calcium binds to the basolateral CaSR.
●This leads to generation of prostaglandins and cytochrome P450 metabolites in the cell, which inhibit
the apical potassium channel (ROMK) [30,31].
●Inhibition of ROMK inhibits sodium chloride reabsorption in the thick ascending limb and reduces
paracellular magnesium and calcium reabsorption (figure 1). Inhibition of ROMK in this nephron
segment resulting from stimulation of the CaSR is the mechanism underlying type V Bartter syndrome.
Thus, hypercalcemia can produce a Bartter-like phenotype. (See "Bartter and Gitelman syndromes",
section on 'Type V'.)
●In addition, stimulation of the CaSR decreases paracellular permeability of the thick ascending limb to
both magnesium and calcium [32], likely due to increased expression of claudin-14 [33,34], which
negatively regulates claudin-16 and claudin-19. (See 'Familial hypomagnesemia with hypercalciuria and
nephrocalcinosis (FHHNC)' below.)
Other acquired tubular dysfunction — Magnesium wasting can be seen as part of the tubular dysfunction
associated with recovery from acute tubular necrosis, following renal transplantation, or during a
postobstructive diuresis.
Familial renal magnesium wasting — Primary renal magnesium wasting is an unusual disorder that may
present sporadically or as a familial disease [35-39]. Several types have been recognized [40].

The diagnosis of primary renal magnesium wasting is one of exclusion. It is established by the demonstration
of inappropriately high urinary magnesium excretion in the absence of any other apparent cause. (See
"Evaluation and treatment of hypomagnesemia".)

Gitelman syndrome — Gitelman syndrome is the most common form of familial renal magnesium wasting
and is usually associated with salt wasting, hypokalemic metabolic alkalosis, and hypocalciuria. It is caused
by recessive mutations in the gene coding for the thiazide-sensitive sodium chloride cotransporter
(SLC12A3). Although the hypokalemia in this syndrome is usually attributed to decreased sodium chloride
transport, direct effects of hypomagnesemia may also contribute [41]. (See "Bartter and Gitelman
syndromes".)

The hypomagnesemia in Gitelman syndrome is significantly more marked than that observed with thiazide
administration. In addition, mice lacking the sodium chloride cotransporter had hypomagnesemia and
hypocalciuria but exhibited only subtle changes in sodium homeostasis [42].

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) — This form of primary
renal magnesium wasting is autosomal recessive and associated with hypercalciuria; affected patients
usually present in childhood or adolescence with symptomatic hypocalcemia [43-47]. Recurrent
nephrolithiasis and nephrocalcinosis are also seen, and progression to renal insufficiency and an acidification
defect are common. The problem with acidification has been attributed to defective ammonia transfer to the
deep nephrons and impaired medullary hydrogen ion secretion due to nephrocalcinosis [48]. Affected patients
may also have polyuria and polydipsia due to nephrogenic diabetes insipidus [43,47].

Mutations in the claudin-16 gene (also known as paracellin-1) are the major cause of FHHNC [12,47,49-53].
Claudin-16 is a tight junction protein that facilitates the passive, paracellular reabsorption of both magnesium
and calcium in the thick ascending limb of the loop of Henle. Some of these patients present with
hypokalemia due to either secondary hyperaldosteronism and/or direct effects of hypomagnesemia on
potassium transport.

FHHNC may occasionally be due to mutations in claudin-19 [54]. In addition to hypomagnesemia,


nephrolithiasis, and nephrocalcinosis, such patients have ocular involvement [55], which may include macular
colobomata, nystagmus, and myopia.
Na-K-ATPase mutation — A gene responsible for autosomal dominant isolated renal magnesium wasting in
two unrelated Dutch families has been mapped to a region on chromosome 11q23 [56]. The abnormality in
this disorder appears to be a dominant negative mutation in the gene encoding the gamma subunit of Na-K-
ATPase, resulting in misrouting of the protein [57,58].
Voltage gated potassium channel — A mutation in the gene (KCNA1) that encodes the voltage-gated
potassium channel (Kv1.1) is the cause of isolated autosomal dominant hypomagnesemia discovered in a
large Brazilian family [59]. This channel colocalizes with the magnesium channel TRPM6 in the distal
collecting tubules. Wild type Kv1.1 appears to control TRPM6 magnesium reabsorption via the creation of an
appropriate potential across the luminal membrane.
Hepatocyte nuclear factor-1-beta gene mutations — Hypomagnesemia and renal magnesium wasting have
been reported in 8 of 18 patients (44 percent) with known mutations in the hepatocyte nuclear factor-1-beta
(HNF-1-beta) gene [60]. HNF-1-beta is a transcription factor that regulates the expression of the gamma
subunit of Na-K-ATPase. These findings suggest that some mutations of HNF-1-beta can activate this subunit,
thereby causing hypomagnesemia, in association with early onset diabetes and renal malformations that
include multicystic dysplastic disease and obstructive uropathy. (See "Classification of diabetes mellitus and
genetic diabetic syndromes".)
Epidermal growth factor gene mutation — Epidermal growth factor (EGF) appears to stimulate distal
tubular magnesium reabsorption by binding to a receptor on the basolateral membrane and activating the
magnesium channel TRPM6 in the apical membrane. A point mutation in pro-EGF leads to impaired
basolateral membrane sorting, inadequate stimulation of renal EGF receptor, insufficient activation of the
magnesium channel, and causes isolated autosomal recessive renal magnesium wasting [61,62]. A similar
inhibition of the EGF receptor likely underlies the effects of cetuximab and other EGF receptor inhibitors on
magnesium transport as previously mentioned [61,62]. (See 'Medications' above.)
Cyclin M2 mutations — Mutations in the cyclin M2 (CNNM2) gene have been implicated in two families
with dominant isolated renal magnesium wasting [63]. CNNM2 encodes a transmembrane protein that is
localized to the basolateral membrane of the thick ascending limb and distal convoluted tubule; it functions
either as a magnesium channel [64] or magnesium-sensitive sodium channel and is upregulated under
conditions of magnesium deficiency.
MISCELLANEOUS — Hypomagnesemia has been described in a number of other settings. The following is
a partial list of potential causes:
●Intravascular chelation can lead to hypomagnesemia and has been described in the following settings:
•Following surgery, at least in part due to chelation by circulating free fatty acids [65].
•After foscarnet therapy of cytomegalovirus chorioretinitis, often in association with hypocalcemia
[66].
•Ionized hypomagnesemia during liver transplantation due to transfusion of citrate-rich blood
products in the absence of adequate hepatic function to metabolize the citrate [67].
●Hypomagnesemia can occur as part of the "hungry bone" syndrome in which there is increased
magnesium uptake by renewing bone following parathyroidectomy for hyperparathyroidism,
thyroidectomy for hyperthyroidism, or correction of severe metabolic acidosis [68]. (See "Hungry bone
syndrome following parathyroidectomy".)
●Hypomagnesemia has been found in up to 10 percent of patients placed on an extremely high-fat diet
to induce ketogenesis as the therapy of intractable epilepsy. The mechanism of this effect is not clear but
may result from malabsorption of magnesium [69]. (See "Evaluation and management of drug-resistant
epilepsy".)
●Hypomagnesemia, in combination with hypertension and dyslipidemia, was described in a kindred
with a mutation in mitochondrial tRNA [70]. The mutation likely resulted in multiple and varied
physiologic disruptions because of its effect on energy consumption. With respect to low magnesium
levels, distal convoluted tubule cells could be adversely affected because magnesium reabsorption
requires significant energy.
●Hypomagnesemia has been associated with leptospirosis and may be due at least in part to urinary
magnesium wasting [71,72].
SUMMARY
●Hypomagnesemia is a common entity occurring in up to 12 percent of hospitalized patients. The
incidence rises to as high as 60 to 65 percent in patients in an intensive care setting. There are two major
mechanisms by which hypomagnesemia can be induced: gastrointestinal or renal losses. (See
'Introduction' above.)
●Gastrointestinal secretions contain some magnesium. Although the obligatory losses are not large,
marked dietary deprivation can lead to progressive magnesium depletion. Magnesium losses from both
the upper and lower gastrointestinal tract can induce hypomagnesemia. Common settings in which
hypomagnesemia may be seen include acute or chronic diarrhea, malabsorption and steatorrhea, and
small bowel bypass surgery. Hypomagnesemia can also be seen in acute pancreatitis. (See
'Gastrointestinal losses' above.)
●Hypomagnesemia has been described with the chronic use of omeprazole (usually for more than one
year) and other proton pump inhibitors (PPIs), presumably due to impaired intestinal absorption. The
United States Food and Drug Administration (FDA) issued a safety warning suggesting that, in patients
expected to be on these drugs for long periods of time and in those taking other medications associated
with hypomagnesemia (eg, diuretics), providers should measure serum magnesium levels prior to
initiation of therapy and periodically during treatment. (See 'Proton pump inhibitors' above.)
●Urinary magnesium losses can occur via a variety of either acquired or intrinsic mechanisms. These
include:
•Medications, including loop and thiazide diuretics and various potential nephrotoxins (see
'Medications' above).
•Sustained expansion of the extracellular fluid volume, as with primary aldosteronism (see 'Volume
expansion' above).
•Alcohol use (see 'Alcohol' above).
•Uncontrolled diabetes mellitus (see 'Uncontrolled diabetes mellitus' above).
•Hypercalcemia, as in patients with primary hyperparathyroidism (see 'Hypercalcemia' above).
•Recovery from acute kidney injury (AKI) and following renal transplantation (see 'Other acquired
tubular dysfunction' above).
•Familial renal magnesium wasting, such as with Gitelman syndrome (see 'Familial renal
magnesium wasting' above).
Clinical manifestations of magnesium depletion
Literature review current through: Jun 2014. | This topic last updated: Oct 07, 2013.
INTRODUCTION — Hypomagnesemia is a common problem, occurring in nearly 12 percent of
hospitalized patients [1]. A higher incidence, as much as 60 to 65 percent, has been found among intensive
care unit patients [2].

Symptomatic magnesium depletion is often associated with multiple biochemical abnormalities such as
hypokalemia, hypocalcemia, and metabolic alkalosis. As a result, it is often difficult to ascribe specific
clinical manifestations solely to hypomagnesemia.

This topic reviews the clinical manifestations of magnesium depletion. The causes, evaluation, and treatment
of magnesium depletion are discussed elsewhere. (See "Causes of hypomagnesemia" and "Evaluation and
treatment of hypomagnesemia".)

OVERVIEW OF CLINICAL MANIFESTATIONS — The major clinical manifestations of


hypomagnesemia include:
●Neuromuscular manifestations, including neuromuscular hyperexcitability (eg, tremor, tetany,
convulsions), weakness, apathy, delirium, and coma. (See 'Neuromuscular' below.)
●Cardiovascular manifestations, including widening of the QRS and peaking of T waves with moderate
magnesium depletion, and widening of the PR interval, diminution of T waves, and atrial and ventricular
arrhythmias with severe depletion. (See 'Cardiovascular' below.)
●Abnormalities of calcium metabolism, including hypocalcemia, hypoparathyroidism, parathyroid
hormone (PTH) resistance, and decreased synthesis of calcitriol. (See 'Calcium metabolism' below.)
●Hypokalemia. (See 'Hypokalemia' below.)

Magnesium depletion is also associated with several other disorders, such as insulin resistance and the
metabolic syndrome [3] and hypertension. Patients with primary hypertension (formerly called "essential"
hypertension) may have reduced free magnesium concentrations in red blood cells [4], and magnesium
supplementation can reduce blood pressure [5]. In addition, magnesium deficiency has been implicated in
both migraine headaches and asthma, and some studies suggest that magnesium therapy is effective in these
disorders [6,7].

NEUROMUSCULAR — Neuromuscular hyperexcitability may be the presenting complaint of patients with


magnesium deficiency. Hypocalcemia is often observed in patients with magnesium deficiency and may
contribute to the clinical findings. Neuromuscular hyperexcitability may manifest as:
●Tetany – Patients may develop positive Trousseau and Chvostek signs, muscle spasms, and muscle
cramps [8,9]. Tetany can occur in the absence of hypocalcemia and alkalosis, and is presumably due to
lowering of the threshold for nerve stimulation [2,10].
●Seizures – Hypomagnesemic patients can develop seizures that may be generalized and tonic clonic in
nature or multifocal motor. This has been observed in neonates and children, as well as adults. The
effects of magnesium deficiency on brain neuronal excitability may be mediated by increased glutamate-
activated depolarization in the brain [11].
●Involuntary movements – Patients with hypomagnesemia can manifest athetoid or choreiform
movements [12].
In addition to neuromuscular hyperexcitability, patients with hypomagnesemia may manifest apathy, delirium,
or coma [13]. Vertical nystagmus is a rare but diagnostically useful sign of severe hypomagnesemia. In the
absence of a structural lesion of the cerebellar and vestibular pathways, the only recognized metabolic causes
are Wernicke's encephalopathy and severe magnesium deficiency [14]. Weakness of the respiratory muscles is
a major concern in critically ill patients with hypomagnesemia, and may be a variable in the genesis of
respiratory failure [2].

CARDIOVASCULAR — Magnesium has complex effects on myocardial ion fluxes, among which its effect
on the sodium pump (Na-K-ATPase) is probably the most important. As magnesium is an obligate co-factor in
all reactions that require ATP, it is essential for the activity of Na-K-ATPase [15]. During magnesium
deficiency, Na-K-ATPase function is impaired.

Magnesium depletion induces the following changes in the electrocardiogram, which usually reflect abnormal
cardiac repolarization:

●Widening of the QRS complex and peaking of T waves have been described with modest magnesium
loss [16].
●Prolongation of the PR interval, progressive widening of the QRS complex, and diminution of the T
wave can be seen with more severe magnesium depletion [17].
●Frequent atrial and ventricular premature systoles may be present, and sustained atrial fibrillation may
also develop.
●Hypomagnesemia facilitates the development of digoxin cardiotoxicity [18]. Because cardiac
glycosides and magnesium depletion both inhibit Na-K-ATPase, their additive effects on intracellular
potassium depletion may account for their enhanced toxicity in combination [19].
●The clinical disturbance of greatest potential importance, however, is the association of
hypomagnesemia with ventricular arrhythmias, particularly during myocardial ischemia or
cardiopulmonary bypass. A discussion of these issues can be found elsewhere. (See "Significance of
hypomagnesemia in cardiovascular disease".)
CALCIUM METABOLISM — Hypocalcemia is a classical sign of hypomagnesemia. In hypomagnesemic
patients, symptomatic hypocalcemia is almost always associated with plasma magnesium levels below 1
meq/L (0.5 mmol/L or 1.2 mg/dL). Mild hypomagnesemia (plasma magnesium concentration between 1.1
and 1.3 meq/L) can also lower the plasma calcium concentration, but the change is quite small (0.2 mg/dL or
0.05 mmol/L) [20]. Occasionally, patients with normal plasma magnesium concentrations may have
hypocalcemia that improves with magnesium therapy, possibly due to cellular magnesium depletion. (See
'Normomagnesemic magnesium depletion' below.)

The major factors resulting in hypocalcemia in hypomagnesemic patients are hypoparathyroidism,


parathyroid hormone (PTH) resistance, and vitamin D deficiency. (See 'Hypoparathyroidism and parathyroid
hormone resistance' below and 'Vitamin D deficiency' below.)

Dietary magnesium depletion in animals has been shown to lead to a decrease in skeletal growth and
increased skeletal fragility. In humans, epidemiologic studies suggest a correlation between bone mass and
dietary magnesium intake. Several mechanisms may account for a decrease in bone mass in magnesium
deficiency. Since both PTH and calcitriol are trophic for bone, impaired secretion or skeletal resistance may
result in osteoporosis [21]. In addition, magnesium is mitogenic for cell growth, which may result in a
decrease in bone formation.

Hypoparathyroidism and parathyroid hormone resistance — Low magnesium levels impair parathyroid
hormone (PTH) release in response to hypocalcemia. Immunoreactive PTH levels in most hypomagnesemic-
hypocalcemic patients have been either normal or low (and in some cases undetectable), indicating
inappropriately low PTH secretion [22-24]. Thus, a state of hypoparathyroidism exists in most
hypomagnesemic-hypocalcemic patients. In the majority of these patients, parenteral magnesium
supplementation leads to a rapid rise in plasma PTH levels [22,24].

Failure of hormone secretion cannot explain all of the hypocalcemia that is observed, and bone resistance to
PTH also plays a role [24]. Studies in isolated perfused bone have shown that magnesium depletion interferes
with the generation of cyclic AMP in response to perfusion with PTH [25]. Why this occurs is not clear. It is
possible that severe hypomagnesemia may interfere with G protein activation in response to PTH, thereby
minimizing the stimulation of adenylate cyclase.

Several findings suggest that PTH resistance may be of greater importance than diminished secretion in most
patients. In general, PTH-induced release of calcium from bone is substantially impaired when the plasma
magnesium concentration falls below 0.8 meq/L (1 mg/dL or 0.4 mmol/L); in comparison, diminished PTH
secretion appears to require more severe hypomagnesemia. In addition, magnesium therapy produces a rise in
PTH secretion that occurs significantly earlier than restoration of PTH responsiveness [24]. This observation
is compatible with a primary role for PTH resistance.

Vitamin D deficiency — Low plasma levels of calcitriol (1,25-dihydroxyvitamin D, the most active
metabolite of vitamin D) have been noted in hypocalcemic, hypomagnesemic subjects and can contribute to
the decreased calcium concentration. Several factors may explain low calcitriol levels. Patients with
magnesium deficiency and hypocalcemia frequently have low serum levels of 25-hydroxyvitamin D. The
major reason, however, appears to be a decrease in the conversion of 25-hydroxyvitamin D to 1,25-
dihydroxyvitamin D by the kidney [26]. This results from both impaired PTH secretion, as mentioned above,
and a direct effect of magnesium depletion on the kidney.
Normomagnesemic magnesium depletion — A small number of patients have been reported with
hypocalcemia responsive to magnesium administration in the absence of detectable hypomagnesemia
[24,27,28]. In most of these patients, other findings suggested the presence of magnesium depletion, such as
alcoholism or diarrhea. In a prospective study of 82 patients with alcohol-related admission diagnoses, for
example, 30 had unexplained hypocalcemia (8 mg/dL or 2 mmol/L); 14 were hypomagnesemic while 16 had
a normal plasma magnesium concentration [28]. However, both of the hypocalcemic groups had low
mononuclear cell magnesium levels, a finding also seen in normocalcemic patients, and both groups showed
normalization of the plasma calcium concentration after the administration of 32 to 64 meq of elemental
magnesium per day for three to five days.

These findings, however, do not conclusively demonstrate that intracellular magnesium depletion is the cause
of unexplained hypocalcemia in patients with a normal plasma magnesium concentration. Most patients with
chronic alcoholism and diarrhea have tissue magnesium depletion that is independent of the presence or
absence of hypocalcemia [29]. Sepsis, hypoalbuminemia, stress, and vitamin D deficiency are among the
many factors in these patients that can lower the total and ionized calcium. In addition, there were no
untreated time controls in this study and it is possible that resolution of the hypocalcemia may have occurred
without magnesium repletion as the clinical status of the patients improved after admission. Nevertheless, it
seems reasonable to consider a trial of magnesium replacement in patients with normal renal function who
have persistent, unexplained hypocalcemia and are at risk for magnesium deficiency. (See "Evaluation and
treatment of hypomagnesemia".)

HYPOKALEMIA — Hypokalemia is a common event in hypomagnesemic patients, occurring in 40 to 60


percent of cases [30]. This relationship is in part due to underlying disorders that cause both magnesium and
potassium loss, such as diarrhea and diuretic therapy. (See "Causes of hypomagnesemia".)

There is also evidence of renal potassium wasting in hypomagnesemic patients that is due to increased
potassium secretion in the connecting tubule and the cortical collecting tubule [31]. The following sequence
may explain how this might occur. Potassium secretion from the cell into the lumen by the cells of the
connecting tubule and cortical collecting tubule is mediated by luminal potassium (ROMK) channels, a
process that is inhibited by intracellular magnesium. Hypomagnesemia is associated with a reduction in the
intracellular magnesium concentration, which releases this inhibitory effect on potassium efflux [31-33].
Given the very high cell potassium concentration, this change would promote potassium secretion from the
cell into the lumen and enhanced urinary losses. The hypokalemia in this setting is relatively refractory to
potassium supplementation and requires correction of the magnesium deficit [34].

SUMMARY AND RECOMMENDATIONS


●Hypomagnesemia is a common problem, occurring in nearly 12 percent of hospitalized patients. A
higher incidence, as much as 60 to 65 percent, has been found among intensive care unit patients. (See
'Introduction' above.)
●The major clinical manifestations of hypomagnesemia include (see 'Overview of clinical
manifestations' above):
•Neuromuscular manifestations, including neuromuscular hyperexcitability (eg, tremor, tetany,
convulsions), weakness, apathy, delirium, and coma. (See 'Neuromuscular' above.)
•Cardiovascular manifestations, including widening of the QRS and peaking of T waves with
moderate magnesium depletion, and widening of the PR interval, diminution of T waves, and atrial
and ventricular arrhythmias with severe depletion. (See 'Cardiovascular' above.)
•Abnormalities of calcium metabolism, including hypocalcemia, hypoparathyroidism, parathyroid
hormone (PTH) resistance, and decreased synthesis of calcitriol. (See 'Calcium metabolism'
above.)
•Hypokalemia. (See 'Hypokalemia' above.)

Evaluation and treatment of hypomagnesemia


INTRODUCTION — Most of the body's magnesium stores are intracellular, principally within bone. In the
extracellular fluid, magnesium can be ionized (free), bound to anions, or bound to protein. (See "Regulation
of magnesium balance".)
The plasma magnesium concentration is not usually measured as part of routine blood tests. Thus, the
identification of patients with hypomagnesemia often requires clinical suspicion in patients with risk factors
for hypomagnesemia (eg, chronic diarrhea, proton pump inhibitor therapy, alcoholism, diuretic use) or with
clinical manifestations of hypomagnesemia (eg, unexplained hypocalcemia, refractory hypokalemia,
neuromuscular disturbances, ventricular arrhythmias) [1,2]. (See "Causes of hypomagnesemia" and "Clinical
manifestations of magnesium depletion".)

This topic will review the evaluation and treatment of hypomagnesemia. The regulation of magnesium
balance, and the causes and clinical manifestations of hypomagnesemia are presented in detail elsewhere.
(See "Regulation of magnesium balance" and "Causes of hypomagnesemia" and "Clinical manifestations of
magnesium depletion".)

EVALUATION — In patients diagnosed with hypomagnesemia, the cause can usually be obtained from the
history. (See "Causes of hypomagnesemia".)

If no etiology is apparent, the distinction between gastrointestinal and renal losses can be made by measuring
the 24-hour urinary magnesium excretion or the fractional excretion of magnesium on a random urine
specimen.

The latter can be calculated from the following formula (calculator 1 and calculator 2):

UMg x PCr
FEMg = ——————————————— x 100 percent
(0.7 x PMg) x UCr

The terms "U" and "P" refer to the urine and plasma concentrations of magnesium (Mg) and creatinine (Cr).
The plasma magnesium concentration is multiplied by 0.7 since only about 70 percent of the circulating
magnesium is free (not bound to albumin) and therefore able to be filtered across the glomerulus.

Renal magnesium excretion should be reduced in patients with plasma magnesium depletion. Thus,
measurement of 24-hour urinary magnesium excretion or the fractional excretion of magnesemia can help
distinguish between gastrointestinal and renal losses of magnesium [3,4]:

●A daily excretion of more than 10 to 30 mg (in a 24-hour urine specimen) or a fractional excretion of
magnesium above 2 percent in a person with hypomagnesemia and normal renal function indicates renal
magnesium wasting.
●In contrast, a 24-hour urinary magnesium excretion less than 10 mg or a fractional excretion of
magnesium less than 2 percent usually indicates an extrarenal source of magnesium losses (typically
gastrointestinal).

In one study of 74 hypomagnesemic patients, for example, the mean fractional excretion of magnesium in
patients with hypomagnesemia of extrarenal origin was 1.4 percent (range 0.5 to 2.7 percent) [4]. By
comparison, the fractional excretion of magnesium in those with renal magnesium loss was 15 percent (range
of 4 to 48 percent). (See "Causes of hypomagnesemia".)

Normomagnesemic magnesium depletion — The possibility of normomagnesemic magnesium depletion (in


which there is isolated cellular magnesium depletion) should be considered as a possible cause of refractory
hypokalemia or unexplained hypocalcemia in patients at high risk for magnesium loss [3]. (See "Clinical
manifestations of magnesium depletion", section on 'Normomagnesemic magnesium depletion'.)

One suggested method to detect underlying magnesium depletion is to demonstrate reduced excretion (less
than 80 percent over 24 hours) of an infused magnesium load (2.4 mg/kg of lean body weight given over the
initial four hours) [3,5,6]. However, the utility of this test is uncertain. Patients with malnutrition, cirrhosis,
diarrhea, or long-term diuretic use typically have a positive test, whether or not they have signs or symptoms
referable to magnesium depletion [7]. It seems prudent, therefore, to simply administer magnesium to these
patients if they have unexplained hypocalcemia and/or hypokalemia.

TREATMENT — The route and dose of magnesium repletion should be selected on the basis of the severity
of the clinical manifestations and the degree of hypomagnesemia.
Patients with severe symptoms — Symptomatic patients, such as those with tetany, arrhythmias, or seizures
should receive intravenous magnesium. Such patients should have continuous cardiac monitoring.
●In the acute setting, hemodynamically unstable patients (including those with arrhythmias consistent
with torsade de pointes or hypomagnesemic hypokalemia), 1 to 2 g magnesium sulfate (8 to 16 meq [4
to 8 mmol]) can be given initially over two to fifteen minutes [8]. (See "Acquired long QT syndrome",
section on 'Acute therapy of TdP' and "Clinical manifestations and treatment of hypokalemia", section
on 'Hypomagnesemia and redistributive hypokalemia'.)
●In hemodynamically stable patients with severe symptomatic hypomagnesemia (less than or equal to 1
mg/dL [0.4 mmol/L or 0.8 meq/L]), 1 to 2 grams of magnesium sulfate (8 to 16 meq [4 to 8 mmol]) in
50 to 100 mL of 5 percent dextrose in water can be given initially over 5 to 60 minutes followed by an
infusion (infusion described in the following bullet) [8].
●A simple infusion regimen for nonemergent repletion is 4 to 8 g magnesium sulfate (32 to 64 meq [16
to 32 mmol]) given slowly over 12 to 24 hours [9]. This dose can be repeated as necessary to maintain
the plasma magnesium concentration above 1 mg/dL (0.4 mmol/L or 0.8 meq/L). In the
normomagnesemic patient with hypocalcemia, it has been suggested to repeat this dose daily for three to
five days [5,6].
●Patients with renal insufficiency (creatinine clearance less than 30 mL/min/1.73 m2) are at risk for
severe hypermagnesemia if large doses of magnesium are given because plasma magnesium
concentrations are regulated solely by renal excretion. Thus, we reduce the intravenous magnesium dose
in such patients by 50 percent or more and closely monitoring magnesium concentrations. (See 'Treating
patients with impaired renal function' below and "Causes and treatment of hypermagnesemia", section
on 'Renal insufficiency'.)
●In children, we use a slow infusion of magnesium sulfate; the dose is 25 to 50 mg/kg (0.2 to 0.4
meq/kg [0.1 to 0.2 mmol/kg]) with a maximum single dose of 2 g (16 meq [8 mmol]) [10,11]. (See
"Significance of hypomagnesemia in cardiovascular disease".)

(Conversion relationships: 1 mmol = 2 meq = 24 mg of elemental magnesium = 240 mg magnesium sulfate.)

The magnesium concentration should be measured 6 to 12 hours after each dose of intravenous magnesium.
Repeat doses are given based upon the follow-up measurement.

Inefficiency of intravenous magnesium supplementation — It must be appreciated that plasma magnesium


concentration inhibits magnesium reabsorption in the loop of Henle, the major site of active magnesium
transport. (See "Regulation of magnesium balance".) Thus, when an intravenous magnesium infusion is given,
an abrupt but temporary elevation in the plasma magnesium concentration will partially inhibit the stimulus to
magnesium reabsorption in the loop of Henle. Thus, up to 50 percent of the infused magnesium will be
excreted in the urine. In addition, magnesium uptake by the cells is slow and therefore adequate repletion
requires sustained correction of the hypomagnesemia.

Because of the inefficiencies of intravenous magnesium just described, oral replacement therapy should be
given to asymptomatic patients whenever the oral route of administration is available and oral magnesium
supplements can be tolerated.

Patients with no or minimal symptoms — If available and tolerable, oral replacement should be given to
the hypomagnesemic patient with no or minimal symptoms. However, many patients are unable to take oral
magnesium or have side effects such as gastrointestinal discomfort and diarrhea. Thus, many hospitalized
patients with hypomagnesemia are given intravenous rather than oral magnesium supplementation, even if
symptoms are minimal or absent.
Oral repletion if available and tolerable — A number of oral magnesium salts are available. Each differs in
the content of elemental magnesium, but all suffer from limited bioavailability. A typical daily dose in a
patient with normal renal function is 240 to 1000 mg (20 to 80 meq [10 to 40 mmol]) of elemental magnesium
in divided doses.

Sustained-release preparations have the advantage that they are slowly absorbed and thereby minimize renal
excretion of the administered magnesium. Available sustained-release preparations include: magnesium
chloride containing 64 to 71.5 mg elemental magnesium (eg, Mag Delay, Slow-Mag) and magnesium L-
lactate containing 84 mg elemental magnesium (eg, Mag-Tab SR). Six to eight tablets (30 to 56 meq [15 to 28
mmol]) should be taken daily in divided doses for severe magnesium depletion. Two to four tablets (10 to 28
meq [5 to 14 mmol]) may be sufficient for mild hypomagnesemia. The use of sustained-release preparations
may permit the use of lower doses, which minimizes the associated diarrhea (the major dose limiting side
effect).

If a sustained-release preparation is not available, magnesium oxide 800 to 1600 mg (20 to 40 mmol [40 to 80
meq]) daily in divided doses may be used for moderate to severe hypomagnesemia. Diarrhea frequently
occurs with magnesium oxide therapy.

Intravenous repletion in stable hospitalized patients — In some hospitalized patients, oral magnesium
supplementation may be unavailable or not tolerable (eg, in postoperative patients who cannot take
medications orally). Even if such patients with hypomagnesemia are asymptomatic or minimally
symptomatic, intravenous magnesium therapy can be used.

For routine intravenous repletion or maintenance in the inpatient setting, we use the following regimen in
which the dose and rate of repletion depends upon the plasma magnesium concentration [9,12]: severe
depletion (eg, <1 mg/dL), moderate (1 to 1.5 mg/dL) and mild (1.6 to 1.9 mg/dL combined with suspicion of
magnesium depletion) with an estimated repletion dose:

●If the plasma magnesium is less than 1 mg/dL (0.4 mmol/L or 0.8 meq/L), give 4 to 8 grams (32 to 64
meq [16 to 32 mmol]) over 12 to 24 hours, and repeat as needed.
●If the plasma magnesium is 1 to 1.5 mg/dL (0.4 to 0.6 mmol/L or 0.8 to 1.2 meq/L), give 2 to 4 grams
(16 to 32 meq [8 to 16 mmol]) over 4 to 12 hours.
●If the plasma magnesium is 1.6 to 1.9 mg/dL (0.7 to 0.8 mmol/L or 1.4 to 1.6 meq/L), give 1 to 2
grams (8 to 16 meq [4 to 8 mmol]) over one to two hours.
Correction of the underlying disease — The underlying disease should also be corrected, if possible.
Patients with hypomagnesemia induced by a thiazide or loop diuretic who cannot discontinue diuretic therapy
may benefit from the addition of a potassium-sparing diuretic such as amiloride. These drugs may decrease
magnesium excretion by increasing its reabsorption in the distal nephron [13]. (See "Effect of diuretics on
magnesium handling by the kidney".)

Amiloride also may be helpful in conditions associated with persistent urinary magnesium wasting such as
Bartter or Gitelman syndrome or cisplatin nephrotoxicity. In these settings, magnesium repletion alone may
be relatively ineffective since raising the plasma magnesium concentration will, as mentioned above, lead to
increased magnesium excretion. (See "Bartter and Gitelman syndromes".)

Treating patients with impaired renal function — In general, great caution should be exercised in treating
patients who have acute or chronic kidney injury with magnesium containing medications. However, patients
with reduced kidney function may require magnesium repletion if they have severe hypomagnesemia (ie, <1
mg/dL [0.4 mmol/L or 0.8 meq/L]).

There are no published data to guide therapy in such patients, and it is critical that the plasma magnesium
concentration be followed closely (ie, after each magnesium dose). In addition, the patient should be
monitored for signs of hypermagnesemia such as facial flushing, decreased tendon reflexes, hypotension, and
atrioventricular block. (See "Symptoms of hypermagnesemia".)

In the absence of published data, we take the following approach:

●A symptomatic patient who has moderately reduced kidney function (ie, estimated glomerular
filtration rate of 15 to 30 mL/min per 1.73 m2) and severe hypomagnesemia should be treated with 2 to 4
g of intravenous magnesium sulfate given slowly over 4 to 12 hours. The plasma magnesium should be
checked prior to subsequent doses, and daily if doses are given less frequently.
●Asymptomatic patients who have severe hypomagnesemia and moderately decreased kidney function
may be treated with approximately half the dose of the selected oral preparation that is recommended for
the patient with normal renal function. The plasma magnesium concentration should be measured before
giving a subsequent dose.

It would be extremely unusual for a patient with no kidney function (ie, on dialysis) to have severe
magnesium depletion in the absence of an extrarenal loss such as diarrhea. In such cases, treating the diarrhea
may be sufficient to correct the hypomagnesemia.

Duration of therapy — Serum magnesium levels usually rise quickly with therapy, but intracellular stores
take longer to replete. It is therefore advisable in patients with normal renal function to continue magnesium
repletion for at least one to two days after the serum magnesium concentration normalizes.
SUMMARY AND RECOMMENDATIONS
●Hypomagnesemia should be suspected in patients who have risk factors for hypomagnesemia (eg,
chronic diarrhea, proton pump inhibitor therapy, alcoholism, diuretic use) or clinical manifestations of
hypomagnesemia (eg, unexplained hypocalcemia, refractory hypokalemia, neuromuscular disturbances,
ventricular arrhythmias). (See 'Introduction' above.)
●If an etiology is not apparent from the history, gastrointestinal and renal losses may be distinguished by
measuring the 24-hour urinary magnesium excretion or the fractional excretion of magnesium on a
random urine specimen (calculator 1 and calculator 2). The daily excretion of more than 10 to 30 mg or
a fractional excretion of magnesium above 2 percent in a patient with normal renal function indicates
renal magnesium wasting. (See 'Evaluation' above.)
●Normomagnesemic magnesium depletion, or isolated cellular magnesium depletion, may be a cause of
refractory hypokalemia or unexplained hypocalcemia. Normomagnesemic magnesium depletion may be
detected by demonstrating reduced excretion of an infused magnesium load. Alternatively, magnesium
may be empirically administered to patients at high risk for magnesium depletion who have unexplained
hypocalcemia and/or hypokalemia. (See 'Normomagnesemic magnesium depletion' above.)
●The route of magnesium repletion varies with the severity of the clinical manifestations. Patients with
severe signs and symptoms of hypomagnesemia should receive intravenous magnesium with cardiac
monitoring. Oral replacement should be given to the asymptomatic outpatient, preferably with a
sustained-release preparation, in order to prevent abrupt elevations in the plasma magnesium
concentration. (See 'Patients with severe symptoms' above and 'Patients with no or minimal symptoms'
above.)
●The underlying disease should also be corrected, if possible. Patients with hypomagnesemia due to
renal losses may benefit from the addition of a potassium-sparing diuretic such as amiloride. (See
'Correction of the underlying disease' above.)
●In general, patients with reduced kidney function should not receive magnesium-containing
medications. However, patients with moderately reduced kidney function who have severe
hypomagnesemia may require magnesium repletion. The appropriate regimen for magnesium repletion
in such patients depends upon the presence or absence of signs and symptoms of hypomagnesemia. It is
critical that the plasma magnesium be followed closely (ie, after each dose), and the patient be
monitored for signs of hypermagnesemia. (See 'Treating patients with impaired renal function' above.)

Regulation of magnesium balance

INTRODUCTION — Magnesium balance, like that of other ions, is a function of intake and excretion. The
average daily magnesium intake is 360 mg (15 mmol). Approximately one-third of this magnesium is
absorbed, principally in the small bowel through both a saturable transport system (presumably mediated by a
channel encoded by the TRPM6 gene) and passive diffusion. (See "Causes of hypomagnesemia".)

Two other processes occur in the gut: the secretion of approximately 40 mg (1.7 mmol) in intestinal
secretions, and the absorption of another 20 mg (0.8 mmol) in the large bowel. In the healthy adult, there is no
net gain or loss of magnesium from bone so that balance is achieved by the urinary excretion of the
approximately 100 mg (4.1 mmol) that is absorbed. Changes in intake are balanced by changes in urinary
magnesium reabsorption, principally in the loop of Henle and the distal tubule.

UNITS OF MEASUREMENT — Before discussing the factors responsible for the regulation of magnesium
balance, it is useful to review the different units that may be used to measure the plasma (or serum)
magnesium concentration. Laboratories in the United States usually report the results in units of meq/L or
mg/dL, while other countries primarily use mmol/L. The relationship among these units can be expressed by
the following equations:

mmol/L = [mg/dL x 10] ÷ mol wt

meq/L = mmol/L x valence

Since the molecular weight of magnesium is 24.3 and the valence is +2, 1 meq/L is equivalent to 0.50 mmol/L
and to 1.2 mg/dL. Thus, a normal range of the plasma magnesium concentration of 1.4 to 1.7 meq/L is
equivalent to 0.70 to 0.85 mmol/L and 1.7 to 2.1 mg/dL.

RENAL HANDLING OF MAGNESIUM — Magnesium transport differs from that of most other ions in
that the proximal tubule is not the major site of reabsorption. Approximately 80 percent of the total plasma
magnesium is filtered at the glomerulus. Only 15 to 25 percent of the ultrafiltrable magnesium is reabsorbed
passively in the proximal tubule (down concentration gradients generated by the reabsorption of sodium and
water) and 5 to 10 percent in the distal tubule. Micropuncture studies (in which small pipettes are inserted into
different nephron segments) indicate that the major site of magnesium transport is the thick ascending limb of
the loop of Henle, where 60 to 70 percent of the ultrafiltrable magnesium is reabsorbed [1,2].
Loop of Henle — The bulk of magnesium transport in the thick ascending limb, like that of calcium, is
passive, occurring by paracellular diffusion between the cells and driven by the favorable electrical (lumen-
positive) gradient resulting from the reabsorption of sodium chloride (figure 1) [1,3-5]. This lumen-positive
voltage is generated by two distinct processes:
●Reabsorption of sodium, potassium, and chloride via the Na-K-2Cl cotransporter, with apical recycling
of potassium via ROMK channels back into the lumen, is thought to be the major contributor to the
electrical gradient (figure 2).
●Net reabsorption of sodium chloride dilutes the tubular fluid and generates a transepithelial
concentration gradient favoring backflux of sodium chloride from the peritubular to the tubular space.
The presence of a paracellular pathway that is selective for sodium over chloride ions generates an
electrical diffusion potential that augments the lumen-positive voltage, favoring additional reabsorption
of magnesium [6].

Paracellular magnesium reabsorption appears to be facilitated by a complex of two tight junction proteins,
specifically, claudin-16 (also known as paracellin-1) [7] and claudin-19 [8]. Their physiological roles are not
established. The major prevailing theories are:

●They may act as paracellular divalent cation pores and directly mediate magnesium reabsorption
[9,10].
●They may act primarily to form a Na-selective paracellular pore, thereby facilitating the generation of
the NaCl diffusion potential that contributes to the driving force for Mg reabsorption [11,12].

Factors controlling magnesium transport act through changes in the voltage and/or permeability of the
paracellular pathway. Thus, decreased reabsorption and magnesium wasting can be induced by the
administration of a loop diuretic, which inhibits sodium and chloride reabsorption, or by mutations in claudin-
16 or -19, which cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis [7,8]. (See "Effect
of diuretics on magnesium handling by the kidney" and "Causes of hypomagnesemia", section on 'Familial
hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC)' and "Causes of hypomagnesemia".)

Several other factors alter magnesium transport in the loop of Henle:

●Plasma magnesium concentration – Loop magnesium reabsorption (particularly in the cortical aspect
of the thick ascending limb) varies with changes in the plasma magnesium concentration, which is the
main physiologic regulator of urinary magnesium excretion [1,2]. Hypermagnesemia inhibits loop
magnesium (and calcium) transport, while hypomagnesemia stimulates magnesium transport in both
normal and magnesium-depleted animals, thereby decreasing further magnesium losses.
●Plasma calcium concentration – Hypercalcemia also inhibits magnesium (and calcium) reabsorption,
leading to hypermagnesuria and hypercalciuria. This seems to occur by activation of the calcium-sensing
receptor on the basolateral membrane of the thick ascending limb. Downstream of the calcium-sensing
receptor is a complex signaling sequence whereby calcineurin and NFATc1 stimulate the transcription of
two micro-RNAs, miR-9-1 and miR-374, that normally inhibit the expression of the tight junction
protein, claudin-14 [13-15]. Claudin-14, once expressed, physically binds to and inhibits the claudin-16
and -19 complex, thereby inhibiting Mg reabsorption. Further discussion of the role of this receptor in
the modulation of calcium and sodium transport is discussed separately. (See "Disorders of the calcium-
sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia".)
●Hormones – A number of hormones have been shown to alter magnesium transport in the thick
ascending limb in experimental studies. These include parathyroid hormone (PTH), calcitonin,
glucagon, arginine vasopressin (AVP), and the beta-adrenergic agonists, all of which are coupled to
adenylate cyclase in the thick ascending limb. Postulated mechanisms include an increase in luminal-
positive voltage (via activation of basolateral membrane chloride conductance and apical Na-K-2Cl
cotransport) and an increase in paracellular permeability (possibly by phosphorylation of paracellular
pathway proteins) [16]. It is not known if these effects have any important role in normal magnesium
homeostasis.
●Other factors – Metabolic alkalosis stimulates and metabolic acidosis, hypokalemia, and phosphate
depletion inhibit magnesium reabsorption in the loop of Henle, contributing to changes in urinary
magnesium excretion [1]. The mechanisms for these changes are unknown.
Distal reabsorption — Distal reabsorption of magnesium occurs in the distal convoluted tubule (DCT) via
transcellular transport (figure 3). It is important for the fine tuning of renal magnesium excretion and hence is
potentially a key step for physiological regulation.

Genetic diseases that produce hypomagnesemia have helped elucidate important components of distal
magnesium transport (see "Causes of hypomagnesemia"):

●Magnesium enters the DCT cells from the tubular lumen via a magnesium channel complex composed
of TRPM6 and TRPM7; this occurs passively, driven by a favorable electrical gradient produced by
potassium flux from the cell into the tubular lumen [17,18]. Passive influx of magnesium is believed to
be the rate-limiting step in distal magnesium reabsorption.
●Mutations in TRPM6 cause autosomal recessive hypomagnesemia with secondary hypocalcemia,
which is due both to impaired intestinal absorption of magnesium and a renal magnesium leak [19,20].
Several factors regulate TRPM6, including dietary magnesium [21], estrogens [21], and acid-base
balance [22]. In addition, epidermal growth factor (EGF) regulates TRPM6 by stimulating protein
trafficking to the plasma membrane [23]. This is why mutations in pro-EGF cause isolated renal
hypomagnesemia [24], as does treatment with EGF inhibitors such as cetuximab. As magnesium entry is
driven by the electrical gradient across the apical membrane, it is also regulated by the setpoint of the
membrane potential. Mutations in the apical voltage-gated potassium channel, Kv1.1, cause autosomal
dominant hypomagnesemia, presumably by altering the apical membrane potential [25].
●The mechanism for basolateral exit of magnesium in the DCT is incompletely understood. CNNM2
encodes a transmembrane protein that is localized to the basolateral membrane of the thick ascending
limb and DCT and has been proposed to function either as a magnesium channel [26] or magnesium-
sensitive sodium channel [27]. CNNM2 is also upregulated under conditions of magnesium deficiency
[26] and is mutated in dominant isolated renal magnesium wasting [27]. Thus, CNNM2 could be a
candidate for the basolateral exit pathway, although the driving force for magnesium exit is unclear.
●In addition, distal magnesium reabsorption is known to be dependent upon the gamma subunit of the
Na-K-ATPase (encoded by the FXYD2 gene) since mutations in FXYD2 [28], or in hepatocyte nuclear
factor 1B (that regulates transcription of FXYD2) [29], cause dominant isolated renal hypomagnesemia
and hypomagnesemia with renal malformations. Exactly how the gamma subunit of the Na-K-ATPase
regulates magnesium transport is unclear; it may determine the basolateral membrane sodium gradient
or ensure hyperpolarization of the membrane potential and hence drive apical magnesium entry.
●Mutations in the basolateral potassium channel, Kir4.1, cause a syndrome called SeSAME or EAST,
which consists of seizures, sensorineural deafness, ataxia, mental retardation, and various electrolyte
abnormalities that include renal magnesium wasting [30,31]. Kir4.1 is proposed to act by recycling
potassium across the basolateral membrane, thus facilitating Na-K-ATPase activity.

Distally acting diuretics can also affect magnesium handling. Chronic use of thiazide diuretics is associated
with hypomagnesemia and renal magnesium wasting; in addition, Gitelman syndrome, which is due to an
abnormality in the gene coding for the thiazide-sensitive cotransporter (NCC), is characterized by
hypomagnesemia due to urinary magnesium wasting [32]. (See "Bartter and Gitelman syndromes" and
"Causes of hypomagnesemia".)

Both thiazide diuretics and murine knockout of NCC downregulate TRPM6 expression; this likely explains
the mechanism of the magnesuria caused by thiazides and Gitelman syndrome [33]. In addition, the potassium
depletion associated with these conditions may contribute to the hypomagnesemia [1,34]. (See "Effect of
diuretics on magnesium handling by the kidney".)

In contrast to thiazides, amiloride is a magnesium-sparing diuretic, possibly acting by hyperpolarizing of the


membrane potential, thereby increasing the driving force for magnesium entry [35].

REGULATION OF PLASMA MAGNESIUM CONCENTRATION — In contrast to other ions,


magnesium is treated by the body as an orphan: there are no hormones that have a substantial role in
regulating urinary magnesium excretion, and bone, the principal reservoir of magnesium, does not readily
exchange with circulating magnesium. This is in marked contrast to the roles of aldosterone and atrial
natriuretic peptide in sodium excretion; antidiuretic hormone in water excretion; aldosterone and cell
potassium stores in the regulation of potassium balance; and parathyroid hormone (PTH), vitamin D,
calcitonin, and bone stores in the maintenance of calcium balance.
The inability to readily mobilize magnesium stores means that, with negative magnesium balance, the initial
losses come primarily from the extracellular fluid; equilibration with bone stores does not begin for several
weeks [36]. Thus, the plasma magnesium concentration falls rapidly with negative magnesium balance,
leading to a marked reduction in magnesium excretion, unless urinary magnesium wasting is present. (See
"Causes of hypomagnesemia".) It is the enhanced reabsorption in the loop of Henle and distal tubule and fall
in urinary magnesium excretion that protects the plasma magnesium concentration against further losses. The
fractional excretion of magnesium, which is between 3 and 5 percent in subjects with normal renal function
ingesting a typical diet, can fall to below 0.5 percent with magnesium depletion due to extrarenal losses [2].
(See "Evaluation and treatment of hypomagnesemia".)

Conversely, there is no protection against hypermagnesemia with loss of renal function. In this setting,
continued intake leads to magnesium retention that is predominantly in the extracellular fluid. (See "Causes
and treatment of hypermagnesemia".)

CELLULAR MAGNESIUM STORES AND CYTOSOLIC MAGNESIUM ACTIVITY — The total


intracellular magnesium content approximates 8 to 10 mmol/L (10 to 20 meq/L). However, most of the cell
magnesium is bound to ATP and other intracellular nucleotides and enzyme complexes. Some studies, using
magnesium-sensitive dyes based upon the FURA compound, indicate that the free cytosolic concentration is
in the range of 0.6 to 0.8 mmol/L (1.2 to 1.6 meq/L) [37]. Changes in the plasma magnesium levels alter
cellular magnesium content slowly. It is not yet known how magnesium enters cells, but energy is not
required because of the favorable electrochemical gradient. As the intracellular free magnesium is
significantly below electrochemical equilibrium, however, there must be some type of energy-dependent
extrusion mechanism [38]. An ATP-dependent sodium-magnesium exchanger has been described in several
tissues, but its physiologic importance is not known.
SUMMARY
●Magnesium balance is a function of intake and excretion. The average daily magnesium intake is 360
mg (15 mmol). Changes in intake are balanced by changes in renal magnesium reabsorption. (See
'Introduction' above.)
●Eighty percent of the total plasma magnesium is filtered at the glomerulus. Fifteen to 25 percent is
reabsorbed in the proximal tubule; 60 to 70 percent is reabsorbed in the thick ascending limb of the loop
of Henle; and 5 to 10 percent in the distal tubule. (See 'Renal handling of magnesium' above.)
●The majority of magnesium transport in the thick ascending limb occurs by paracellular diffusion
between the cells and is driven by the favorable electrical gradient resulting from the reabsorption of
sodium chloride. Diffusion is facilitated by tight junction proteins called claudin-16 and claudin-19. (See
'Loop of Henle' above.)
●The plasma magnesium concentration is the major physiologic regulator of urinary magnesium
excretion. Hypermagnesemia inhibits loop magnesium transport (thus increasing urinary excretion of
magnesium), while hypomagnesemia stimulates magnesium transport (inhibiting its excretion). Other
factors that decrease magnesium transport in the loop of Henle include hypercalcemia, metabolic
acidosis, hypokalemia, phosphate depletion, the administration of loop diuretics, and mutations in
paracellin-1 and related proteins. (See 'Loop of Henle' above.)
●Factors that alter distal tubule magnesium transport include diuretics and genetic mutations. Whereas
amiloride, a magnesium-sparing diuretic, stimulates magnesium transport, thiazide diuretics are
occasionally associated with magnesium wasting and hypomagnesemia. (See 'Distal reabsorption'
above.)
●Bone magnesium is the principal reservoir of magnesium. Because bone magnesium does not readily
exchange with circulating magnesium, the plasma magnesium concentration falls rapidly with negative
magnesium balance. This leads to a marked reduction in magnesium excretion, provided urinary
magnesium wasting is not present. (See 'Regulation of plasma magnesium concentration' above.)
●There is no protection against hypermagnesemia with loss of renal function. In this setting, continued
intake leads to magnesium retention that is predominantly in the extracellular fluid. (See 'Regulation of
plasma magnesium concentration' above.)