Hypomagnesemia: a clinical perspective

Figures & data

Figure 1 Number of PubMed citations (November 2013).

Table 1 Magnesium functions and hypomagnesemia related clinical manifestations

General functions	Specific involvement	Signs/symptoms and altered metabolisms associated with hypomagnesemia*
Enzymatic activities: functioning as substrate or direct enzyme activation	Kinases, ATPases or GTPases, cyclases, phosphofructokinase, creatine kinase, 5-phosphoribosyl-pyrophosphate synthetase, adenylate cyclase, Na^+-K^+-ATPase	Altered glucose metabolism, electrolyte imbalances (hypokalemia, hypocalcemia), osteoporosis, enhanced digoxin sensitivity, enhanced apoptosis, arrhythmias, atherosclerosis
Membrane function	Cell adhesion, transmembrane electrolyte flux	Arrhythmias: atrial tachycardia and fibrillation, supraventricular and ventricular arrhythmias, Torsade de pointes, rhabdomyolysis, hemolysis, myocardial infarction
Calcium antagonist	Neuromuscular function	Neuromuscular hyperexcitability: tremors, fasciculation, tetany, convulsions, neuropsychiatric changes, eg, apathy, depression, psychosis, vertigo, nystagmus, athetoid movements and choreiform movements, migraine, asthma (reactive airways), impaired exercise performance, electrolyte imbalances (hypokalemia, hypocalcemia), hypertension, atherosclerosis
Structural function, ion complex formation	Proteins, polyribosomes, nucleic acids, multiple enzyme complexes, mitochondria, ion complexes	Enhanced apoptosis, osteoporosis, kidney stones

Notes: Copyright © 2003. Australasian Association of Clinical Biochemists. Adapted from Swaminathan R. Magnesium metabolism and its disorders. Clin Biochem Rev. 2003;24(2):47–66.³

* Signs and symptoms are listed based on possible and/or presumed mechanisms of hypomagnesemia-induced defective structural or physiological functions. Many signs and symptoms are multifactorial, not fully understood, and beyond the scope of the current paper.

Abbreviations: ATPase, adenosine triphosphatase; GTPase, guanosine triphosphatase; Na⁺-K⁺-ATPase, sodium-potassium adenosine triphosphatase.

Figure 2 Kidney handling of magnesium.

Abbreviations: CLD, claudin; TRPM6, transient receptor potential channel 6.

Figure 3 Magnesium reabsorption at the distal convoluted tubule.

Table 2 Congenital causes of hypomagnesemia

Sources of magnesium loss	Sites of defect in magnesium metabolism		Congenital
Gastro-intestinal absorption	Passive reabsorption
	Active reabsorption	TRPM6	Hypomagnesemia with secondary hypocalcemia
Cellular shift; tissue sequestration	–		–
Kidney handling	Glomerular filtration		–
	Proximal tubular reabsorption		Proximal renal tubular acidosis with or without associated Fanconi’s syndrome
	Thick ascending limb of loop of Henle	Claudin-16	Familial hypomagnesemia with hypercalciuria, and nephrocalcinosis
		Claudin-19	Familial hypomagnesemia, with hypercalciuria, nephrocalcinosis, and ocular manifestation
		NKCC2	Antenatal Bartter syndrome type 1 with low-normal serum magnesium
		ROMK	Antenatal Bartter syndrome type II with low-normal serum magnesium
		ClC-Kb	Classic Bartter syndrome type III, hypomagnesemia in 20%
		CaSR	Bartter syndrome type V
	Distal convoluted tubule:	TRPM6	Hypomagnesemia, secondary hypocalcemia
			Apical regulators/effectors of TRPM6
		Kv1.1	Isolated autosomal dominant hypomagnesemia
		Kir4.1/Kir5.1	Kir4.1 mutation: SeSAME/EAST syndrome; Kir5.1 mutation: hypomagnesemia, hypokalemia, hyperchloremic metabolic acidosis and hypercalciuria
		NCCT	Gitelman syndrome
			Basolateral regulators/effectors of TRPM6
		Na^+-K^+-ATPase	FXYD2: autosomal dominant hypomagnesemia with hypocalciuria; HNF1B: renal cysts and diabetes mellitus with renal magnesium wasting and hypocalciuria
		EGF	Isolated recessive hypomagnesemia with normocalciuria
		CaSR	Activating mutations
		CNNM2	Autosomal dominant hypomagnesemia
			Hormonal regulators of TRPM6
		Insulin	TRPM6 polymorphisms Ile1393Val and Lys1584Glu: reduced insulin activation of TRPM6, particularly if low dietary magnesium intake; tendency for diabetes mellitus
Other sources of loss	Nonspecific tubular injury/cellular leak		–
		Other	–

Abbreviations: NKCC2, sodium potassium 2 chloride cotransporter; ROMK, renal outer medullary potassium channel; ClC-Kb, chloride channel Kb; CaSR, calcium sensing receptor; Kv1.1, potassium voltage-gated channel subfamily A member 1; Kir4.1/Kir5.1, inward-rectifier type potassium channel 4.1/5.1 dimer; NCCT, sodium chloride cotransporter; Na⁺-K⁺-ATPase, sodium-potassium adenosine triphosphatase; HNF1B, hepatocyte nuclear factor 1 homeobox B; EGF, epidermal growth factor; CNNM2, cyclin M2; TPRM 6, transient receptor potential melastatin 6; SeSAME/EAST syndrome, SEizures, Sensorineural deafness, Ataxia, Mental retardation, and Electrolyte imbalance Epilepsy, Ataxia, Sensorineural deafness, and renal Tubulopathy.

Table 3 Acquired causes of hypomagnesemia

Sources of magnesium loss	Sites of defect in magnesium metabolism		Acquired
Gastro-intestinal absorption	Passive reabsorption		Low dietary Mg^2+ intake; prolonged nasogastric suction; diarrhea; enteric fistulas; steatorrhea; short-gut syndrome; alcoholism
	Active reabsorption	TRPM6	See DCT TRPM6 below
Cellular shift; tissue sequestration	–		Acute pancreatitis (magnesium and calcium saponification in necrotic fat); hungry bone syndrome; refeeding syndrome; foscarnet (magnesium incorporation into bone matrix following complex formation with foscarnet); massive blood transfusions; third trimester pregnancy; lactation; excessive parenteral alimentation; cardiopulmonary bypass
Kidney handling	Glomerular filtration		Hyperfiltration (diabetes mellitus, post-obstructive or acute tubular necrosis diuresis, osmotic diuresis, post-kidney transplantation); extracellular volume expansion; increased filterable Mg (metabolic acidosis, low organic anions)
	Proximal tubular reabsorption		Acquired Fanconi’s syndrome, drug toxicity (cisplatin, gentamicin, pentamidine); high dietary salt intake
	Thick ascending limb of loop of Henle	Claudin-16	–
		Claudin-19	–
		NKCC2	Loop diuretics; hypokalemia
		ROMK	Hypokalemia
		ClC-Kb	–
		CaSR	Increase in serum calcium and magnesium; aminoglycosides
	Distal convoluted tubule:	TRPM6	Calcineurin inhibitors (cyclosporine and tacrolimus shown to reduce renal TRPM6 expression); rapamycin (reduced TRPM6 messenger (m)RNA stability); chronic metabolic acidosis
			Apical regulators/effectors of TRPM6
		Kv1.1	Hypokalemia
		Kir4.1/Kir5.1	–
		NCCT	Thiazide diuretics; cyclosporine
			Basolateral regulators/effectors of TRPM6
		Na^+-K^+-ATPase	Hypophosphatemia; calcineurin inhibitors (cyclosporin shown to inhibit Na^+-K^+-ATPase); ethanol (inhibits Na^+-K^+-ATPase activity)
		EGF	Anti-EGF receptor antibodies (cetuximab, panitumumab); cisplatin (reduced EGF and TRPM6 mRNA); cyclosporine (reduce TRPM6, NCC, EGF mRNA)
		CaSR	Increase in serum calcium and magnesium; aminoglycoside (gentamicin, amikacin); ?cinacalcet
		CNNM2	–
			Hormonal regulators of TRPM6
		Insulin	Diabetes mellitus?
Other sources of loss	Nonspecific tubular injury/cellular leak		Amphotericin; pentamidine
		Other	Severe burns (skin loss)

Abbreviations: NKCC2, sodium potassium 2 chloride cotransporter; ROMK, renal outer medullary potassium channel; ClC-Kb, chloride channel Kb; CaSR, calcium sensing receptor; Kv1.1, potassium voltage-gated channel subfamily A member 1; Kir4.1/Kir5.1, inward-rectifier type potassium channel 4.1/5.1 dimer; NCCT, sodium chloride cotransporter; Na⁺-K⁺-ATPase, sodium-potassium adenosine triphosphatase; EGF, epidermal growth factor; CNNM2, cyclin M2; NCC, Thiazide-sensitive sodium chloride channel; TPRM6, transient receptor potential melastatin 6; DCT, distal convoluted tubule.

Table 4 Selected food sources of magnesium

Food	mg per serving	Percent daily value
Almonds, dry roasted, 1 ounce	80	20
Spinach, boiled, ½ cup	78	20
Cashews, dry roasted, 1 ounce	74	19
Peanuts, oil roasted, ¼ cup	63	16
Cereal, shredded wheat, 2 large biscuits	61	15
Soymilk, plain or vanilla, 1 cup	61	15
Black beans, cooked, ½ cup	60	15
Edamame, shelled, cooked, ½ cup	50	13
Peanut butter, smooth, 2 tablespoons	49	12
Bread, whole wheat, 2 slices	46	12
Avocado, cubed, 1 cup	44	15
Potato, baked with skin, 3.5 ounces	43	11
Rice, brown, cooked, ½ cup	42	11
Yogurt, plain, low fat, 8 ounces	42	11
Breakfast cereals, fortified with magnesium	40	10

Note: Adapted from US Department of Health and Human Services. National Institutes of Health. Magnesium fact sheet for health professionals. Available from ods.od.nih.gov/factsheets/Magnesium-HealthProfessional/#h3.⁸³

Table 5 Common oral magnesium formulations

Common formulations	Trade names	Elemental magnesium content (mg)
Magnesium oxide	Mag-Ox 400 tablets (400 mg)	241
	Uro-Mag capsules (140 mg)	84
Magnesium gluconate	Magnesium gluconate tablets (500 mg)	27
Magnesium chloride	Slow-Mag tablets (535 mg plus 212 mg calcium)	64
Magnesium oxide with soy protein	Mg Pro Plus tablets (133 mg plus 26 mg soy protein)	133
Magnesium L-lactate dihydrate	Mag Tab SR tablets (84 mg)	84
Magnesium-L-aspartate hydrochloride	Maginex tablets (615 mg)	61

Notes: Mag-Ox 400, Uro-Mag, Blaine Pharmaceuticals, Santa Fe Springs, CA, USA; Magnesium gluconate 500 mg, eg, Mag-G, Pernix Therapeutics, Houston, TX, USA; Slow-Mag, Purdue Pharma LP, Stamford, CT, USA; Mg Plus Protein, Miller Pharmacal Group, Inc., Carol Stream, IL, CA, USA; Mag Tab SR, Niche Pharmaceuticals, Southlake, TX, USA; Maginex 615 mg, Health Care Prod/Hi-Tech, Amityville, NY, USA.

Abbreviation: SR, slow release.

SwaminathanRMagnesium metabolism and its disordersClin Biochem Rev2003242476618568054

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US Department of Health and Human Services. National Institutes of HealthMagnesium fact sheet for health professionals Available from ods.od.nih.gov/factsheets/Magnesium-HealthProfessional/#h3Accessed March 27, 2014

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