Normal magnesium physiology
1. How is magnesium measured?
The molecular weight of magnesium is 24.3 g/mol, with a 2+ valence (Mg2+). The normal serum magnesium level is 0.7 to 0.85 mmol/L, but it is often expressed as equivalents per liter, 1.4 to 1.7 mEq/L (mEq/L = mmol/L × valence), or in conventional units, 1.7 to 2.1 mg/dL (mg/dL = mmol/L × molecular weight divided by 10). Normal reference levels vary from laboratory to laboratory ( Table 77.1 ).
|UNITS||NORMAL MAGNESIUM CONCENTRATION|
2. Where is magnesium found in the body?
The average human body contains a total of 25 g of magnesium, which is roughly equivalent to 2000 mEq or 1 mole of magnesium. Nearly 99% of this magnesium is intracellular, with just over half trapped in bone. Only 1% is extracellular, a third of which (2.6 mmol) is present in plasma ( Fig. 77.1 ). Like calcium, only the ionized fraction of magnesium is metabolically active, and represents 55% to 70% of serum magnesium.
The intracellular magnesium concentration is 10 to 20 mM/L; however, the majority of this magnesium is bound to adenosine triphosphate (ATP), while a smaller potion is bound to nucleotides and proteins. Only 5% of the cytosolic magnesium (0.5 to 1 mM/L) is unbound.
3. What are the roles of magnesium?
Magnesium is a critical cofactor for over 600 enzymatic reactions. It maintains the stability of ATP as well as the tertiary structure of DNA. Given magnesium’s central role in ATP generation, it should not be a surprise that magnesium is important for muscle contraction, relaxation, normal neurological function, and release of neurotransmitters. Magnesium also has a role in DNA replication and repair, RNA transcription, amino acid synthesis, protein formation, and glucose metabolism.
There is evidence that magnesium has a role in insulin secretion, and some clinical trials have shown improved metabolic profiles in diabetics given magnesium supplementation.
4. What are the primary nutritional sources of magnesium?
Dietary sources of magnesium are primarily dark leafy vegetables, whole grains, nuts, beans, and seafood. A typical Western diet contains less than the FDA recommended 420 mg for males and 320 mg for women, because the soil in which fruits and vegetables are grown is depleted of magnesium. Also, Western diets are rich in refined grains, and as much as 90% of the Mg is lost in processing. Hard water is a source of dietary magnesium. Globally, magnesium intake has dropped due to increased consumption of processed (refined) grains and increased water softening.
5. How does the gastrointestinal (GI) tract absorb and excrete magnesium?
Only about a quarter, or 100 mg, of the ingested magnesium is absorbed by the GI tract and the rest is excreted. Much of the absorption takes place through passive paracellular transport, driven by an electrochemical gradient and solvent drag. There is a second active transport system mediated by TPRM 6 and 7 channels (TRPM stands for “transmembrane receptor potential subfamily melastatin”). The active magnesium transport becomes more active with low magnesium status and is downregulated with magnesium excess. This active transport system is more active in the terminal ileum and proximal colon ( Fig. 77.2 ).
6. What is different about kidney magnesium handling from other electrolytes?
Unlike most other electrolytes, where absorption takes place in the proximal tubule, magnesium reabsorption occurs predominantly at the thick ascending limb of the loop of Henle (TAH). That being said, roughly 20% of filtered magnesium is reabsorbed in the proximal tubule. About 70% of the filtered magnesium is absorbed in the thick ascending loop of Henle. This occurs through paracellular tight junctions down the electrical gradient. The electrical gradient is established by the renal outer medullary potassium (ROMK) channel, which allows intracellular potassium to flow into the tubule. Potassium is the rate-limiting reagent for the sodium, potassium, two chloride (NK2Cl) channel ( Fig. 77.3 ).
The kidneys are able to dynamically adjust the reabsorption of magnesium to respond to changes in magnesium levels. In the presence of low magnesium, fractional reabsorption of magnesium can rise to 99.5%. With magnesium excess, the fractional excretion of magnesium can fall to 30%.
7. What hormones regulate magnesium levels?
No known hormone has any appreciable effect on renal magnesium handling.
8. What is the difference between hypomagnesemia and magnesium deficiency?
Hypomagnesemia is defined as serum magnesium level less than 1.7 mg/dL (1.4 mEq/L or 0.7 mmol/L). However, since serum magnesium represents on 0.3% of total body magnesium, serum magnesium may not correspond with total body magnesium. Some patients with normal serum magnesium may have signs or symptoms of low magnesium. This is referred to as normomagnesemic magnesium depletion and should be considered in patients with risk factors for hypomagnesemia (alcoholics, patients with poorly controlled diabetes, or diarrhea), and refractory hypokalemia or unexplained hypocalcemia.
9. How common is hypomagnesemia and who is at risk for hypomagnesemia?
Hypomagnesemia is found in 10% of hospitalized patients. In the intensive care unit (ICU) this may be as high as 60%. Patients at risk include chronically malnourished, alcoholic, and patients with diabetes.
10. What type of GI disorders lead to hypomagnesemia?
GI losses occur with diarrhea and vomiting. Lower GI losses cause more hypomagnesemia due to a higher magnesium content in the secretions (up to 15 mEq/L with lower GI compared with 1 mEq/L with upper GI losses). This is particularly important in malabsorptive syndromes.
In acute pancreatitis, lipase metabolizes triglycerides to free fatty acids. The fatty acids are capped by carboxyl group with a charge of –1. The carboxyl group binds cations, specifically calcium and magnesium. The carboxyl complex precipitates out of solution lowering the calcium and magnesium. This process is called saponification .
Proton pump inhibitors can cause severe hypomagnesemia. The mechanism has not been fully worked out, but it appears that renal magnesium handling is intact and most attention is focused on active magnesium absorption by TRPMP6 channels in the terminal ileum and colon. It is hypothesized that the higher pH of intestinal secretions with proton pump inhibitor (PPI) decreases TPRM6/7 affinity for magnesium. It resolves with discontinuation of the drug but returns with rechallenge.
Primary intestinal hypomagnesemia is a rare congenital hypomagnesemic condition. Patients will typically also have renal magnesium wasting, because the molecular defect in the apical magnesium channel, TRPM6, is also found in the kidney. The condition has variable inheritance. It typically presents in infancy and early childhood but can present in young adults.
11. What type of kidney disorders lead to hypomagnesemia?
Kidney magnesium losses are increased with increased urine output. This occurs with diuretics, osmotic diuresis (as seen in diabetes), excessive intravenous saline, postobstructive diuresis, the recovery phase of acute tubular necrosis (ATN), and following a kidney transplant.
Loop diuretics specifically disrupt the NaK2Cl channel needed to generate the positive tubular lumen charge that drives magnesium and calcium reabsorption in the TAH. Thiazide diuretics induce hypomagnesemia by preventing the distal absorption of magnesium.
Hypercalcemia increases kidney magnesium wasting through a mechanism similar to that of loop diuretics. The cells of the TAH have a calcium-sensing receptor (CaSR) on the basolateral membrane. When activated, the CaSR antagonizes the ROMK channel, preventing the generation of the positive luminal charge that drives magnesium reabsorption ( Fig. 77.3 ).
A number of other drugs can cause hypomagnesemia through increased kidney loss of magnesium, including:
Epidermal growth factor (EGF) monoclonal antibodies
Chronic ethanol abuse causes a kidney magnesium leak. It can take weeks of abstinence to reverse this injury. In addition to the kidney leak, these patients often have poor dietary magnesium and increased GI losses, which contributes to the hypomagnesemia.
There are numerous inherited magnesium wasting nephropathies; none of them are common. The two most well known are Gitelman syndrome and Bartter syndrome.
Gitelman syndrome is an autosomal recessive disorder resulting from an inactivating mutation of the thiazide-sensitive sodium chloride cotransporter gene (NCCT) of the distal convoluted tubules. These patients present with signs and symptoms of chronic thiazide ingestion, including mild salt wasting, volume depletion, hypokalemia, metabolic alkalosis, and hypomagnesemia.
Bartter syndrome is a kidney sodium wasting nephropathy that mimics chronic loop diuretic use. It is typically autosomal recessive, though there is an autosomal-dominant form. Patients typically have low blood pressure, hypokalemia, metabolic alkalosis, hypocalcemia, and hypomagnesemia. The hypomagnesemia tends to be less severe than that seen in Gitelman syndrome.
The congenital kidney magnesium wasting syndromes are summarized in Table 77.2 .
|Gitelman (most common)||AR||Thiazide-sensitive sodium chloride cotransporter (SLC12A3)||Children/adolescents/adults with salt wasting, hypokalemic metabolic alkalosis, and hypocalciuria|
|Bartter syndrome||AR||Loop-sensitive sodium, potassium, 2Chloride channel (Na-K-2Cl)||Neonate/Infancy with salt wasting, hypokalemic metabolic alkalosis, and hypercalciuria|
|Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC)||AR||Caludin-16 gene||Children/adolescent with hypercalciuria , recurrent nephrocalcinosis, and progressive renal failure|
|Isolated dominant hypomagnesemia with hypocalciuria||AD||Gamma subunit of Na-K-ATPase pump resulting in misrouting||Children with hypomagnesemia and hypocalciuria and no stones|
|Voltage-gated potassium channel||AD||Voltage-gated potassium channel (KCNA1), which interacts with TMRP6||Isolated hypomagnesemia and renal magnesium wasting|