Aetiology

Magnesium deficiency can be caused by decreased magnesium intake from the diet, decreased magnesium absorption, or increased renal magnesium excretion (renal magnesium wasting). Deficiency may result in an associated hypomagnesaemia, which depends on the severity of the magnesium loss and the effectiveness of the compensatory homoeostatic responses. Hypomagnesaemia without magnesium deficiency can be caused by modest acute magnesium losses that deplete circulating magnesium, or by redistribution of extracellular magnesium to the intracellular compartment.

Nutritional

Dietary magnesium deficiency

  • Dietary deficiency is the most common cause. Dietary sources of magnesium include green vegetables, fruits, fish, fresh meat, and cereals.[14]​ Magnesium dietary intake in the US has been decreasing, most likely due to the increasing use of processed foods and fertilisers.[15]​ 

  • Diabetic patients with poor magnesium intake are prone to hypomagnesaemia.

Malnutrition

  • Magnesium deficiency can also occur in generalised malnutrition, especially in patients with alcoholism, or those with decreased food intake in the prolonged postoperative state.

Toxic/iatrogenic

Drug-induced[16][17]​​

  • Medications can induce renal magnesium wasting. Thiazide diuretics inhibit the sodium-chloride co-transporter, decreasing the voltage gradient that drives magnesium reabsorption. Other diuretics increase magnesium loss by increasing tubular flow.

  • Proton pump inhibitors (PPIs) reduce intestinal magnesium absorption through TRPM6 and produce renal magnesium wasting by an unknown mechanism.[18][19] The incidence of severe hypomagnesaemia associated with PPI use is increasing. The US FDA has issued a warning about this iatrogenic complication. Serum magnesium level should be carefully monitored in patients taking a PPI in conjunction with anti-arrhythmic drugs.[20]

  • Digitalis increases intracellular sodium and calcium levels, with a resultant displacement and loss of magnesium.

  • Ciclosporin (cyclosporine) and cisplatin impair renal reabsorption, and promote renal excretion of magnesium.[21][22]

  • Cetuximab inhibits the extracellular growth factor receptor (EGFR), which controls magnesium channels.[21]

  • Antibiotics such as aminoglycosides, gentamicin, and tobramycin inhibit renal reabsorption in the loop of Henle.

  • Insulin causes increased intracellular uptake of magnesium, and can therefore produce hypomagnesaemia.[17]

Alcohol misuse[17][23]

  • Magnesium deficiency is due partly to alcohol-induced osmotic diuresis, leading to renal magnesium wasting, and partly to associated malnutrition.

Other causes

  • Laxative abuse increases the production and loss of gastrointestinal (GI) secretions, which contain large amounts of magnesium.[17]​ Volume expansion due to intavenous fluids impairs passive magnesium transport, leading to renal magnesium wasting.[24]

Gastrointestinal

Secretory diarrhoea

  • Upper GI secretions contain 0.5 mmol/L (1 mEq/L) magnesium, and lower GI secretions contain 7.5 mmol/L (15 mEq/L) magnesium. Any condition that significantly increases GI secretions can produce excessive magnesium loss. Common examples include gastroenteritis (due to any cause), inflammatory bowel disease, GI cancers, and Whipple's disease.[24][25]

Malabsorption syndromes

  • Magnesium absorption occurs in the ileum; it can be decreased by malabsorption syndromes such as coeliac disease, or by short gut syndrome produced by extensive bowel resection or radiation enteritis.[24]

Pancreatitis

  • The aetiology of magnesium loss is multifactorial. Acute pancreatitis causes hypomagnesaemia by increasing magnesium and calcium deposition into areas of fat necrosis. In chronic pancreatitis, patients may develop a malabsorption syndrome, leading to magnesium deficiency.[26]​ In addition, some magnesium loss may occur due to increased magnesium level in pancreatic secretions.

Cirrhosis[27]

  • In the liver, cirrhosis produces volume expansion, which impairs passive magnesium transport, leading to renal and faecal magnesium wasting.

Endocrine

Diabetic ketoacidosis

  • Osmotic diuresis, which occurs in diabetic ketoacidosis, leads to renal magnesium wasting.

  • Insulin therapy given to treat diabetic ketoacidosis also produces hypomagnesaemia, by causing a shift of magnesium into the intracellular compartment.[17][24]​​

Hyperaldosteronism[28]

  • Elevated aldosterone level increases sodium retention by the kidneys, leading to an expansion of intravascular volume. This, in turn, impairs passive magnesium transport, leading to renal magnesium wasting.

Hypoparathyroidism

  • Decreased parathyroid hormone (PTH) level leads to decreased mobilisation of magnesium from bone, producing hypomagnesaemia, as well as to renal magnesium wasting, which results in magnesium deficiency. Hypomagnesaemia, in turn, can cause PTH resistance and decreased PTH secretion.[29]

Hyperthyroidism[30]

  • Increased thyroid hormone level produces renal magnesium wasting, leading to magnesium deficiency and hypomagnesaemia. The hypomagnesaemia is exacerbated by concurrent stimulation of magnesium uptake into cells.

Hungry bone syndrome[24]

  • Hyperparathyroidism and hyperthyroidism produce an increase in bone turnover. When PTH or thyroid hormone levels are rapidly normalised following a parathyroidectomy or a thyroidectomy, osteoclast activity normalises faster than osteoblast activity. This leads to a net uptake of calcium, phosphate, and magnesium into bone, which can cause severe hypomagnesaemia and hypocalcaemia.

Renal

Recovery phase of acute tubular necrosis[24]

  • Acute tubular necrosis is caused by ischaemic or nephrotoxic injury to renal tubular epithelial cells, which results in cell death or detachment from the basement membrane.

  • The pathogenesis has three stages. The initiation phase involves an acute decrease in glomerular filtration, produced by worsening injury. The maintenance phase is a period of established renal injury associated with renal failure. During the recovery phase, the injury is repaired and renal function recovers; the diuresis that occurs during this phase can produce magnesium wasting.

Renal tubular acidosis

  • Includes a range of disorders in which the excretion of fixed acid (in distal disease) or the reabsorption of filtered bicarbonate (in proximal disease) is impaired, to a degree disproportionate to any existing impairment of glomerular filtration rate. The acid retention or bicarbonate loss results in the development of hyperchloraemic metabolic acidosis.

  • Magnesium wasting occurs because of increased renal flow, loss of the voltage gradient that drives magnesium re-uptake, or direct toxic damage to the kidney.

Post-obstructive diuresis

  • Patients with obstructive uropathy develop diuresis once the obstruction is relieved, as a physiological response to volume expansion, and local accumulation of solutes in the obstructed kidney. The condition can cause magnesium wasting. The diuresis typically resolves once homoeostasis is achieved, but may progress to a pathological form.

Primary renal magnesium wasting

  • Encompasses a range of genetic conditions in which there is a loss of function of magnesium channels, their regulatory receptors, or the transporters that generate the voltage gradient to drive magnesium reabsorption. These conditions may be caused by mutations in TRPM6, claudins,​​ renal Na/K-ATPase, thiazide-sensitive sodium-chloride co-transporter (Gitelman's syndrome and Bartter's syndrome),​​ or the calcium sensing receptor.[5][31][32][33][34][35]​​[36]

Obstetric

Pregnancy

  • Produces an expansion in plasma volume and an increase in magnesium demand, which can lead to hypomagnesaemia if magnesium intake is not increased. Hypomagnesaemia is associated with premature labour.[37]

Pre-eclampsia

  • Patients with pre-eclampsia and eclampsia have lower serum magnesium levels than normal pregnant patients.[38][39] It is not known whether hypomagnesaemia is a cause or a consequence of this condition.

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