5th April 2024

Disorders of Magnesium

Magnesium is the second most abundant intracellular and fourth most extracellular cation in the human body, with normal plasma concentrations between 0.70 – 0.85 mmol/L. It is required for the following physiological functions:

• Enzyme processes involving ATP – to be biologically active, ATP must be bound to a magnesium ion 
• Protein synthesis (including DNA and RNA) where magnesium is a cofactor
• Cardiac excitability – magnesium regulates ion transporters, including potassium and calcium channels
• Glucose metabolism – insulin secretion requires magnesium. Deficiency results in impaired insulin secretion
• Regulation of parathyroid hormone secretion

Magnesium is also involved in cellular proliferation and apoptosis; mitochondrial function, neuromuscular excitability, vasomotor tone and blood pressure regulation. 

There is evidence for the efficacy of magnesium in pre-eclampsia, eclampsia, asthma and arrhythmia. Given its role in a wide range of physiological activity, changes in concentration can have a sweeping impact on many bodily functions. 

The majority of magnesium (65%) is sequestered in bone with the remaining in soft tissue cells and about 1% in extracellular fluid. Sources of magnesium include whole grains, spinach, nuts, potatoes and legumes. The plasma concentration is a reflection of dietary magnesium intake and the ability of the gastrointestinal tract and kidneys to retain it. 

Hypermagnesemia

This is defined as serum magnesium levels of greater than 1 mmol/L and is less common than hypomagnesaemia. In health, excess magnesium intake is excreted by the kidneys. Hypomagnesaemia is encountered in:

• End stage renal failure due to impaired excretion 
• When taking medications containing magnesium (antacids, laxatives and enemas)
• Parenteral nutrition
• In pregnancy, if treated with intravenous magnesium for eclampsia or preeclampsia. 

Causes of mild hypermagnesemia include hypercalcaemia, hypothyroidism, Addison’s disease, dialysis and lithium therapy.

Clinical manifestations 

Features of hypermagnesaemia depend on approximate serum concentrations: 

• 2.0 -3.5 mmol/L – nausea and vomiting, flushing and ECG changes
• 4.0 – 5.0 mmol/L – hypotension, absent deep tendon reflexes, drowsiness and slurred speech
• > 6.0 mmol/L – respiratory depression, coma and paralytic ileus
• > 8.0 mmol/L – cardiac arrest and complete heart block

Investigations 

In addition to checking serum magnesium levels, calcium levels should be taken as often there is hypocalcaemia present. 

Where hypermagnesemia is recurrent or unexplained thyroid function tests and early morning cortisol tests should be performed to investigate Addison’s disease. 

ECG changes in hypermagnesemia include an increased PR interval, broad QRS complexes and Qt prolongation.

Management 

The extent of hypermagnesaemia and presence of comorbidities such as renal failure determines whether treatment is required. A person with normal renal function and good urine output who has received intravenous magnesium for eclampsia will be able to correct the resultant hypermagnesaemia without further treatment. In contrast, a patient with significant renal impairment impacting renal excretion of magnesium, who received a magnesium containing enema, will be at risk of problematic hypermagnesaemia and require treatment.  

For mild hypermagneseamia (2.0 – 4.0 mmol/L) or in asymptomatic patients the source of magnesium should be identified and removed; good urine output maintained and serum concentrations checked after 24 hours. 

Treatment is indicated with senior support and intensive care team involvement where serum magnesium concentrations are > 4.0 mmol/L or if there are significant features of hypermagnesaemia:

• Calcium salts, such as 10 ml of 10% calcium gluconate, administered as a slow intravenous injection over five minutes, are used to antagonise the neuromuscular and cardiovascular side effects of magnesium. Administration may be repeated in arrhythmias. 
• Continuous cardiac monitoring 
• Regular monitoring of serum magnesium levels
  

Hypomagnesemia

This is defined as serum magnesium concentrations < 0.7 mmol/L and may be caused by malabsorption syndromes, including Coeliac and inflammatory bowel disease, chronic diarrhoea, short bowel syndrome and prolonged nasogastric suctioning. Other causes include:

• Protein calorie malnutrition – anorexia nervosa
• Parathyroid gland disorders – low magnesium suppresses PTH release and blunts the end organ response to PTH. The resulting hypocalcaemia is refractory to replacement until magnesium is replete. 
• Chronic alcohol excess
• Diabetes where poor glycaemic control results in glucose-induced diuresis
• Medications – proton pump inhibitors, diuretics, digoxin, calcineurin inhibitors, theophylline, cisplatin and some aminoglycosides
• Renal disorders resulting in reduced resorption – renal tubular acidosis, post obstructive diuresis, acute tubular necrosis
• Refeeding syndrome 
• Severe burns
• Acute pancreatitis

Clinical manifestations 

Hypomagnesaemia is usually asymptomatic until levels reach < 0.5 mmol/L, and it is commonly associated with other metabolic abnormalities such as hypokalaemia, hypocalcaemia and metabolic acidosis. Cardiovascular manifestations of hypomagnesaemia include both ventricular and supraventricular dysrhythmias such as atrial fibrillation, premature atrial and ventricular complexes and ventricular tachycardia. 

Neuromuscular features of low magnesium include:

• Tremor
• Weakness
• Paraesthesia
• Tetany
• Muscle fasciculations
• Seizures, confusion and coma

Investigations 

As a small amount of total body magnesium is extracellular, serum magnesium may be normal in early mild deficiency and a more accurate picture can be obtained with ionised magnesium levels. The majority of extracellular magnesium is protein bound; therefore protein levels are important as protein loss can affect the reading. 

Calcium, phosphate and potassium levels should be checked as hypomagnesaemia is associated with hypokalemia,  hypocalcemia and hypophosphatemia. Due to the association with diabetes, glucose levels should be checked. 

The ECG in hypomagnesaemia may include broad QRS complexes, Qt interval and PR prolongation.  

To determine the cause of low magnesium, 24-hour urinary magnesium excretion is sometimes used, with high urinary levels indicating renal wasting. Fractional excretion of magnesium provides a ratio which is useful to determine if the cause is renal or extra-renal. 

Management 

The cause of low magnesium should be identified and any contributing medications stopped where possible. Oral replacement can be used for biochemical hypomagnesaemia in asymptomatic patients but severe deficiency requires intravenous replacement with magnesium sulphate. Local guidelines should be followed and the maximum infusion rate should not exceed 2 g/hour. Serum magnesium or 24-hour urinary magnesium excretion may be monitored to measure response to treatment. 

References

• Magnesium metabolism and its disorders. PubMed. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1855626/
• Magnesium disorders. Patient information professional article. Available at: https://patient.info/doctor/magnesium-disorders