HYPOMAGNESEMIA

PRESENTED BYSHREYA JHA

The total body stores of magnesium are between 21 and 28 g in the average 70 kg adult.

Normal serum magnesium usually has a range of 1.7 to 2.5 mg/dL.

Most of the body's magnesium is in the skeletal bone mass, which accounts for more than 50% of the body's stores.

The remainder is located in soft tissue, of which only 1% is located extracellularly.

Magnesium is the second-most abundant intracellular cation and, overall, the fourth-most abundant cation.

Intracellular magnesium is an important cofactor for various enzymes, transporters, and nucleic acids that are essential for normal cellular function, replication, and energy metabolism

In plasma• 60% of Mg exists as physiologically active

ionised form

• 30% is protein bound mainly to albumin

• remaining 10 % forms complexes with plasma anions such as phosphates and citrates

About 30-40% of dietary magnesium (140–360 mg/d) is absorbed, principally in the jejunum and ileum.

Absorption is stimulated by 1,25(OH)2 D.

Magnesium excretion in urine usually matches net intestinal absorption (100 mg/d).

METABOLISM

Serum magnesium concentration is regulated by renal magnesium reabsorption.

Parathyroid hormone increases magnesium reabsorption in the cTAL, whereas hypercalcemia and hypermagnesemia inhibit magnesium reabsorption.

About 60% of magnesium is reabsorbed in the cortical thick ascending limb of loop of Henle (cTAL), whereas 20% of filtered magnesium is reabsorbed in the proximal tubule, and another 5–10% in the distal convoluted tubule.

PROXIMAL TUBULE• Mg absorption in the proximal tubule is

dependant on the filtered load as well as net salt and water reabsorption.

RENAL HANDLING

THICK ASCENDING LIMB OF LOOP OF HENLE

• Paracellular Mg transport is driven by a favorable lumen positive electrochemical gradient which is generated by a transcellular reabsorption of NaCl

• It is dependant on the activity of Na+-k+-cl- cotransporter, renal outer medullary channel, Na+-k+-ATPase pump and renal Cl- channel

• Claudins are the major components of tight-junction strands in the TAL, where the reabsorption of magnesium occurs

DISTAL CONVOLUTED TUBULE• The transport rate in this segment defines the

final urinary Mg+ concentration as no reabsorption takes place beyond this level

• The cells in this nephron segment have highest energy consumption of the nephrons

• Na+-cl- cotransporter, which is exclusively present in the DCT is important for active reabsorption of Mg

Approx 3% of filtered Mg is excreted in the urine

Hypomagnesemia is an electrolyte disturbance in which there is an abnormally low level of magnesium in the blood.

Hypomagnesemia is not necessarily magnesium deficiency. Hypomagnesemia can be present without magnesium deficiency and vice versa.

HYPOMAGNESEMIA

I. Related to decreased Mg intake Starvation Alcohol dependence Total parenteral nutrition

II. Related to redistribution of Mg from ECF to ICF

Hungry bone syndrome Treatment of diabetic ketoacidosis Alcohol withdrawal syndromes Refeeding syndrome Acute pancreatitis

CAUSES

III. Related to GI Mg loss Diarrhea Vomiting and nasogastric suction Gastrointestinal fistulas and ostomies Hypomagnesemia with secondary

hypocalcemia (HSH)

IV. Related to renal Mg loss Gitelman syndrome Classic Bartter syndrome (Type III Bartter

syndrome) Familial hypomagnesemia with hypercalciuria and

nephrocalcinosis (FHHNC) Autosomal-dominant hypocalcemia with

hypercalciuria (ADHH) Isolated dominant hypomagnesemia (IDH) with

hypocalciuria Isolated recessive hypomagnesemia (IRH) with

normocalcemia

DRUGS Diuretics - Loop diuretics, osmotic diuretics,

and chronic use of thiazides Antimicrobials - Amphotericin B,

aminoglycosides, pentamidine, capreomycin, viomycin, and foscarnet

Chemotherapeutic agents - Cisplatin Immunosuppressants - Tacrolimus and

cyclosporine Proton-pump inhibitors Ethanol

OTHERS Hypercalcemia Chronic metabolic acidosis Volume expansion Primary hyperaldosteronism Recovery phase of acute tubular necrosis Postobstructive diuresis

Alcoholics and individuals on magnesium-deficient diets or on parenteral nutrition for prolonged periods can become hypomagnesemic without abnormal gastrointestinal or kidney function.

The addition of 4-12 mmol of magnesium per day to total parenteral nutrition has been recommended to prevent hypomagnesemia.

DECREASED MAGNESIUM INTAKE

Hungry bone syndrome, in which magnesium is removed from the extracellular fluid space and deposited in bone following parathyroidectomy or total thyroidectomy or any similar states of massive mineralization of the bones

Hypomagnesemia may also occur following insulin therapy for diabetic ketoacidosis and may be related to the anabolic effects of insulin driving magnesium, along with potassium and phosphorus, back into cells.

REDISTRIBUTION OF MAGNESIUM FROM ECF TO ICF

Hyperadrenergic states, such as alcohol withdrawal, may cause intracellular shifting of magnesium and may increase circulating levels of free fatty acids that combine with free plasma magnesium.

Refeeding syndrome is a condition in which previously malnourished patients are fed high carbohydrate loads, resulting in a rapid fall in phosphate, magnesium, and potassium, along with an expanding extracellular fluid space volume, leading to a variety of complications.

When the small bowel is involved, due to disorders associated with malabsorption, chronic diarrhea, or steatorrhea, or as a result of bypass surgery on the small intestine.

Patients with ileostomies can develop hypomagnesemia as there is some degree of magnesium absorption in the colon

GASTROINTESTINAL LOSSES

Hypomagnesemia with secondary hypocalcemia (HSH) is a rare autosomal-recessive disorder characterized by profound hypomagnesemia associated with hypocalcemia.

Pathophysiology is related to impaired intestinal absorption of magnesium accompanied by renal magnesium wasting as a result of a reabsorption defect in the DCT.

Mutations in the gene coding for TRPM6, a member of the transient receptor potential (TRP) family of cation channels, have been identified as the underlying genetic defect.

Patients usually present within the first 3 months of life with the neurologic symptoms of hypomagnesemic hypocalcemia, including seizures, tetany, and muscle spasms.

Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC), an autosomal-recessive disorder, there is profound renal magnesium and calcium wasting.

The hypercalciuria often leads to nephrocalcinosis, resulting in progressive renal failure.

Other symptoms reported in patients with FHHNC include urinary tract infections, nephrolithiasis, incomplete distal tubular acidosis, and ocular abnormalities

RENAL LOSSES

Autosomal-dominant hypocalcemia with hypercalciuria (ADHH) is another disorder of urinary magnesium wasting.

Individuals who are affected present with hypocalcemia, hypercalciuria, and polyuria

About 50% of these patients have hypomagnesemia

ADHH is produced by mutation of CaSR gene (calcium-sensing receptor) which is involved in renal calcium and magnesium reabsorption

Isolated dominant hypomagnesemia (IDH) with hypocalciuria is an autosomal-dominant condition associated with few symptoms other than chondrocalcinosis.

Patients always have hypocalciuria and variable (but usually mild) hypomagnesemic symptoms

Isolated recessive hypomagnesemia (IRH) with normocalcemia is an autosomal-recessive disorder in which the individuals who are affected present with symptoms of hypomagnesemia early during infancy.

Hypomagnesemia due to increased urinary magnesium excretion appears to be the only abnormal biochemical finding.

IRH is distinguished from the autosomal-dominant form by the lack of hypocalciuria

Bartter’s syndrome Autosomal recessive disorder involving

impaired Thick Ascending Limb salt reabsorption

Gitelman syndrome autosomal recessive disorder involving loss

of function of the thiazidesensitive sodium-chloride symporter located in the distal convoluted tubule

Drugs like loop diuretics (including furosemide, bumetanide, and ethacrynic acid), produce large increases in magnesium excretion through the inhibition of the electrical gradient necessary for magnesium reabsorption in the TAL.

Long-term thiazide diuretic therapy also may cause magnesium deficiency due to enhanced magnesium excretion, it specifically reduces renal expression levels of the epithelial magnesium channel TRPM6

Aminoglycosides are thought to induce the action of the CaSR on the TAL and DCT, producing magnesium wasting

Cisplatin and amphotericin B induced magnesium deficiency is associated with hypocalciuria, which suggests injury to the DCT

Many nephrotosic drugs also cause hypomagnesemia by increased urinary magnesium excretion, but the causes are still unknown

The risk of hypomagnesemia can be summarized as follows:

2% in the general population10-20% in hospitalized patients50-60% in intensive care unit (ICU) patients30-80% in persons with alcoholism25% in outpatients with diabetes

A careful family history is important, particularly when acquired causes of hypomagnesemia have to be excluded

Often associated with multiple biochemical abnormalities, including hypokalemia, hypocalcemia, and metabolic acidosis.

As a result, hypomagnesemia is sometimes difficult to attribute solely to specific clinical manifestations

Clinical presentation

Hypokalemia is a common event in patients with hypomagnesemia, occurring in 40-60% of cases

Partly due to underlying disorders that cause magnesium and potassium losses, including diuretic therapy and diarrhea

The mechanism for hypomagnesemia-induced hypokalemia relates to the intrinsic biophysical properties of renal outer medullary K+ (ROMK) channels mediating K+ secretion in the TAL and the distal nephron.

RELATED METABOLIC CONDITION

The classic sign of severe hypomagnesemia (< 1.2 mg/dL) is hypocalcemia.

The mechanism is multifactorial. Impaired magnesium-dependent adenyl cyclase

mediates the decreased release of PTH causing hypocalcemia.

Skeletal resistance to this hormone in magnesium deficiency has also been implicated.

Hypomagnesemia also alters the normal heteroionic exchange of calcium and magnesium at the bone surface, leading to an increased bone release of magnesium ions in exchange for an increased skeletal uptake of calcium from the serum.

The cardiovascular effects of magnesium deficiency include effects on electrical activity, myocardial contractility, potentiation of digitalis effects, and vascular tone

Hypomagnesemia is also recognized to cause cardiac arrhythmia like Monomorphic ventricular tachycardia, Torsade de pointes, Ventricular fibrillation.

Changes in electrocardiogram are non specific like prolongation of conduction and slight ST depression, Nonspecific T-wave changes, U waves may b seen, Prolonged QT and QU interval seen

Effect on CVS

Hypertension is seen in cases of hypomagnesemia due to decrease in intracellular free magnesium that causes an increase in total peripheral resistance due to increased vascular tone and reactivity

Epidemiologic studies also show an association between magnesium deficiency and coronary artery disease (CAD)

The earliest manifestations of magnesium deficiency are usually neuromuscular and neuropsychiatric disturbances, the most common being hyperexcitability.

Neuromuscular irritability, including tremor, fasciculations, tetany, Chvostek and Trousseau signs, and convulsions, may be present.

Other manifestations include Apathy, Muscle cramps, Hyperreflexia, Acute organic brain syndromes, Depression, Generalized weakness, Anorexia, Vomiting

Neuromuscular manifestations

INVESTIGATION Measurement of serum magnesium Its use in evaluating total body stores is

limited

Mg++ Normal

sMg 1.7 – 2.5 mg/dl

RBC Mg 4.04 – 6.9 mg/dl

24 hr urinary Mg 120 – 150 mg

Because 30% of magnesium is bound to albumin and is therefore inactive, hypoalbuminemic states may lead to spuriously low magnesium values

Patient's protein status is an important consideration in interpreting magnesium levels.

GOLD STANDARD

A surrogate for direct intracellular magnesium is the measurement of magnesium retention after acute magnesium loading

An infused magnesium load - 2.4 mg/kg of lean body weight over the initial 4 h is given

A magnesium deficiency is indicated if a patient has reduced excretion (< 80% over 24 h)

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.

Excretion Analysis

FEMg = [(UMg x PCr) / (PMg x UCr x 0.7)]

distinction between gastrointestinal and renal losses can be made by measuring the 24-hour urinary magnesium excretion or the FE of magnesium on a random urine specimen

daily excretion of more than 24 mg or calculated FE of magnesium above 3% in a subject with normal renal function indicates renal magnesium wasting.

Diet The normal recommended daily allowance of

Mg is 420 mg for men and 320 mg for women

Green vegetables such as spinach are good sources of magnesium (which is contained in the chlorophyll molecule)

Some legumes (beans and peas), nuts and seeds, and whole, unrefined grains are also good sources of magnesium

MANAGEMENT

oral replacement should be given in the asymptomatic patient, preferably with a sustained-release preparation

Bioavailability of oral preparations is assumed to be 33% in the absence of intestinal malabsorption

• Mag-Ox 400, containing magnesium oxide• Slow-Mag, containing magnesium chloride• and Mag-Tab, containing magnesium lactate

These preparations provide about 60 – 84 mg of Mg per tablet

500mg of magnesium gluconate contain 27 mg of elemental magnesium & 1gm of magnesium sulfate contains 98 mg of elemental magnesium

The hypocalcemic-hypomagnesemic patient with tetany or the patient who is suspected of having hypomagnesemic-hypokalemic ventricular arrhythmias are given 50 mEq of intravenous magnesium, given slowly over 8-24 hours

This dose can be repeated as necessary to maintain the plasma magnesium concentration above 1.0

Non emergency cases 64 mEq in first 24 hrs and 32 mEq daily for 2 to 6 days, should be continued for 1 – 2 days after serum Mg level normalises

The main adverse effect of Mg replacement is hypermagnesemia due to administration at an excessive rate or excessive amount

Side effect include facial flushing, loss of deep tendon reflex, hypotension, AV block

May precipitate tetany as well in cases of hypocalcemia by increasing urinary calcium excretion

antidotes for hypermagnesemia is Intravenous calcium chloride or gluconate (1-2 ampules should be administered immediately )

Patients with diuretic-induced hypomagnesemia who cannot discontinue diuretic therapy may benefit from the addition of a potassium-sparing diuretic

Amiloride, spirolonolactone and triamterene can be used.

Also useful in patient with hypomagnesemia refractory to oral therapy or in cases where oral therapy result in diarrhoea

Passive reabsorption of Mg in late distal convoluted tubule

These drugs may decrease magnesium excretion by increasing its reabsorption in the collecting tubule.

These drugs also may be useful in Bartter and Gitelman syndrome or in cisplatin nephrotoxicity.

Potassium sparing diuretics

Brenner and Rector’s THE KIDNEY 9th edition

Harrison’s principles of internal medicine, 17th edition

Medscape.com

REFERENCE

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