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Hypomagnesaemia: Is defined as an abnormally low serum magnesium level

Magnesium depletion occurring with intestinal malabsorption or dietary deficiency can cause hypocalcemia. Relative PTH deficiency and end-organ resistance to its action occur with magnesium depletion, resulting in plasma concentrations of < 1.0 mEq/L (< 0.5 mmol/L); repletion of magnesium improves PTH levels and renal Ca conservation.

Symptomatic hypomagnesemia may manifest clinically as CNS and neuromuscular hyperexcitability. Early manifestations may include painful muscle cramps, nausea, vomiting, and lethargy

Pathophysiology: Hypomagnesemia is widespread among hospitalized patients. Hypomagnesemia has been reported in as many as 60% of ICU patients. Prolonged administration of magnesium-free parenteral fluids may be a contributing factor. Prolonged nasogastric suction, infectious diarrhea, steatorrhea, inflammatory bowel disease, and GI neoplasms may cause hypomagnesemia. A congenital defect in GI magnesium absorption also has been described.

Physical:

· At serum magnesium levels less than 1.0 mEq/L, patients with hypomagnesemia may have tremor, hyperactive deep-tendon reflexes, hyperreactivity to sensory stimuli, muscular fibrillations, positive Chvostek and Trousseau signs, and carpopedal spasms progressing to tetany.

· Mental status changes may become evident and include irritability, disorientation, depression, and psychosis.

· Reversible respiratory muscle failure may occur in severe hypomagnesemia.

Background: Magnesium (Mg) is the second-most abundant intracellular cation and, overall, the fourth-most abundant cation. Almost all enzymatic processes using phosphorus as an energy source require magnesium for activation. Magnesium is involved in nearly every aspect of biochemical metabolism (eg, deoxyribonucleic acid [DNA] and protein synthesis, glycolysis, oxidative phosphorylation). Almost all enzymes involved in phosphorus reactions (eg, adenosine triphosphatase [ATPase]) require magnesium for activation. Magnesium serves as a molecular stabilizer of ribonucleic acid (RNA), DNA, and ribosomes. Because magnesium is bound to ATP inside the cell, shifts in intracellular magnesium concentration may help regulate cellular bioenergetics such as mitochondrial respiration.

Extracellularly, magnesium ions block neurosynaptic transmission by interfering with the release of acetylcholine. Magnesium ions also may interfere with the release of catecholamines from the adrenal medulla. Magnesium has been proposed as an endogenous endocrine modulator of the catecholamine component of the physiologic stress response.

Approximately 60% of total body magnesium is located in bone, and the remainder is in the soft tissues. This soft tissue intracellular compartment comprises about 38% of total body magnesium; relatively higher concentrations.

· Magnesium depletion occurring with intestinal malabsorption or dietary deficiency can cause hypocalcemia. Relative PTH deficiency and end-organ resistance to its action occur with magnesium depletion, resulting in plasma concentrations of < 1.0 mEq/L (< 0.5 mmol/L); repletion of magnesium improves PTH levels and renal Ca conservation.

· Acute pancreatitis causes hypocalcemia when Ca is chelated by lipolytic products released from the inflamed pancreas.

· Hypoproteinemia of any cause can reduce the protein-bound fraction of plasma Ca. Hypocalcemia due to diminished protein binding is asymptomatic. Since the ionized Ca fraction is unaltered, this entity has been termed factitious hypocalcemia.

· Enhanced bone formation with inadequate Ca intake can cause hypocalcemia. This situation occurs particularly after surgical correction of hyperparathyroidism in patients with severe osteitis fibrosa cystica and has been termed the hungry bone syndrome.

· Septic shock may be associated with hypocalcemia due to suppression of PTH release and conversion of 25(OH)D3 to 1,25(OH)2D3.

· Hyperphosphatemia also causes hypocalcemia by one or a variety of poorly understood mechanisms. Patients with renal failure and subsequent phosphate retention are particularly prone to this form of hypocalcemia.

· Drugs associated with hypocalcemia include those generally used to treat hypercalcemia (see Hypercalcemia, below); anticonvulsants (phenytoin, phenobarbital) and rifampin, which alter vitamin D metabolism; transfusion with blood products treated with citrate as well as radiocontrast agents containing the divalent ion chelating agent ethylenediaminetetraacetate.

Although excessive secretion of calcitonin might be expected to cause hypocalcemia, low plasma Ca levels rarely occur in patients with large amounts of circulating calcitonin from medullary carcinoma of the thyroid

Incidence of hypomagnesemia among people with alcohol dependence is approximately 25% and mainly is due to magnesium diuresis caused by alcohol.

Several drugs can cause increased urinary loss of magnesium. Magnesium deficiency is especially common in patients receiving furosemide diuretics. A congenital defect in tubular reabsorption of magnesium also has been described.

Severe hypomagnesemia may occur during the recovery phase of diabetic ketoacidosis. Patients with diabetes who have chronically poor glycemic control may have a total body magnesium deficit, possibly caused by ineffective insulin-mediated cellular uptake of magnesium.

Frequency:

· In the US: Although the incidence of hypomagnesemia in the general population has been estimated at less than 2%, hospitalized patients are more prone to develop hypomagnesemia. Exact inpatient incidence is unknown. Recent studies of ICU patients have estimated frequencies in that setting as high as 60%.

Lab Studies:

o Laboratory analysis by atomic absorption spectrophotometry (AAS) is the most specific technique available to measure total serum magnesium. Ion-selective electrodes for measurement of free magnesium have been developed; however, their use has not been rigorously tested, and they currently are not readily available for clinical use.

Other Tests:

o Hypomagnesemia may be associated with nonspecific ECG changes, including ST-segment depression, altered T waves, or loss of voltage. Severe magnesium deficiency may cause PR prolongation or widened QRS complexes.

Sarcoidosis is associated with hypercalcemia in up to 20% of patients and hypercalciuria in up to 40% of patients. Hypercalcemia and hypercalciuria have also been described in other granulomatous diseases, such as TB, leprosy, berylliosis, histoplasmosis, and coccidioidomycosis. In sarcoidosis, the hypercalcemia and hypercalciuria appear to be due to unregulated conversion of 25(OH)D3 to 1,25(OH)2D3, presumably due to expression of the 1- -hydroxylase enzyme in mononuclear cells within the sarcoid granulomas. Similarly, elevated plasma levels of 1,25(OH)2D3 have been reported in hypercalcemic patients with TB, silicosis, and lymphoma. Other mechanisms must account for hypercalcemia in some instances, since depressed 1,25(OH)2D3 levels have been described in some patients with hypercalcemia in association with leprosy, T-cell lymphoma, or leukemia.

Normal calcium homeostasis
Hormonal influences
Calcium homeostasis is maintained by two hormones, parathormone (parathyroid hormone or PTH) and calcitriol (1,25-dihydroxy vitamin D). Minute-to-minute regulation of serum ionized calcium is regulated by PTH. PTH secretion is stimulated when ambient serum ionized calcium is decreased. PTH acts on peripheral target cell receptors, increasing the efficiency of renal tubular calcium reabsorption. In addition, PTH enhances calcium resorption from mineralized bone and stimulates conversion of vitamin D to its active form, calcitriol, which subsequently increases intestinal absorption of calcium and phosphorus. Pharmacologic doses of calcitonin act as an antagonist to PTH, lowering serum calcium and phosphorus, and inhibiting bone reabsorption.

Renal function
Normal, healthy kidneys are capable of filtering large amounts of calcium that is subsequently reclaimed by tubular reabsorption. The kidneys are capable of increasing calcium excretion nearly fivefold to maintain homeostatic serum calcium concentrations. However, hypercalcemia may occur when the concentration of calcium present in the extracellular fluid overwhelms the kidneys' compensatory mechanisms.

Hypercalcemia:

Hypercalcemia: Is defined as an abnormally high concentration of calcium in the blood.



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Serum Calcium Concentration



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Symptoms <3.5 mmol/L >/= 3.5 mmol/L



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CNS symptoms 41% 80% constipation 21% 25% malaise-fatigue 65% 50% anorexia 47% 59% nausea and/or vomiting 22% 30% polyuria and/or polydipsia 34% 35% pain 51% 35%



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Clinical manifestations can be categorized according to body systems and functions.

Neurological symptoms
Calcium ions have a major role in neurotransmission. Increased calcium levels decrease neuromuscular excitability, which leads to hypotonicity in smooth and striated muscle. Symptom severity correlates directly with the magnitude of serum ionized calcium concentrations and inversely with their rate of change. Neuromuscular symptoms include weakness and diminished deep tendon reflexes. Muscle strength is impaired, and respiratory muscular capacity may be decreased. Central nervous system impairment may manifest as delirium with prominent symptoms of personality change, cognitive dysfunction, disorientation, incoherent speech, and psychotic symptoms such as hallucinations and delusions. Obtundation is progressive as serum calcium concentrations increase and may progress to stupor or coma.[1,2] Local neurologic signs are not common, but hypercalcemia has been documented to increase cerebrospinal fluid protein, which may be associated with headache. Headache can be exacerbated by vomiting and dehydration.[2] Abnormal electroencephalograms are seen in patients with marked hypercalcemia.[1]

Cardiovascular symptoms
Hypercalcemia is associated with increased myocardial contractility and irritability. Electrocardiographic changes are characterized by slowed conduction, including prolonged P-R interval, widened QRS complex, shortened Q-T interval, S-T segments may be shortened or absent, and the proximal limb of T waves may slope abruptly and peak early. Hypercalcemia enhances patients' sensitivity to the pharmacologic effects of digitalis glycosides (e.g., digoxin). When serum calcium concentrations exceed 16 mg/dL (>8.0 mEq/L or 3.99 mmol/L), T waves widen, secondarily increasing the Q-T interval. As calcium concentrations increase, bradyarrhythmias and bundle branch block may develop. Incomplete or complete AV block may develop at serum concentrations around 18 mg/dL (9.0 mEq/L or 4.49 mmol/L) and may progress to complete heart block, asystole, and cardiac arrest.[1,2]

Gastrointestinal symptoms
Gastrointestinal symptoms are probably related to the depressive action of hypercalcemia on the autonomic nervous system and resulting smooth muscle hypotonicity. Increased gastric acid secretion often accompanies hypercalcemia and may intensify gastrointestinal manifestations. Anorexia, nausea, and vomiting are intensified by increased gastric residual volume. Constipation is aggravated by dehydration that accompanies hypercalcemia. Abdominal pain may progress to obstipation and can be confused with acute abdominal obstruction.

Renal symptoms
Hypercalcemia causes a reversible tubular defect in the kidney resulting in the loss of urinary concentrating ability and polyuria. Decreased fluid intake and polyuria lead to symptoms associated with dehydration, including thirst, dry mucosa, diminished or absent sweating, poor skin turgor, and concentrated urine. Decreased proximal reabsorption of sodium, magnesium, and potassium occur as a result of salt and water depletion that is caused by cellular dehydration and hypotension. Renal insufficiency may occur as a result of diminished glomerular filtration, a complication observed most often in patients with myeloma.

Although nephrolithiasis and nephrocalcinosis are usually not associated with hypercalcemia of malignancy, calcium phosphate crystals can precipitate within renal tubules to form renal calculi as a consequence of long-standing hypercalciuria. When they occur, coexisting primary hyperparathyroidism should be considered.