Hypocalcemia

Are You Sure the Patient Has Hypocalcemia?

Symptoms

Most patients with hypocalcemia are asymptomatic, particularly in the outpatient setting. Symptomatic hypocalcemia most commonly occurs in an inpatient setting with serum ionized calcium below 4.3 mg/dL [1.1 mmol/L] or serum total calcium concentration below 7.0 mg/dL [1.8 mmol/L]. However, the presence and extent of symptoms depends on the rapidity of onset of hypocalcemia as well as the degree of hypocalcemia. Patients with chronic hypocalcemia may be asymptomatic despite low calcium levels, whereas a patient who had been hypercalcemic for some time may experience symptoms of hypocalcemia due to a rapid drop in calcium levels to the low-normal range (i.e. after parathyroidectomy).

Hypocalcemia, particularly in conjunction with alkalosis, increases neuromuscular irritability. This is most commonly manifested as numbness and tingling, particularly of the distal extremities or as circumoral paresthesias. Muscle cramping, twitching, or stiffness may also be signs of hypocalcemia. More severe symptoms include laryngospasm, bronchospasm or seizures.

Altered central nervous system function, ranging from generalized fatigue and depression to confusion, delerium or coma, may also be manifestations of acute hypocalcemia

Signs

The physical findings which classically demonstrate increased neuromuscular irritability due to hypocalcemia are Trousseau’s sign and Chvostek’s sign. Trousseau’s sign occurs when inflating a blood pressure cuff above the systolic blood pressure for three minutes precipitates carpal spasm. Chvostek’s sign occurs when a momentary spasm of the ipsilateral facial muscles or twitching of the upper lip is elicited by tapping the facial nerve anterior to the earlobe and just below the zygomatic arch.

The characteristic electrocardiographic finding in hypocalcemia is a prolonged QTc. Cardiomyopathy or congestive heart failure may rarely result from prolonged hypocalcemia.

Papilledema can rarely result from hypocalcemia of any cause.

Longstanding hypocalcemia due to hypoparathyroidism can result in calcification of the basal ganglia and other intracerebral calcifications, cataracts, dermatological manifestations including dry, puffy skin, and coarse, brittle and sparse hair. Congenital hypoparathyroidism can be associated with dental abnormalities such as dental hypoplasia as well as osteosclerosis.

Hypocalcemia due to severe vitamin D deficiency in children presents as rickets with bowing deformities of the lower extremities. In adults, it may present as osteomalacia with atraumatic fractures.

Key Laboratory Findings

Hypocalcemia is defined as an ionized calcium concentration below the lower limit of the normal range (generally below 4.0-4.8 mg/dL [1.0-1.2 mmol/L]). It is the ionized calcium level that is a critical factor in numerous intracellular and extracellular functions and is responsible for the symptoms of hypocalcemia. Therefore, an accurate measurement of the ionized calcium level is the best assessment of hypocalcemia. However, ionized calcium is unstable, so the sample must be transferred on ice with laboratory measurement to be done as soon as possible after the sample is drawn.

In reality, the initial assessment for hypocalcemia usually consists of a total serum calcium level as part of a general chemistry panel. There are several conditions in which the serum calcium level may be a poor reflection of ionized calcium. One common situation is hypoalbuminemia. Since a significant portion of calcium circulates bound to albumin, low serum albumin levels may result in a low serum total calcium despite normal ionized calcium levels. One commonly used correction for hypoalbuminemia is done with the following formula:

• Adjusted total calcium level = measured total calcium level in mg/dL + [0.8 x (4.0 – measured serum albumin in g/dL)]

This adjusted total calcium level should be compared to the normal range for serum total calcium.

Other factors including pH and circulating substances such as citrate (i.e. after a transfusion), phosphate, and paraproteins can also influence the serum total calcium. Therefore, a serum ionized calcium should be done to confirm the diagnosis before pursuing an extensive workup regarding the etiology of hypocalcemia.

Sensitivity and Specificity of Trousseau's and Chvostek's signs

In one small study, Trousseau’s sign was positive in 94% of patients with biochemically confirmed hypocalcemia and in 1% of patients with normocalcemia. Chvostek’s sign is less sensitive and specific than Trousseau’s sign; it is negative in 29% of people with hypocalcemia and positive in up to 10% of people with normal calcium.

What Else Could the Patient Have?

Etiologies of hypocalcemia

Parathyroid Hormone (PTH) – mediated

• Hypoparathyroidism is most commonly the result of parathyroid or thyroid surgery during which most or all functioning parathyroid tissue has been removed or damaged. Patients with post-surgical hypoparathyroidism are more likely to be symptomatic if they were vitamin D deficient or hypercalcemic prior to the surgery. The next most common cause of hypoparathyroidism is autoimmune hypoparathyroidism, which may be an isolated deficiency or combined with other endocrine deficiencies. Other causes of hypoparathyroidism include genetic disorders of parathyroid hormone biosynthesis or parathyroid gland development, radiation-induced destruction of parathyroid tissue, or infiltrative causes including iron overload, Wilson’s disease, or metastatic infiltration.

• “Hungry bone syndrome” or recalcification tetany occurs after parathyroidectomy for hyperparathyroidism, particularly in patients with pre-operative vitamin D deficiency. It can occur in patients with and without post-operative hypoparathyroidism. Hungry bone syndrome is due to intense skeletal uptake of calcium and phosphate after the acute fall in PTH. The patient may require large doses of calcium and vitamin D metabolites for weeks.

• Hypomagnesemia can cause hypocalcemia through either decreased production of PTH or resistance to PTH action. It may be related to gastrointestinal losses, renal magnesium-wasting states such as Gitelman’s syndrome, or drug-induced by medications such as cisplatin, diuretics, aminoglycosides or amphotericin. Hypomagnesemia may also be related to inadequate nutritional intake of magnesium, such as in alcoholism.

• Hypermagnesemia can also result in inadequate PTH production. It is most commonly related to the use of magnesium-containing drugs, particularly in patients with chronic kidney disease.

• PTH resistance, or pseudohypoparathyroidism, occurs when genetic mutations cause a blunted response to PTH, resulting in hypocalcemia and hyperphosphatemia in the absence of vitamin D deficiency. The classic form of PTH resistence is seen in Albright’s hereditary osteodystrophy, though there are other inherited and sporadic types of pseudohypoparathyroidism which do not have the associated physical findings or endocrine disorders of Albright’s.

Vitamin D – mediated

• Vitamin D deficiency is the most common cause of asymptomatic hypocalcemia but can precipitate symptoms of hypocalcemia in patients with other coexisting etiologies. Vitamin D deficiency may be caused by nutritional deficiency, malabsorption, lack of sun exposure, end-stage liver disease, or chronic kidney disease. Though vitamin D deficiency is common, hypocalcemia does not occur in most patients with vitamin D deficiency. Low ionized calcium levels generally occur only in patients with longstanding, severe vitamin D deficiency.

• Vitamin D resistance (vitamin D-dependent rickets) is a rare cause of hypocalcemia which is diagnosed in early childhood. These patients must be treated with high doses of calcitriol for life.

• Medications which can cause vitamin D deficiency or resistance include phenytoin, phenobarbital, carbamazepine, isoniazide, theophylline and rifampin. These medications induce cytochrome P450, which causes increased degradation of vitamin D.

Other

• Hyperphosphatemia due to renal failure, excess absorption from oral supplements or enemas, or massive phosphate release from tumor lysis or crush injury can cause low circulating calcium levels due to precipitation of calcium-phosphate salts in soft tissue or other areas of the body.

• Medications which can cause hypocalcemia include foscarnet, cinacalcet and fluoride. Inhibitors of bone resorption such as bisphosphonates (particularly administered intravenously) or calcitonin can cause hypocalcemia especially in patients with vitamin D insufficiency or deficiency.

• Calcium chelators such as ethylenediaminetetraacetic acid (EDTA) or citrate can also cause hypocalcemia. Citrate in particular should be considered as a cause of hypocalcemia after large volume blood or plasma transfusion.

• Malabsorption of calcium in patients with low gastric acid or other malabsorptive conditions and extremely low dietary intake of calcium are rare causes of hypocalcemia.

• Osteoblastic bone metastases can cause hypocalcemia as calcium is deposited in osteoblastic lesions.

• Acute critical illness is often associated with hypocalcemia. It is usually multifactorial and related to poor nutrition, vitamin D deficiency, acid-base abnormalities, renal failure and other causes.

• Acute pancreatitis can cause acute hypocalcemia due to precipitation of calcium-containing salts in the inflamed pancreatic tissue. The hypocalcemia often correlates to disease severity.

Differential diagnosis

Pseudohypocalcemia results when substances interfere with the laboratory assay for total calcium. Gadolinium salts in magnetic resonance imaging (MRI) contrast agents, particularly in patients with renal failure, are the most common cause of pseudohypocalcemia, which does not cause symptoms of hypocalcemia. Total calcium levels will appear to be low in these patients due to the nature of the calcium assay. However, ionized calcium levels will be normal.

Other causes of toxic-metabolic encephalopathy should be considered in the differential diagnosis for patients presenting with tetany, particularly if the ionized calcium levels have been stable and in the normal range. Some such causes include hypoxia/ischemia, hypoglycemia, other electrolyte abnormalities (particularly acute hypo- or hypernatremia), uremia, hepatic failure, intoxications (with sedatives, anticholinergic agents, salicylates and numerous other medications), acid-base abnormalities, or infections.

Key Laboratory and Imaging Tests

• Serum calcium – A total serum calcium level should be measured in any patient in whom hypocalcemia is suspected. To correct for hypoalbuminemia, the adjusted total calcium levelshould be compared to the reference range for the total calcium level. In conditions in which other substances may be affecting total calcium and in acutely ill patients, ionized calcium may more accurately determine if the patient is hypocalcemic.

• Albumin – Since a significant proportion of circulating calcium is albumin-bound, an adjusted total calcium level should be calculated in patients with abnormal calcium levels.

• Ionized calcium- Normally about 50% of circulating calcium is the biologically-active ionized form; the remainder is bound to proteins or anions. An accurately measured ionized calcium is crucial to make the diagnosis of hypocalcemia, particularly in the acute inpatient setting. An ionized calcium is needed to exclude pseudohypocalcemia in patients with chronic kidney disease who have recently received gadolinium-containing MRI contrast.

• Magnesium – Both low and elevated magnesium levels may contribute to hypocalcemia.

• Phosphate – Elevated phosphate levels are expected when hyperphosphatemia causes hypocalcemia due to precipitation of calcium-phosphate salts. Phosphate levels are particularly helpful when differentiating hypoparathyroidism (in which phosphate levels are high or high-normal) and hungry bone syndrome (in which phosphate levels are low due to skeletal remineralization).

• Serum intact PTH – Measurement of intact PTH is necessary when differentiating etiologies of hypocalcemia. In hypoparathyroidism, PTH levels are low. Patients with hypomagnesemia have inappropriately low to normal PTH levels in the setting of hypocalcemia. In contrast, PTH is elevated in vitamin D deficiency or resistance, chronic kidney disease, hungry bone syndrome and PTH resistance.

• 25 hydroxy vitamin D – This vitamin D metabolite is the best reflection of vitamin D stores and is used to assess for vitamin D insufficiency (levels between 20 and 30 ng/ ml [50-75 nmol/L]) and vitamin D deficiency (less than 20 ng/ml [50nmol/L]).

• Creatinine – Chronic kidney disease can result in vitamin D deficiency, and both acute and chronic kidney disease may be associated with hyperphosphatemia.

Other Tests That May Prove Helpful Diagnostically

• 24 hour urinary calcium – Elevated urinary calcium is seen in hypoparathyroidism, with the most extreme elevations in patients with autosomal-dominant hypoparathyroidism. Urinary calcium is low in vitamin D deficiency with secondary hyperparathyroidism.

• 24 hour urinary magnesium – A significantly elevated urinary magnesium suggests renal magnesium wasting as opposed to gastrointestinal losses.

• Alkaline phosphatase – Alkaline phosphatase may be elevated in bone metastases or in osteomalacia as a result of vitamin D deficiency.

• 1,25 dihydroxy vitamin D – Levels of activated vitamin D are generally not necessary in the initial evaluation of hypocalcemia.

• Gene sequencing or other specialized testing can be used to diagnose the cause of hypoparathyroidism in some instances. Referral to an endocrinologist or geneticist is indicated if suspicion for a genetic cause of hypoparathyroidism is high.

Management and Treatment of the Disease

Approach to treatment

The severity, symptoms and cause of hypocalcemia should be taken into account when determining treatment. In the short-term, the goal of therapy is to decrease neuromuscular irritability and therefore alleviate symptoms. Urgent treatment including intravenous calcium is indicated if the patient is experiencing severe symptoms such as seizures, severe tetany, laryngospasm, bronchospasm, altered mental status or electrocardiogram (EKG) abnormalities, even if the serum calcium level is only mildly reduced. An intravenous calcium bolus will raise serum calcium for 2-3 hours, so patients with hypocalcemia should also be started on a longer-lasting treatment.

Intravenous calcium infusions are often used for patients with adjusted calcium levels less than 7.0-7.5 mg/dL [1.75-1.875 mmol/L], even if they are asymptomatic. Once the patient’s symptoms have resolved and calcium levels are stable in the lower part of the normal range, the calcium infusion may be gradually tapered over 24-48 hours while oral calcium and vitamin D are initiated and titrated. Oral medications may be used as the initial treatment for chronic, asymptomatic, mild hypocalcemia. When starting an initial oral regimen, serum calcium, phosphate and creatinine should be measured every week to month.

The active form of vitamin D, calcitriol (1,25 dihydroxy vitamin D), helps to maintain a normal serum calcium by increasing gastrointestinal absorption of intestinal calcium and phosphorus, by promoting bone resorption of calcium, and by increasing renal tubular calcium reabsorption. Patients with vitamin D insufficiency or deficiency should receive vitamin D replacement with ergocalciferol or cholecalciferol. Patients with renal failure or hypoparathyroidism are unable to activate vitamin D and will require the administration of calcitriol (1,25 dihydroxy vitamin D) to treat hypocalcemia.

Long-term goals of treatment of hypocalcemia are to heal demineralized bones, to maintain an acceptable calcium level in the low-normal range, and to avoid complications of overtreatment such as hypercalciuria, renal dysfunction, nephrolithiasis and nephrocalcinosis. Since excess treatment can be toxic, treatment should be tailored to the expected duration of the hypocalcemia. For example, patients with permanent autoimmune hypoparathyroidism will require treatment indefinitely whereas patients with transient post-operative hypoparathyroidism would be expected to maintain calcium balance without therapy after some time.

Patients with chronic hypoparathyroidism do not have PTH-related regulation of calcium and require close monitoring to ensure adequate treatment of hypocalcemia without overtreatment. Please see the section entitled “Adjusting treatment in patients with hypoparathyroidism” for more detail.

Urgent therapy

Intravenous calcium boluses

Intravenous calcium boluses should be used if the patient is experiencing severe symptoms. However, intravenous calcium irritates the veins and can cause necrosis if it extravasates, so good intravenous access, preferably through a central vein, is preferred.

Calcium gluconate is most commonly used, since it is less irritating to the veins than calcium citrate. Calcium gluconate contains 93 mg elemental calcium in 10mL of a 10% solution. A 10mL ampule, diluted in 50-100 mL of D5, should be infused over ten minutes to treat emergent symptoms. This dose may be repeated once or twice more if necessary. As dysrhythmias may occur with rapid correction, continuous clinical and cardiac monitoring is recommended. The effect of calcium gluconate on serum calcium begins to wear off after two hours, so a continuous infusion will be necessary for patients with severe hypocalcemia.

Calcium chloride contains 270 mg elemental calcium in 10mL of a 10% solution. Since it contains more elemental calcium than calcium gluconate, it raises serum calcium more quickly. However, it irritates the veins more than calcium gluconate, so it should not be used for prolonged infusions.

Calcium infusion

Since a bolus of intravenous calcium will not have a prolonged effect, a continuous infusion is usually necessary. Calcium gluconate is preferred over calcium chloride, which is excessively irritating to veins.

A calcium gluconate infusion is made by adding ten ampules 10% calcium gluconate to 900 mL D5W, resulting in a concentration of 1 mg elemental calcium per mL of solution. This should be administered at a starting rate of 1-3 mg/kg/hr. At this rate, serum calcium should rise by 1.2-2 mg/dL [0.3-0.5 mmol/L] over 4-6 hours. In order to monitor therapy, ionized calcium levels should be measured every 1-2 hours with adjustment of the infusion rate as indicated to raise calcium to the lower end of the normal range.

When the patient’s condition and calcium levels have been stable on a steady infusion rate, calcium levels may be measured every 6-8 hours. If symptoms recur, the ionized calcium should be repeated immediately as the infusion rate may need to be increased. The calcium infusion may be administered for 1-3 days to maintain serum calcium and minimize symptoms until oral therapy is effective. Patients with hungry bone syndrome may require aggressive calcium replacement for longer periods than patients with transient hypoparathyroidism. The calcium infusion may be gradually tapered off over 1-2 days as oral calcium and vitamin D supplementation is increased.

Vitamin D

Calcitriol (1,25 dihydroxy vitamin D) is the most active vitamin D metabolite. It does not require hydroxylation in the liver or the kidney, and it has a rapid onset of action. As it may take some time to determine PTH and vitamin D levels, it is prudent to treat a patient with severe hypocalcemia and possible hypoparathyroidism or vitamin D deficiency with calcitriol in addition to calcium. If the patient is later determined to have vitamin D deficiency without hypoparathyroidism or renal failure, treatment may be changed to ergocalciferol (see “Maintenance/ outpatient therapy”). The starting dose of calcitriol is 0.25 mcg intravenously (IV) 1-2 times daily.

Maintenance/outpatient therapy

Oral calcium

Once the patient is able to tolerate oral medications and symptoms are controlled, oral calcium and vitamin D replacement may be started. Typical starting doses are 1-2 grams elemental calcium divided twice or three times daily. Doses may need to be adjusted based on tolerance, compliance, and treatment goals.

Calcium carbonate contains approximately 40% elemental calcium by weight (1250 mg calcium carbonate = 500 mg elemental calcium). Calcium carbonate is best absorbed in an acidic environment, so it should be administered with meals and should not be prescribed for patients on proton pump inhibitors. The main side effects are gastrointestinal, particularly constipation.

Calcium citrate contains approximately 21% elemental calcium by weight. It is preferred over calcium carbonate in patients with achlorhydria, patients on proton pump inhibitors, and those with gastrointestinal intolerance of calcium carbonate. It does not need to be taken with food.

Other oral calcium supplements, including calcium lactate, calcium gluconate, and calcium glubionate, contain a smaller percentage of elemental calcium than calcium citrate or calcium carbonate, so a larger number of pills is required for treatment of hypocalcemia. Dietary calcium such as dairy foods or juice supplemented with calcium citrate malate may also provide some calcium supplementation. However, consistency of dosing dietary calcium may be difficult to ensure, and it may be challenging for patients to take large doses of calcium in food.

Vitamin D

Vitamin D metabolites and analogues are important for the management of hypocalcemia. However, vitamin D intoxication may cause hypercalcemia, hypercalciuria, and hyperphosphatemia as well as symptoms of hypercalcemia including gastrointestinal disturbance, altered mental status, soft tissue calcification or renal damage. The timing and duration of toxicity are determined by the half-life of the analogue used. Calcium, phosphorus, creatinine and 25 hydroxy vitamin D levels should be monitored regularly during vitamin D therapy to avoid toxicity. Twenty-four hour urine calcium levels should be monitored annually for patients on vitamin D, and vitamin D doses may need to be decreased due to hypercalciuria.

For patients who do not have hypoparathyroidism or renal failure, ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3)may be used. These medications are both available over the counter. For patients with hypocalcemia due to vitamin D deficiency, ergocalciferol 50,000 IU weekly for 12 weeks should be used to replete nutritional vitamin D stores, followed by maintenance doses of 1,000-2,000 IU daily once 25 hydroxy vitamin D levels have risen to 30 ng/mL [75 nmol/L] or more, even in patients receiving activated vitamin D. Higher doses may be needed in patients with vitamin D deficiency due to malabsorption. The onset of action is approximately two weeks, with effects persisting for up to several months, so levels may be checked and doses adjusted every 1-3 months.

Calcitriol (1,25 dihydroxy vitamin D) does not require hydroxylation in the liver or the kidney, so it is often used in patients with renal failure. Parathyroid hormone is required for renal activation of vitamin D, so patients with hypoparathyroidism should also receive calcitriol. The starting dose is 0.25-1 mcg 1-2 times daily, which may be administered IV or by mouth. Patients on hemodialysis may use 0.25-1 mcg daily or three times weekly at dialysis. Calcitriol has its peak effect in ten hours and its effect lasts 2-3 days.

Other conditions which may affect treatment

Electrolyte abnormalities

• Hypomagnesemia – Correction of hypomagnesemia is necessary before calcium replacement will be successful. Magnesium supplementation can be stopped once oral intake improves and serum magnesium remains consistently above 2 mg/dL. If a patient is unable to maintain normal magnesium levels through a regular diet, oral supplementation may be continued. Magnesium sulfate 2-4 grams may be administered intravenously every eight hours initially. Magnesium oxide 400-500mg may be given once or twice daily for oral supplementation once the patient is tolerating medications by mouth.

• Hyperphosphatemia – The highest risk of precipitation of calcium-phosphate salts in soft tissues such as the lens, basal ganglia and kidney occurs when the calcium-phosphate product (the product of serum calcium and phosphate, both measured in mg/dL) is greater than 55. Patients with elevated phosphorus should be on a low phosphate diet, and oral phosphate binders should be administered prior to administering calcium supplementation if phosphate remains above 6 mg/dl (1.5 mmol/L).

• Metabolic acidosis – If a patient has metabolic acidosis and hypocalcemia, the hypocalcemia should be corrected prior to treatment of the acidosis so that the ionized calcium does not drop further. Additionally, sodium bicarbonate must be administered in a separate line from calcium salts. For patients with renal failure, metabolic acidosis and hypocalcemia, hemodialysis with a high calcium, high bicarbonate bath can safely correct the hypocalcemia and acidosis.

Coexisting medical conditions

• Renal failure -Large doses of calcitriol may be required in patients with renal failure after parathyroidectomy since renal failure prevents activation of vitamin D. Calcitriol may be administered intravenously at first and later by mouth. Administering calcitriol and calcium for several days before parathyroidectomy may help to prevent severe hypocalcemia.

• Liver failure – Activation of vitamin D may be impaired in patients with hepatic disease, so administration of calcitriol is recommended rather than ergocalciferol or cholecalciferol.

• Congestive heart failure – Patients with congestive heart failure due to chronic hypocalcemia should receive parenteral correction of the hypocalcemia initially. They will require medical treatment such as oxygen and diuretics in addition to correction of hypocalcemia.

• Digoxin use – Patients taking digoxin have increased cardiac sensitivity to fluctuations in serum calcium, so intravenous calcium administration should be done with caution and careful electrocardiographic monitoring.

• Malnutrition – Patients with malabsorption as a cause of vitamin D deficiency should have the underlying disease treated if possible (i.e. gluten free diet for celiac disease). These patients may require extremely high doses of vitamin D treatment.

• Pregnancy and lactation – Serum calcium concentrations should be measured frequently during late pregnancy and lactation in women with hypoparathyroidism who may have a rise in serum calcium, requiring a decrease in calcitriol dose.

Adjusting treatment in patients with hypoparathyroidism

Patients with chronic hypoparathyroidism require close monitoring to ensure adequate treatment of hypocalcemia without overtreatment since they do not have PTH-mediated regulation of calcium. A patient with chronic hypoparathyroidism who is on a stable regimen of calcium and calcitriol should have bloodwork monitored every 3-6 months and urinary calcium and creatinine levels monitored annually to ensure an adjusted total calcium level in the low-normal range, a 24 hour urinary calcium level below 300mg and a calcium-phosphate product below 55.

Initial treatment of hypercalciuria in patients being treated for hypoparathyroidism is reduction of calcium and vitamin D dosing. For patients who experience hypercalciuria with the lowest calcium and vitamin D doses required to maintain serum calcium, thiazide diuretics, which have calcium-retaining actions, may be added. Thiazide diuretics should be started when the 24 hour urinary calcium level approaches 250. The dosing range for both hydrochlorothiazide and chlorthalidone is 25-100 mg daily, though doses at the higher end of the dosing range are often required for lowering of urinary calcium. Potassium-sparing diuretics such as amiloride may be added to prevent hypokalemia, but loop diuretics should be avoided.

Few small trials have been done treating patients with hypoparathyroidism with injectable human PTH (1-34). However, PTH (1-34) is not approved by the Food and Drug Administration for this indication.

What’s the Evidence?/References

Cooper, MS, Gittoes, NJL. “2008 Clinical Review: Diagnosis and management of hypocalcemia”. BMJ. vol. 336. pp. 1298-302. (Good, focused review of hypocalcemia including use of diagnostic testing to determine etiology, physical exam findings.)

Peacock, M. “2010 Calcium Metabolism in Health and disease”. Clin J Am Soc Nephrol. vol. 5. pp. S23-S30. (Review of calcium physiology and pathophysiology that can result in hypocalcemia.)

Shoback, D. “Chapter 68. Hypocalcemia: Definition, Etiology, Pathogenesis, Diagnosis, and Management”. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 2008. pp. 313-7. (Includes information about etiology of hypocalcemia, including the genes involved.)

Shobak, D. “Clinical Practice: Hypoparathyroidism”. NEJM. vol. 359. 2008. pp. 391-403. (Excellent review of hypoparathyroidism including details about genetic causes.)

Liamis, G, Milionis, H, Elisaf, M. “A review of drug-induced hypocalcemia”. J Bone Miner Metab. vol. 27. 2009. pp. 635-42. (Includes numerous medications which cause hypocalcemia and the mechanism by which they do so.)

Umpaichitra, V, Bastian, W, Castells, S. “Hypocalcemia In Children: Pathogenesis and Management”. Clin Pediatrics. vol. 40. 2001. pp. 305-12. (Includes details about childhood causes of hypocalcemia and their treatment.)

Cooper, MS, Gittoes, NJL. “Clinical Review: Diagnosis and management of hypocalcemia”. BMJ. vol. 336. 2008. pp. 1298-302. (Excellent review of hypocalcemia including biochemical profiles for different etiologies and treatment algorithms.)

Bushinsky, DA, Monk, RD. “Electrolyte quintet: Calcium”. Lancet. vol. 352. 1998. pp. 306-11. (Practical information about the treatment of hypocalcemia, particularly in patients with renal insufficiency.)

Walker Harris, V, Jan De Beur, S. “Postoperative Hypoparathyroidism: Medical and Surgical Therapeutic Options Thyroid”. vol. 19. 2009. pp. 967-73. (Detailed review of treatments for postoperative hypoparathyroidism, including information about parathyroid autotransplantation.)

Winer, K, Wen Ko, C, Reynolds, JC, Dowdy, K, Keil, M, Peterson, D, Gerber, LH, McGarvey, C, Cutler, GB. “Long-Term Treatment of Hypoparathyroidism: A Randomized Controlled Study Comparing Parathyroid Hormone- (1-34) Versus Calcitriol and Calcium”. J Clin Endocrinol Metab. vol. 88. 2003. pp. 4214-20. (Randomized, parallel group, open-label trail comparing treatment with PTH to conventional therapy in adults with hypoparathyroidism.)

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