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Ca is required for the proper functioning of muscle contraction, nerve conduction, hormone release, and blood coagulation. In addition, Ca helps regulate many enzymes.
Maintenance of the body Ca stores depends on dietary Ca intake, absorption of Ca from the GI tract, and renal Ca excretion. In a balanced diet, roughly 1000 mg of Ca is ingested each day. About 200 mg/day is lost in the bile and other GI secretions. Depending on the concentration of circulating vitamin D, particularly 1,25(OH)2D (1,25-dihydroxycholecalciferol, calcitriol , or active vitamin D hormone, which is converted in the kidney from 25(OH)D, the inactive form), roughly 200 to 400 mg of Ca is absorbed from the intestine each day. The remaining 800 to 1000 mg appears in the stool. Ca balance is maintained through renal Ca excretion averaging 200 mg/day.
Both extracellular and intracellular Ca concentrations are tightly regulated by bidirectional Ca transport across the plasma membrane of cells and intracellular organelles, such as the endoplasmic reticulum, the sarcoplasmic reticulum of muscle cells, and the mitochondria. Cytosolic ionized Ca is maintained within the micromolar range (less than 1/1000 of the plasma concentration). Ionized Ca acts as an intracellular 2nd messenger; it is involved in skeletal muscle contraction, excitation-contraction coupling in cardiac and smooth muscle, and activation of protein kinases and enzyme phosphorylation. Ca is also involved in the action of other intracellular messengers, such as cyclic adenosine monophosphate (cAMP) and inositol 1,4,5-triphosphate, and thus mediates the cellular response to numerous hormones, including epinephrine , glucagon, ADH ( vasopressin ), secretin, and cholecystokinin.
Despite its important intracellular roles, roughly 99% of body Ca is in bone, mainly as hydroxyapatite crystals. Roughly 1% of bone Ca is freely exchangeable with the ECF and, therefore, is available for buffering changes in Ca balance. Normal total plasma Ca levels range from 8.8 to 10.4 mg/dL (2.20 to 2.60 mmol/L). About 40% of the total blood Ca is bound to plasma proteins, primarily albumin. The remaining 60% includes ionized Ca plus Ca complexed with phosphate (PO4) and citrate. Total Ca (ie, protein-bound, complexed, and ionized Ca) is usually what is determined by clinical laboratory measurement. Ideally, the ionized or free Ca should be determined, because this is the physiologically active form of Ca in plasma; this determination, because of its technical difficulty, is usually restricted to patients in whom significant alteration of protein binding of plasma Ca is suspected. Ionized Ca is generally assumed to be roughly 50% of the total plasma Ca.
Regulation of
Calcium Metabolism
The metabolism of Ca and of PO4 (see Fluid and Electrolyte Metabolism: Disorders of Phosphate Concentration) are intimately related. The regulation of both Ca and PO4 balance is greatly influenced by circulating levels of parathyroid hormone (PTH), vitamin D, and, to a lesser extent, calcitonin . Ca and inorganic PO4 concentrations are also linked by their ability to chemically react to form CaPO4. The product of concentrations of Ca and PO4 (in mEq/L) is estimated to be 60 normally; when the product exceeds 70, precipitation of CaPO4 crystals in soft tissue is much more likely. Precipitation in vascular tissue accelerates arteriosclerotic vascular disease.
PTH is secreted by the parathyroid glands. It has several actions, but perhaps the most important is to defend against hypocalcemia. Parathyroid cells sense decreases in plasma Ca and, in response, release preformed PTH into the circulation. PTH increases plasma Ca within minutes by increasing renal and intestinal absorption of Ca and by rapidly mobilizing Ca and PO4 from bone (bone resorption). Renal Ca excretion generally parallels Na excretion and is influenced by many of the same factors that govern Na transport in the proximal tubule. However, PTH enhances distal tubular Ca reabsorption independently of Na. PTH also decreases renal PO4 reabsorption and thus increases renal PO4 losses. Renal PO4 loss prevents the solubility product of Ca and PO4 from being exceeded in plasma as Ca levels rise in response to PTH.
PTH also increases plasma Ca by stimulating conversion of vitamin D (see Vitamin Deficiency, Dependency, and Toxicity: Vitamin D) to its most active form, 1,25(OH)2D. This form of vitamin D increases the percentage of dietary Ca absorbed by the intestine. Despite increased Ca absorption, long-term increases in PTH secretion generally result in further bone resorption by inhibiting osteoblastic function and promoting osteoclastic activity. PTH and vitamin D both function as important regulators of bone growth and bone remodeling (see Vitamin Deficiency, Dependency, and Toxicity: Vitamin D Deficiency and Dependency).
Testing parathyroid function includes measuring circulating PTH levels by radioimmunoassay and measuring total or nephrogenous cAMP excretion in urine. Urinary cAMP is seldom measured now that accurate assays for PTH are widely available. Assays for the intact PTH molecule are best.
Calcitonin is secreted by the thyroid parafollicular cells (C cells). Calcitonin tends to lower plasma Ca concentration by enhancing cellular uptake, renal excretion, and bone formation. The effects of calcitonin on bone metabolism are much weaker than those of either PTH or vitamin D.
Hypocalcemia
(For hypocalcemia in neonates, see Metabolic, Electrolyte, and Toxic Disorders in Neonates: Hypocalcemia.)
Hypocalcemia
is total plasma Ca concentration < 8.8
mg/dL (< 2.20 mmol/L) in
the presence of normal plasma protein concentrations, or a plasma
ionized Ca concentration < 4.7
mg/dL (< 1.17 mmol/L).
Causes include hypoparathyroidism, vitamin D deficiency, and renal
disease. Manifestations include paraesthesias, tetany, and, if severe,
seizures, encephalopathy, and heart failure. Diagnosis involves
measurement of plasma Ca. Treatment is administration of Ca, sometimes
with vitamin D.
Etiology
and Pathophysiology
Hypocalcemia has a number of causes. Several are listed below.
Hypoparathyroidism:
Hypoparathyroidism is characterized by hypocalcemia and hyperphosphatemia and often produces chronic tetany. Hypoparathyroidism results from deficient parathyroid hormone (PTH) often because of the accidental removal of or damage to several parathyroid glands during thyroidectomy. Transient hypoparathyroidism is common after subtotal thyroidectomy. Permanent hypoparathyroidism occurs after < 3% of thyroidectomies performed by experienced surgeons. Manifestations of hypocalcemia usually begin about 24 to 48 h postoperatively but may occur after months or years. PTH deficiency is more common after radical thyroidectomy for cancer or as the result of surgery on the parathyroid itself (subtotal or total parathyroidectomy). Risk factors for severe hypocalcemia after subtotal parathyroidectomy include severe preoperative hypercalcemia, removal of a large adenoma, and elevated alkaline phosphatase.
Idiopathic hypoparathyroidism is an uncommon sporadic or inherited condition in which the parathyroid glands are absent or atrophied. It manifests in childhood. The parathyroid glands are occasionally absent with thymic aplasia and abnormalities of the arteries arising from the brachial arches (DiGeorge syndrome). Other inherited forms include the X-linked genetic syndrome of hypoparathyroidism, Addison's disease, and mucocutaneous candidiasis.
Pseudohypoparathyroidism:
Pseudohypoparathyroidism is an uncommon group of disorders characterized not by hormone deficiency but by target organ resistance to PTH. Complex genetic transmission of these disorders occurs.
Patients with type Ia pseudohypoparathyroidism (Albright's hereditary osteodystrophy) have a mutation in the stimulatory Gs-α
1 protein of the adenylyl cyclase complex (GNAS1). The result is failure of normal renal phosphaturic response or increase in urinary cyclic adenosine monophosphate (cAMP) to PTH. Patients are usually hypocalcemic as a result of hyperphosphatemia. Secondary hyperparathyroidism and hyperparathyroid bone disease can occur. Associated abnormalities include short stature, round facies, mental retardation with calcification of the basal ganglia, shortened metacarpal and metatarsal bones, mild hypothyroidism, and other subtle endocrine abnormalities. Because only the maternal allele for GNAS1 is expressed in the kidneys, patients whose abnormal gene is paternal, although they have many of the somatic features of the disease, do not have hypocalcemia, hyperphosphatemia, or secondary hyperparathyroidism; this condition is sometimes described as pseudopseudohypoparathyroidism.
Less is known about type Ib pseudohypoparathyroidism. These patients have hypocalcemia, hyperphosphatemia, and secondary hyperparathyroidism but do not have the other associated abnormalities.
Type II pseudohypoparathyroidism is even less common than type I. In affected patients, exogenous PTH raises the urinary cAMP normally but does not raise plasma Ca or urinary phosphate (PO4). An intracellular resistance to cAMP has been proposed.
Vitamin
D deficiency:
Vitamin D deficiency may result from inadequate dietary intake or decreased absorption due to hepatobiliary disease or intestinal malabsorption. It can also result from alterations in vitamin D metabolism as occur with certain drugs (eg, phenytoin , phenobarbital , rifampin ) or lack of skin exposure to sunlight. The latter is an important cause of acquired vitamin D deficiency in the institutionalized elderly and in northern climates among people wearing clothing that covers them completely (eg, Muslim women in England). Type I vitamin D–dependent rickets (pseudovitamin D deficiency rickets) is an autosomal recessive disorder involving a mutation in the gene encoding the 1-α-hydroxylase enzyme. Normally expressed in the kidney, 1-α-hydroxylase is needed to convert 25(OH)D to the active form of vitamin D, 1,25(OH)2D. In type II vitamin D–dependent rickets, target organs cannot respond to 1,25(OH)2D. Vitamin D deficiency, hypocalcemia, and severe hypophosphatemia occur. Muscle weakness, pain, and typical bone deformities can occur (see Vitamin Deficiency, Dependency, and Toxicity: Symptoms and Signs).
Renal
disease:
Renal tubular disease, including acquired proximal renal tubular acidosis due to nephrotoxins (eg, heavy metals) and distal renal tubular acidosis, can cause severe hypocalcemia due to abnormal renal loss of Ca and decreased renal conversion to 1,25(OH)2D. Cadmium, in particular, causes hypocalcemia by injuring proximal tubular cells and interfering with vitamin D conversion.
Renal failure can result in hypocalcemia from diminished formation of 1,25(OH)2D from direct renal cell damage as well as suppression of 1- α-hydroxylase by hyperphosphatemia.
Other
causes:
Mg depletion, which occurs with intestinal malabsorption or dietary deficiency, can cause hypocalcemia. Relative PTH deficiency and end-organ resistance to PTH action occur, resulting in plasma Mg concentrations of < 1.0 mg/dL (< 0.5 mmol/L); repletion improves PTH levels and renal Ca conservation.
Acute pancreatitis causes hypocalcemia when lipolytic products released from the inflamed pancreas chelate Ca.
Hypoproteinemia can reduce the protein-bound fraction of plasma Ca. Hypocalcemia due to diminished protein binding is asymptomatic. Because ionized Ca is unchanged, this entity has been termed factitious hypocalcemia.
Enhanced bone formation with inadequate Ca intake occurs particularly after surgical correction of hyperparathyroidism in patients with severe osteitis fibrosa cystica and has been termed hungry bone syndrome.
Septic shock can cause hypocalcemia due to suppression of PTH release and decreased conversion of 25(OH)D to 1,25(OH)2D.
Hyperphosphatemia causes hypocalcemia by poorly understood mechanisms. Patients with renal failure and subsequent PO4 retention are particularly prone.
Drugs that produce hypocalcemia include those generally used to treat hypercalcemia (see Fluid and Electrolyte Metabolism: Treatment); anticonvulsants ( phenytoin , phenobarbital ) and rifampin , which alter vitamin D metabolism; transfusion of > 10 units of citrate-anticoagulated blood; and 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.
Symptoms and Signs
Hypocalcemia is frequently asymptomatic. The presence of hypoparathyroidism is often suggested by the clinical manifestations of the underlying condition (eg, cataracts, basal ganglia calcification, chronic candidiasis in idiopathic hypoparathyroidism).
Clinical manifestations of hypocalcemia are due to disturbances in cellular membrane potential, resulting in neuromuscular irritability. Muscle cramps involving the back and legs are common. Insidious hypocalcemia may produce mild, diffuse encephalopathy and should be suspected in a patient with unexplained dementia, depression, or psychosis. Papilledema occasionally occurs, and cataracts may develop after prolonged hypocalcemia. Severe hypocalcemia with plasma Ca < 7 mg/dL (< 1.75 mmol/L) may cause tetany, laryngospasm, or generalized seizures.
Tetany characteristically results from severe hypocalcemia but can result from reduction in the ionized fraction of plasma Ca without marked hypocalcemia, as occurs in severe alkalosis. Tetany is characterized by sensory symptoms consisting of paresthesias of the lips, tongue, fingers, and feet; carpopedal spasm, which may be prolonged and painful; generalized muscle aching; and spasm of facial musculature. Tetany may be overt with spontaneous symptoms or latent and requiring provocative tests to elicit. Latent tetany generally occurs at less severely decreased plasma Ca concentrations: 7 to 8 mg/dL (1.75 to 2.20 mmol/L).
Chvostek's and Trousseau's signs are easily elicited at the bedside to identify latent tetany. Chvostek's sign is an involuntary twitching of the facial muscles elicited by a light tapping of the facial nerve just anterior to the exterior auditory meatus. It is present in ≤ 10% of healthy people and in most people with acute hypocalcemia but is often absent in chronic hypocalcemia. Trousseau's sign is the precipitation of carpopedal spasm by reduction of the blood supply to the hand with a tourniquet or BP cuff inflated to 20 mm Hg above systolic BP applied to the forearm for 3 min. Trousseau's sign also occurs in alkalosis, hypomagnesemia, hypokalemia, and hyperkalemia and in about 6% of people with no identifiable electrolyte disturbance.
Arrhythmia or heart block occasionally develops in patients with severe hypocalcemia. In hypocalcemia, the ECG typically shows prolongation of the QTc and ST intervals. Changes in repolarization, such as T-wave peaking or inversion, also occur.
Many other abnormalities may occur with chronic hypocalcemia, such as dry and scaly skin, brittle nails, and coarse hair. Candida infections occasionally occur in hypocalcemia but most commonly occur in patients with idiopathic hypoparathyroidism. Cataracts occasionally occur with long-standing hypocalcemia and are not reversible by correction of plasma Ca.
Diagnosis
Hypocalcemia is diagnosed by a total plasma Ca level < 8.8 mg/dL (< 2.20 mmol/L). However, because low plasma protein can lower total, but not ionized, plasma Ca, ionized Ca should be estimated based on albumin level (
see Sidebar 1: Fluid and Electrolyte Metabolism: Estimation of Ionized Calcium Levels ). Suspicion of low ionized Ca mandates its direct measurement, despite normal total plasma Ca. Hypocalcemic patients should undergo measurement of renal function (eg, BUN, creatinine), serum PO4, Mg, and alkaline phosphatase.
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Sidebar 1
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If hypocalcemia has no obvious etiology (eg, alkalosis, renal failure, or massive blood transfusion), further testing is needed. Intact PTH levels should be measured. Because hypocalcemia is the major stimulus for PTH secretion, PTH should be elevated in hypocalcemia. Thus, low or even low-normal PTH levels are inappropriate and suggest hypoparathyroidism. An undetectable PTH level suggests idiopathic hypoparathyroidism. Hypoparathyroidism is characterized by low plasma Ca, high plasma PO4, and normal alkaline phosphatase. Hypocalcemia with high plasma PO4 suggests renal failure.
Type I pseudohypoparathyroidism can be distinguished by the presence of hypocalcemia despite normal to elevated levels of circulating PTH. Despite the presence of high levels of circulating PTH, urinary cAMP and urinary PO4 are absent. Provocative testing by injection of parathyroid extract or recombinant human PTH fails to raise plasma or urinary cAMP. Patients with type Ia pseudohypoparathyroidism frequently also have skeletal abnormalities, including short stature and shortened 1st, 4th, and 5th metacarpals. Those with type Ib disease have renal manifestations without skeletal abnormalities.
In type II pseudohypoparathyroidism, exogenous PTH raises urinary cAMP but does not induce phosphaturia or raise plasma Ca concentration. Vitamin D deficiency must be excluded before type II pseudohypoparathyroidism is diagnosed.
In osteomalacia or rickets, typical skeletal abnormalities may be present on x-ray (see Vitamin Deficiency, Dependency, and Toxicity: Diagnosis). The plasma PO4 level is often mildly reduced, and alkaline phosphatase is elevated, reflecting increased mobilization of Ca from bone. Measurement of plasma 25(OH)D and 1,25(OH)2D may help distinguish vitamin D deficiency from vitamin D–dependent states. Familial hypophosphatemic rickets is recognized by the associated renal PO4 wasting.
Treatment
For tetany, Ca gluconate 10 mL of 10% solution IV over 10 min is given. Response can be dramatic but may last for only a few hours. Repeated infusions or the addition of a continuous infusion may be needed with 20 to 30 mL of 10% Ca gluconate in 1 L of 5% D/W over the next 12 to 24 h. Infusions of Ca are hazardous in patients receiving digoxin and should be given slowly and with continuous ECG monitoring. When tetany is associated with hypomagnesemia, it may respond transiently to Ca or K administration but is permanently relieved only by repletion of Mg (see Fluid and Electrolyte Metabolism: Treatment).
In transient hypoparathyroidism after thyroidectomy or partial parathyroidectomy, supplemental oral Ca may be sufficient. However, hypocalcemia may be particularly severe and prolonged after subtotal parathyroidectomy in patients with chronic renal failure or end-stage renal disease. Prolonged parenteral administration of Ca may be necessary postoperatively; supplementation with as much as 1 g/day of elemental Ca may be required for 5 to 10 days before oral Ca and vitamin D are sufficient. Elevated plasma alkaline phosphatase in such settings may be a sign of rapid uptake of Ca into bone. The need for large amounts of parenteral Ca usually does not fall until the alkaline phosphatase levels begin to decrease.
In chronic hypocalcemia, oral Ca and occasionally vitamin D supplements are usually sufficient. Ca may be given as Ca gluconate (90 mg elemental Ca/1 g) or Ca carbonate (400 mg elemental Ca/1 g) to provide 1 to 2 g of elemental Ca/day. Although any vitamin D preparation suffices, 1-hydroxylated compounds, such as synthetic calcitriol [1,25(OH)2D], and pseudo 1-hydroxylated analogs, such as dihydrotachysterol , offer more rapid onset of action and more rapid clearance from the body. Calcitriol is particularly useful in renal failure because it requires no renal metabolic alteration. Patients with hypoparathyroidism usually respond to calcitriol in dosages of 0.5 to 2 μg/day po. Pseudohypoparathyroidism can occasionally be managed with oral Ca supplementation alone. Benefit from calcitriol requires 1 to 3 μg/day.
Vitamin D therapy is not effective unless adequate dietary or supplemental Ca (1 to 2 g elemental Ca/day) and PO4 (see Fluid and Electrolyte Metabolism: Treatment) are supplied. Vitamin D toxicity with severe symptomatic hypercalcemia can be a serious complication of treatment with vitamin D analogs. Plasma Ca concentration should be monitored weekly at first and then at 1- to 3-mo intervals after Ca levels have stabilized. The maintenance dose of calcitriol or dihydrotachysterol usually decreases with time.
Rickets due to vitamin D deficiency responds to as little as 10 μg (400 IU/day) of vitamin D (as vitamin D2 or D3); if osteomalacia is present, 125 μg/day (5000 IU/day) of vitamin D is given for 6 to 12 wk and then reduced to 10 μg/day (400 IU/day). An additional 2 g Ca/day is desirable during the early stages of treatment. In patients with rickets or osteomalacia due to lack of exposure to sunlight, treatment with increased exposure to sunlight or ultraviolet lamp treatment may be all that is required.
Type I vitamin D–dependent rickets responds to calcitriol 0.25 to 1.0 μg/day po. Patients with type II vitamin D–dependent rickets do not respond to any form of vitamin D (the more easily understood term—hereditary resistance to 1,25(OH)2D—has been suggested). Treatment depends on the severity of bone lesions and hypocalcemia. Up to 6 μg/kg body weight or a total of 30 to 60 μg/day of calcitriol with up to 3 g of elemental Ca/day is needed in severe cases. Treatment with vitamin D requires monitoring of plasma Ca levels; although hypercalcemia may result, it generally responds quickly to dose adjustment of vitamin D.
Hypercalcemia
Hypercalcemia
is total plasma Ca concentration > 10.4
mg/dL (> 2.60 mmol/L) or ionized plasma
Ca > 5.2 mg/dL (> 1.30 mmol/L). Principal causes
include hyperparathyroidism, vitamin D toxicity, and cancer. Clinical
features include polyuria, constipation, muscle weakness, confusion,
and coma. Diagnosis is by plasma ionized Ca and parathyroid hormone levels.
Treatment to increase Ca excretion and reduce bone resorption of
Ca involves saline, Na diuresis, and drugs such as pamidronate.
Etiology
and Pathophysiology
Hypercalcemia usually results from excessive bone resorption. The principal causes of hypercalcemia are listed here and in
Table 7: Fluid and Electrolyte Metabolism: Principal Causes of Hypercalcemia .
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Table 7
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Principal Causes
of Hypercalcemia
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Excessive bone resorption
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Cancer with bone metastases: Particularly carcinoma, leukemia, lymphoma, multiple myeloma
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Hyperthyroidism
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Humoral hypercalcemia of malignancy, ie, hypercalcemia of cancer in the absence of bone metastases
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Immobilization: Particularly in young, growing people, in those undergoing orthopedic casting and/or traction, and in those with Paget's disease of bone; also in elderly with osteoporosis, paraplegics, and quadriplegics
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Parathyroid hormone excess: Primary hyperparathyroidism, parathyroid carcinoma, familial hypocalciuric hypercalcemia, advanced secondary hyperparathyroidism
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Vitamin D toxicity; vitamin A toxicity
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Excessive GI Ca absorption and/or intake
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Milk-alkali syndrome
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Sarcoidosis and other granulomatous diseases
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Vitamin D toxicity
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Elevated plasma protein concentration
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Uncertain mechanism
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Aluminum-induced osteomalacia
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Infantile hypercalcemia
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Lithium intoxication, theophylline intoxication
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Myxedema, Addison's disease, postoperative Cushing's disease
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Neuroleptic malignant syndrome
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Thiazide diuretic treatment
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Artifactual
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Exposure of blood to contaminated glassware
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Prolonged venous stasis while obtaining blood samples
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Primary hyperparathyroidism is a generalized disorder resulting from excessive secretion of parathyroid hormone (PTH) by one or more parathyroid glands. It probably is the most common cause of hypercalcemia. Incidence increases with age and is higher in postmenopausal women. It also occurs in high frequency ≥ 3 decades after neck irradiation. Familial and sporadic forms exist. Familial forms due to parathyroid adenoma occur in patients with other endocrine tumors (see Multiple Endocrine Neoplasia (MEN) Syndromes). Primary hyperparathyroidism causes hypophosphatemia and excessive bone resorption. Although asymptomatic hypercalcemia is the most frequent presentation, nephrolithiasis is also common, particularly when hypercalciuria occurs due to long-standing hypercalcemia. Histologic examination shows a parathyroid adenoma in about 90% of patients with primary hyperparathyroidism, although it is sometimes difficult to distinguish an adenoma from a normal gland. About 7% of cases are due to hyperplasia of ≥ 2 glands. Parathyroid cancer occurs in 3% of cases.
The syndrome of familial hypocalciuric hypercalcemia (FHH) is transmitted as an autosomal dominant trait. Most cases involve an inactivating mutation of the Ca-sensing receptor gene, resulting in higher levels of plasma Ca being needed to inhibit PTH secretion. Subsequent PTH secretion induces phosphate (PO4) excretion. There is persistent hypercalcemia (usually asymptomatic), often from an early age; normal to slightly elevated levels of PTH; hypocalciuria; and hypermagnesemia. Renal function is normal, and nephrolithiasis is unusual. However, severe pancreatitis occasionally occurs. This syndrome, which is associated with parathyroid hyperplasia, is not relieved by subtotal parathyroidectomy.
Secondary hyperparathyroidism occurs when long-term hypocalcemia, which is caused by conditions such as renal insufficiency or intestinal malabsorption syndromes, stimulates increased secretion of PTH. Hypercalcemia or, less often, normocalcemia may occur. The sensitivity of the parathyroid to Ca may be diminished because of pronounced glandular hyperplasia and elevation of the Ca set point (ie, the amount of Ca necessary to reduce secretion of PTH).
Tertiary hyperparathyroidism results in autonomous hypersecretion of PTH regardless of plasma Ca concentration. Tertiary hyperparathyroidism generally occurs in patients with long-standing secondary hyperparathyroidism, as in patients with end-stage renal disease of several years' duration.
Cancer is a common cause of hypercalcemia in hospitalized patients. Although there are several mechanisms, elevated plasma Ca ultimately occurs as a result of bone resorption. Humoral hypercalcemia of cancer (ie, hypercalcemia with no or minimal bone metastases) occurs most commonly with squamous cell carcinoma, renal cell carcinoma, breast cancer, prostate cancer, and ovarian cancer. Many cases of humoral hypercalcemia of cancer were formerly attributed to ectopic production of PTH. However, some of these tumors secrete a PTH-related peptide that binds to PTH receptors in both bone and kidney and mimics many of the effects of the hormone, including osteoclastic bone resorption. Hematologic cancers, most often myeloma, but also certain lymphomas and lymphosarcomas, cause hypercalcemia through elaboration of a group of cytokines that stimulate osteoclasts to resorb bone, resulting in osteolytic lesions and/or diffuse osteopenia. Hypercalcemia may result from local elaboration of osteoclast-activating cytokines or prostaglandins and/or direct bone resorption by the metastatic tumor cells.
High levels of endogenous vitamin D [1,25(OH)2D] are another possible cause. Although plasma concentrations are low in most patients with solid tumors, patients with lymphoma sometimes have elevated levels. Exogenous vitamin D in pharmacologic doses produces excessive bone resorption as well as increased intestinal Ca absorption, resulting in hypercalcemia and hypercalciuria (see Vitamin Deficiency, Dependency, and Toxicity: Vitamin D Toxicity).
Granulomatous disease, such as sarcoidosis, TB, leprosy, berylliosis, histoplasmosis, and coccidioidomycosis, leads to hypercalcemia and hypercalciuria. In sarcoidosis, hypercalcemia and hypercalciuria appear to be due to unregulated conversion of 25(OH)D to 1,25(OH)2D, presumably due to expression of the 1-α-hydroxylase enzyme in mononuclear cells within sarcoid granulomas. Similarly, elevated plasma levels of 1,25(OH)2D have been reported in hypercalcemic patients with TB and silicosis. Other mechanisms must account for hypercalcemia in some instances, because depressed 1,25(OH)2D levels occur in some patients with hypercalcemia and leprosy.
Immobilization, particularly complete prolonged bed rest in patients at risk (see Table 7: Fluid and Electrolyte Metabolism: Principal Causes of Hypercalcemia), can result in hypercalcemia due to accelerated bone resorption. Hypercalcemia develops within days to weeks of onset of bed rest. Reversal of hypercalcemia occurs promptly on resumption of weight bearing. People with Paget's disease are particularly prone to hypercalcemia when at bed rest.
Idiopathic hypercalcemia of infancy (see Williams syndrome, discussed in Chromosomal Anomalies:Chromosomal Deletion Syndromes in Table 1: Chromosomal Anomalies: Examples of Contiguous Gene Syndromes) is an extremely rare sporadic disorder with dysmorphic facial features, cardiovascular abnormalities, renovascular hypertension, and hypercalcemia. PTH and vitamin D metabolism are normal, but the response of calcitonin to Ca infusion may be abnormal.
In milk-alkali syndrome, excessive amounts of Ca and absorbable alkali are ingested, usually during self-treatment with Ca carbonate antacids for dyspepsia or to prevent osteoporosis, resulting in hypercalcemia, metabolic alkalosis, and renal insufficiency. The availability of effective drugs for peptic ulcer disease and osteoporosis has greatly reduced the incidence of this syndrome.
Symptoms and Signs
In mild hypercalcemia, many patients are asymptomatic. The condition is frequently discovered during routine laboratory screening. Clinical manifestations of hypercalcemia include constipation, anorexia, nausea and vomiting, abdominal pain, and ileus. Impairment of the renal concentrating mechanism leads to polyuria, nocturia, and polydipsia. Elevation of plasma Ca > 12 mg/dL (> 3.00 mmol/L) causes emotional lability, confusion, delirium, psychosis, stupor, and coma. Neuromuscular symptoms include skeletal muscle weakness. Hypercalciuria with nephrolithiasis is common. Less often, prolonged or severe hypercalcemia produces reversible acute renal failure or irreversible renal damage due to nephrocalcinosis (precipitation of Ca salts within the kidney parenchyma). Peptic ulcers and pancreatitis may occur in patients with hyperparathyroidism for reasons that are not related to hypercalcemia.
Severe hypercalcemia causes a shortened QTc interval on ECG, and arrhythmias may occur, particularly in patients taking digoxin . Hypercalcemia > 18 mg/dL (> 4.50 mmol/L) may cause shock, renal failure, and death.
Diagnosis
Hypercalcemia is diagnosed by a total plasma Ca level > 10.4 mg/dL (> 2.60 mmol/L) or ionized plasma Ca > 5.2 mg/dL (> 1.30 mmol/L). Plasma Ca can be artifactually elevated (see Table 7: Fluid and Electrolyte Metabolism: Principal Causes of Hypercalcemia). Hypercalcemia can also be masked by low serum protein; if protein and albumin are abnormal or if ionized hypercalcemia is clinically suspected (eg, because of symptoms of hypercalcemia), ionized plasma Ca should be measured.
The cause is apparent from the history and clinical findings in ≥ 95% of patients. Initial evaluation should include a review of the history, particularly of past plasma Ca levels; physical examination; a chest x-ray; and laboratory studies, including electrolytes, BUN, creatinine, ionized Ca, PO4, alkaline phosphatase, and serum protein immunoelectrophoresis. Patients without an obvious cause of hypercalcemia after this evaluation should undergo measurement of intact PTH and 24-h urinary Ca.
Asymptomatic hypercalcemia that has been present for years or is present in multiple family members raises the possibility of FHH. Primary hyperparathyroidism generally presents later in life but can be present for several years before symptoms occur. If there are no obvious causes, levels of plasma Ca < 11 mg/dL (< 2.75 mmol/L) suggest hyperparathyroidism or other nonmalignant causes, whereas levels > 13 mg/dL (> 3.25 mmol/L) suggest cancer.
The chest x-ray is particularly helpful, revealing most granulomatous diseases, such as TB, sarcoidosis, and silicosis, as well as primary lung cancer and lytic and Paget's lesions in bones of the shoulder, ribs, and thoracic spine.
X-rays can also demonstrate the bony effects of secondary hyperparathyroidism, most commonly in long-term dialysis patients. In osteitis fibrosa cystica (often due to primary hyperparathyroidism), increased osteoclastic activity from overstimulation by PTH causes rarefaction of bone with fibrous degeneration and cyst and fibrous nodule formation. Because characteristic bone lesions occur only with relatively advanced disease, x-rays are not recommended in asymptomatic patients. X-rays typically show bone cysts, a heterogeneous appearance of the skull, and subperiosteal resorption of bone in the phalanges and distal clavicles.
Diagnosis of the cause of hypercalcemia often relies on laboratory studies.
In hyperparathyroidism, the plasma Ca is rarely > 12 mg/dL (> 3.00 mmol/L), but the ionized plasma Ca is almost always elevated. Low plasma PO4 level suggests hyperparathyroidism, especially when coupled with elevated PO4 renal excretion. When hyperparathyroidism results in increased bone turnover, plasma alkaline phosphatase is frequently increased. Increased intact PTH, particularly inappropriate elevations (ie, in the absence of hypocalcemia), is diagnostic. Primary hyperparathyroidism is suggested by an absence of a family history of endocrine neoplasia, childhood neck irradiation, or other obvious cause. Chronic renal disease suggests the presence of secondary hyperparathyroidism, but primary hyperparathyroidism can also be present. In patients with chronic renal disease, high plasma Ca and normal plasma PO4 suggest primary hyperparathyroidism, whereas elevated PO4 suggests secondary hyperparathyroidism.
The need for localization of parathyroid tissue before surgery on the parathyroid(s) is controversial. High-resolution CT scanning with or without CT-guided biopsy and immunoassay of thyroid venous drainage, MRI, high-resolution ultrasonography, digital subtraction angiography, and thallium 201-technetium 99 scanning all have been used and are highly accurate, but they have not improved the usually high cure rate of parathyroidectomy performed by experienced surgeons. Technetium-99 sestamibi, a radionuclide agent for parathyroid imaging, is more sensitive and specific than earlier agents and may be useful for identifying solitary adenomas.
For residual or recurrent hyperparathyroidism after initial parathyroid surgery, imaging is necessary and may reveal abnormally functioning parathyroid glands in unusual locations throughout the neck and mediastinum. Technetium-99 sestamibi is probably the most sensitive imaging test. Use of multiple imaging studies (MRI, CT, or high-resolution ultrasound in addition to technetium-99 sestamibi) before repeat parathyroidectomy is sometimes necessary.
A plasma Ca > 12 mg/dL (> 3.00 mmol/L) suggests tumors or some other cause of hypercalcemia rather than hyperparathyroidism. In humoral hypercalcemia of cancer, PTH is often decreased or undetectable; PO4 is often decreased; and metabolic alkalosis, hypochloremia, and hypoalbuminemia are often present. Suppressed PTH differentiates this from primary hyperparathyroidism. Humoral hypercalcemia of cancer can also be diagnosed by detection of PTH-related peptide in plasma.
Simultaneous anemia, azotemia, and hypercalcemia suggest myeloma. Myeloma is confirmed by bone marrow examination or by the presence of a monoclonal gammopathy.
If Paget's disease is suspected, testing begins with plain x-rays (see Paget's Disease of Bone).
FHH, thiazide therapy, renal failure, and milk-alkali syndrome can produce hypercalcemia without hypercalciuria. FHH is distinguished from primary hyperparathyroidism by the early age of onset, frequent occurrence of hypermagnesemia, and presence of hypercalcemia without hypercalciuria in other family members. The fractional excretion of Ca (ratio of Ca clearance to creatinine clearance) is low (< 1%) in FHH; it is almost always elevated (1 to 4%) in primary hyperparathyroidism. Intact PTH can be elevated or normal, perhaps reflecting altered feedback regulation of the parathyroid glands.
In addition to a history of increased intake of Ca antacids, milk-alkali syndrome is recognized by the combination of hypercalcemia, metabolic alkalosis, and occasionally, azotemia with hypocalciuria. The diagnosis can be confirmed if the plasma Ca level rapidly returns to normal when Ca and alkali ingestion stops, although renal insufficiency can persist if nephrocalcinosis is present. Circulating PTH usually is suppressed.
In hypercalcemia from sarcoidosis, other granulomatous disorders, and some lymphomas, plasma levels of 1,25(OH)2D may be elevated. Vitamin D toxicity is also characterized by elevated 1,25(OH)2D levels. In other endocrine causes of hypercalcemia, such as thyrotoxicosis and Addison's disease, typical laboratory findings of the underlying disorder help establish the diagnosis.
Treatment
There are 4 main strategies for lowering plasma Ca: decrease intestinal Ca absorption, increase urinary Ca excretion, decrease bone resorption, and remove excess Ca through dialysis. The treatment used depends on both the degree and the cause of hypercalcemia.
In mild hypercalcemia (plasma Ca < 11.5 mg/dL [< 2.88 mmol/L]), in which symptoms are mild, treatment is deferred pending definitive diagnosis. After diagnosis, the underlying cause is treated. If symptoms are significant, treatment aimed at lowering plasma Ca is necessary. Oral PO4 can be used. When taken with meals, it binds some Ca, preventing its absorption. A starting dose is 250 mg of elemental PO4 (as Na or K salt) qid. The dose can be increased to 500 mg qid as needed unless diarrhea develops. Another treatment is increasing urinary Ca excretion by giving isotonic saline plus a loop diuretic. Initially, 1 to 2 L of saline is given over 2 to 4 h unless significant heart failure is present, because nearly all patients with significant hypercalcemia are hypovolemic. Furosemide 20 to 40 mg IV q 2 to 4 h is given as needed to maintain a urine output of roughly 250 mL/h (monitored hourly). Care must be taken to avoid volume depletion. To avoid hypokalemia and hypomagnesemia, K and Mg are monitored as often as q 4 h during treatment and replaced intravenously as needed. Plasma Ca begins to decrease in 2 to 4 h and falls to near-normal levels within 24 h.
Moderate hypercalcemia (plasma Ca > 11.5 mg/dL [< 2.88 mmol/L] and < 18 mg/dL [< 4.51 mmol/L]) can be treated with isotonic saline and a loop diuretic as previously mentioned or, depending on its cause, agents that decrease bone resorption (usually calcitonin , bisphosphonates, or infrequently plicamycin or gallium nitrate), corticosteroids, or chloroquine .
Calcitonin (thyrocalcitonin) is a rapidly acting peptide hormone normally secreted in response to hypercalcemia by the C cells of the thyroid. Calcitonin appears to lower plasma Ca by inhibiting osteoclastic activity. A dose of 4 to 8 IU/kg sc q 12 h of salmon calcitonin is safe. Its usefulness in the treatment of cancer-associated hypercalcemia is limited by its short duration of action, the development of tachyphylaxis, and the lack of response in ≥ 40% of patients. However, the combination of salmon calcitonin and prednisone may control plasma Ca for several months in some patients with cancer. If calcitonin stops working, it can be stopped for 2 days (while prednisone is continued) and then resumed.
Bisphosphonates inhibit osteoclasts. They are usually the drugs of choice for cancer-associated hypercalcemia. Etidronate 7.5 mg/kg IV once/day for 3 to 5 days is used to treat Paget's disease and cancer-associated hypercalcemia. Maintenance with 20 mg/kg po once/day can also be used. Pamidronate can be given for cancer-associated hypercalcemia as a one-time dose of 30 to 90 mg IV, repeated only after 7 days. It lowers plasma Ca for ≤ 2 wk. Zoledronate can also be given in doses of 4 to 8 mg IV and lowers plasma Ca for an average of > 40 days. Oral bisphosphonates ( alendronate or risedronate ) can be given to maintain Ca in the normal range.
Plicamycin 25 μg/kg IV once/day in 50 mL of 5% D/W over 4 to 6 h is effective in patients with hypercalcemia due to cancer but is used infrequently because other treatments are safer. Gallium nitrate is also effective in hypercalcemia due to cancer but is used infrequently because of renal toxicity and limited clinical experience.
The addition of corticosteroids (eg, prednisone 20 to 40 mg po once/day) effectively controls hypercalcemia by decreasing calcitriol production and thus intestinal Ca absorption in most patients with vitamin D toxicity, idiopathic hypercalcemia of infancy, and sarcoidosis. Some patients with myeloma, lymphoma, leukemia, or metastatic cancer require 40 to 60 mg of prednisone once/day. However, > 50% of such patients fail to respond to corticosteroids, and response, when it occurs, takes several days; thus, other treatment usually is necessary.
Chloroquine PO4 500 mg po once/day inhibits 1,25(OH)2D synthesis and reduces plasma Ca levels in patients with sarcoidosis. Routine ophthalmologic surveillance (eg, retinal examinations q 6 to 12 mo) is mandatory to detect dose-related retinal damage.
In severe hypercalcemia (plasma Ca > 18 mg/dL [> 4.50 mmol/L] or with severe symptoms), hemodialysis with low-Ca dialysate may be needed in addition to other treatments above. Although there is no completely satisfactory way to correct severe hypercalcemia in patients with renal failure, hemodialysis is probably the safest and most reliable short-term treatment.
IV
PO4 (disodium PO4 or
monopotassium PO4) should
be used only when hypercalcemia is life threatening and unresponsive
to other methods and when short-term hemodialysis is not possible. No more than 1 g should be given IV in 24 h; usually 1 or 2 doses over 2 days lower plasma Ca for 10 to 15 days. Soft-tissue calcification and acute renal failure may result. Note: IV
infusion of Na sulfate is even more hazardous and less effective than
PO4 infusion and should
not be used.
Treatment of hyperparathyroidism in patients with renal failure is combined with dietary PO4 restriction and PO4-binding agents, such as Ca carbonate or sevelamer , to prevent hyperphosphatemia and metastatic calcification. Aluminum-containing compounds should be avoided in renal failure, especially in patients receiving long-term dialysis, to prevent accumulation in bone resulting in severe osteomalacia. Despite the use of PO4 binders, dietary restriction of PO4 is needed. Vitamin D administration is potentially hazardous in renal failure and requires frequent monitoring of Ca and PO4. Treatment should be limited to patients with symptomatic osteomalacia (unrelated to aluminum), secondary hyperparathyroidism, or postparathyroidectomy hypocalcemia. Although oral calcitriol is often given along with oral Ca to suppress secondary hyperparathyroidism, the results are variable in patients with end-stage renal disease. The parenteral form of calcitriol , or vitamin D analogs such as paricalcitol, may better prevent secondary hyperparathyroidism in such patients, because the higher attained plasma levels of 1,25(OH)2D directly suppress PTH release. Elevation of serum Ca frequently complicates vitamin D therapy in dialysis patients. Simple osteomalacia may respond to 0.25 to 0.5 μg/day of oral calcitriol |
