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Ca is required for the proper functioning of muscle contraction, nerve conduction, hormone release, and blood coagulation. In addition, proper Ca concentration is required for various other metabolic processes.
Maintenance of body Ca stores depends on
In a balanced diet, roughly 1000 mg of Ca is ingested each day and about another 200 mg/day is secreted into the GI tract 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, 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 (< 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. Parathyroid hormone (PTH) increases urinary cAMP.
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 concentration ranges 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) is intimately related. The regulation of both Ca and PO4 balance is greatly influenced by concentrations of circulating 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. Calcification of vascular tissue accelerates arteriosclerotic vascular disease and may occur when the Ca × PO4 product is even lower (> 55), especially in patients with chronic kidney 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 concentrations 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, calcitriol. 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).
Radioimmunoassays for the intact PTH molecule are still the recommended way to test for PTH. Second-generation assays for intact PTH are available. These tests measure bioavailable PTH or complete PTH. They give values equal to 50 to 60% of those obtained with the older assay. Usefulness of the newer assays is under investigation. Sometimes total or nephrogenous cAMP excretion is measured in diagnosis of pseudohypoparathyroidism.
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
(Hypocalcemia in neonates is discussed on 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
paresthesias, tetany, and, when severe, seizures, encephalopathy,
and heart failure. Diagnosis involves measurement of plasma Ca with
adjustment for plasma albumin concentration. Treatment is administration
of Ca, sometimes with vitamin D.
Etiology
Hypocalcemia has a number of causes, including
Hypoparathyroidism:
Hypoparathyroidism is characterized by hypocalcemia and hyperphosphatemia and often produces chronic tetany. Hypoparathyroidism results from deficient parathyroid hormone (PTH), which can occur in autoimmune disorders or after the accidental removal of or damage to several parathyroid glands during thyroidectomy. Transient hypoparathyroidism is common after subtotal thyroidectomy, but permanent hypoparathyroidism occurs after < 3% of such thyroidectomies done 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 glands (subtotal or total parathyroidectomy). Risk factors for severe hypocalcemia after subtotal parathyroidectomy include
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 and thymic aplasia and abnormalities of the arteries arising from the brachial arches (DiGeorge syndrome) are present. Other inherited forms include Addison's disease, autoimmune hypoparathyroidism associated with mucocutaneous candidiasis, and X-linked recessive idiopathic hypoparathyroidism.
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-α1 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 and dependency:
Vitamin D deficiency and dependency are discussed in full elsewhere (see Vitamin Deficiency, Dependency, and Toxicity: Vitamin D Deficiency and Dependency). Vitamin D is ingested in foods naturally high in vitamin D or fortified with it. It is also formed in the skin in response to sunlight. 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 decreased formation in the skin due to lack of exposure to sunlight. Aging also decreases skin synthetic capacity. Decreased skin synthesis is an important cause of acquired vitamin D deficiency among people who spend a great deal of time indoors, who live in high northern or southern latitudes, and who wear clothing that covers them completely. Accordingly, subclinical vitamin D deficiency is fairly common, especially during winter months in temperate climates among the elderly. The institutionalized elderly are at particular risk because of decreased skin synthetic capacity, undernutrition, and lack of sun exposure. In fact, most people with deficiency have both decreased skin synthesis and dietary deficiency (see also Vitamin Deficiency, Dependency, and Toxicity: Vitamin D Deficiency and Dependency).
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 inactive vitamin D to the active form calcitriol.
In type II vitamin D–dependent rickets, target organs cannot respond to calcitriol . Vitamin D deficiency, hypocalcemia, and severe hypophosphatemia occur. Muscle weakness, pain, and typical bone deformities can occur.
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:
Other causes of hypocalcemia include
Although excessive secretion of calcitonin might be expected to cause hypocalcemia, low plasma Ca concentrations 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 disorder (eg, short stature, round facies, mental retardation, basal ganglia calcification in type Ia pseudohypoparathyroidism).
Major clinical manifestations of hypocalcemia are due to disturbances in cellular membrane potential, resulting in neuromuscular irritability.
Neurologic manifestations:
Muscle cramps involving the back and legs are common. Insidious hypocalcemia may produce mild, diffuse encephalopathy and should be suspected in patients with unexplained dementia, depression, or psychosis. Papilledema occasionally occurs. Severe hypocalcemia with plasma Ca < 7 mg/dL (< 1.75 mmol/L) may cause hyperreflexia, 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 the following:
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.
Other manifestations:
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 may be suspected in patients with characteristic neurologic manifestations or cardiac arrhythmias but is often found incidentally. Hypocalcemia is diagnosed by a total plasma Ca concentration < 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 concentration (see Sidebar 2: Fluid and Electrolyte Metabolism: Estimation of Ionized Calcium Concentration ). 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), plasma PO4, Mg, and alkaline phosphatase.
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Sidebar 2
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When no etiology (eg, alkalosis, renal failure, drugs, or massive blood transfusion) is obvious, further testing is needed (see Table 8: Fluid and Electrolyte Metabolism: Typical Laboratory Test Results in Some Disorders Causing Hypocalcemia ). Additional testing begins with plasma concentrations of Mg, PO4, PTH, alkaline phosphatase, and occasionally vitamin D levels (25(OH)D, and 1,25(OH)2D). Urinary PO4 and cAMP concentrations are measured when pseudohypoparathyroidism is suspected.
PTH concentration should be measured as an assay of the intact molecule. Because hypocalcemia is the major stimulus for PTH secretion, PTH should be elevated in hypocalcemia. Thus,
Hypoparathyroidism is further characterized by high plasma PO4 and normal alkaline phosphatase.
In type I pseudohypoparathyroidism, despite the presence of a high concentration 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. Patients with type Ib disease have renal manifestations without skeletal abnormalities.
In vitamin D deficiency, osteomalacia or rickets may be present, usually with typical skeletal abnormalities on x-ray (see Vitamin Deficiency, Dependency, and Toxicity: Vitamin D Deficiency and Dependency). Diagnosis of vitamin D deficiency and dependency and measurement of vitamin D concentrations are discussed in Vitamin Deficiency, Dependency, and Toxicity: Vitamin D Deficiency and Dependency.
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Table 8
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Typical Laboratory Test
Results in Some Disorders
Causing Hypocalcemia
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Disorder
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Findings
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Surgical hypoparathyroidism
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Low or low-normal PTH
Normal or high plasma PO4
Low urinary PO4
Normal serum alkaline phosphatase
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Idiopathic hypoparathyroidism
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Undetectable PTH
High plasma PO4
Low urinary PO4
Normal serum alkaline phosphatase
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Type Ia pseudohypoparathyroidism (Albright's hereditary osteodystrophy)
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High PTH
High plasma PO4
No urinary cAMP or increase in PO4 excretion even after injection of parathyroid extract or PTH
Skeletal and other abnormalities
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Type Ib pseudohypoparathyroidism
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High PTH
High plasma PO4
No urinary cAMP or increase in PO4 excretion even after injection of parathyroid extract or PTH
No skeletal abnormalities
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Type II pseudohypoparathyroidism
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High PTH
High plasma PO4
No urinary cAMP or PO4
Injection of PTH increases urinary cAMP but not urinary PO4
Normal or high vitamin D concentrations
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Vitamin D deficiency
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High PTH
Low plasma PO4
High alkaline phosphatase
Low 25(OH)D*
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Type I hereditary vitamin D–dependent rickets
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High PTH
Low plasma PO4
High alkaline phosphatase
Radiographic evidence of rickets
Normal serum 25(OH)D
Low serum 1,25(OH)2D
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Type II hereditary vitamin D–dependent rickets
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High PTH
Low plasma PO4
High alkaline phosphatase
Radiographic evidence of rickets
Normal or high serum 25(OH)D
Normal or high 1,25(OH)2D
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* Measurement of plasma 25(OH)D and 1,25(OH)2D may help distinguish vitamin D deficiency from vitamin D–dependent states.
cAMP = cyclic adenosine monophosphate; PO4
= phosphate; PTH = parathyroid hormone; 1,25(OH)2D = 1,25-dihydroxychoecalciferol or calcitriol; 25(OH)D = inactive vitamin D.
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Severe hypocalcemia can affect the ECG. It typically shows prolongation of the QTc and ST intervals. Changes in repolarization, such as T-wave peaking or inversion, also occur. ECG may show arrhythmia or heart block occasionally in patients with severe hypocalcemia. However, evaluation of hypocalcemia does not mandate ECG testing.
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 boluses or a continuous infusion with 20 to 30 mL of 10% Ca gluconate in 1 L of 5% D/W over the next 12 to 24 h may be needed. 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, typically given as a 10% Mg sulfate (MgSO4) solution (1 g/10 mL) IV, followed by oral Mg salts (eg, Mg gluconate 500 to 1000 mg po tid).
In transient hypoparathyroidism after thyroidectomy or partial parathyroidectomy, supplemental oral Ca may be sufficient: 1 to 2 g of elemental Ca/day may be given as Ca gluconate (90 mg elemental Ca/1 g) or Ca carbonate (400 mg elemental Ca/1 g). However, hypocalcemia may be particularly severe and prolonged after subtotal parathyroidectomy, particularly in patients with chronic kidney disease or in patients from whom a large tumor was removed. Prolonged parenteral administration of Ca may be necessary postoperatively; supplementation with as much as 1 g/day of elemental Ca (eg, 111 mL of Ca gluconate, which contains 90 mg elemental Ca/10 mL) may be required for 5 to 10 days before oral Ca and vitamin D are sufficient. Elevated plasma alkaline phosphatase in such patients 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 concentration begins to decrease.
In chronic hypocalcemia, oral Ca and occasionally vitamin D supplements are usually sufficient: 1 to 2 g of elemental Ca/day may be given as Ca gluconate or Ca carbonate. In patients without renal failure, vitamin D is given as a standard oral supplement (eg, cholecalciferol 800 IU once/day). Vitamin D therapy is not effective unless adequate dietary or supplemental Ca and PO4 (see Fluid and Electrolyte Metabolism: Treatment) are supplied.
For patients with renal failure, calcitriol or another 1,25(OH)2D analog is used because these drugs require no renal metabolic alteration. Patients with hypoparathyroidism have difficulty converting cholecalciferol to its active form and also usually require calcitriol , usually 0.5 to 2 μg po once/day. Pseudohypoparathyroidism can occasionally be managed with oral Ca supplementation alone. When used, calcitriol requires 1 to 3 μg/day.
Vitamin D analogs include dihydrotachysterol (usually given orally at 0.8 to 2.4 once/day for a few days, followed by 0.2 to 1.0 mg once/day) and calcidiol (eg, 4000 to 6000 IU po once/wk). Use of vitamin D analogs, particularly the longer-acting calcidiol, can be complicated by vitamin D toxicity, with severe symptomatic hypercalcemia. Plasma Ca concentration should be monitored weekly at first and then at 1- to 3-mo intervals after Ca concentrations have stabilized. The maintenance dose of calcitriol or its analog, dihydrotachysterol , usually decreases with time.
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 concentrations. Treatment to increase
Ca excretion and reduce bone resorption of Ca involves saline, Na
diuresis, and drugs such as pamidronate.
Etiology
Hypercalcemia usually results from excessive bone resorption. There are many causes of hypercalcemia (see Table 9: Fluid and Electrolyte Metabolism: Principal Causes of Hypercalcemia), but the most common are hyperparathyroidism and cancer.
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Table 9
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Principal Causes of
Hypercalcemia
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Category
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Examples
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Excessive bone resorption
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Cancer with bone metastases
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Carcinoma
Leukemia
Lymphoma
Multiple myeloma
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Immobilization
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Orthopedic casting or traction
Paget's disease of bone
Osteoporosis in the elderly
Paraplegia or quadriplegia
Young, growing patients
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Parathyroid hormone excess
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Familial hypocalciuric hypercalcemia
Parathyroid carcinoma
Primary hyperparathyroidism
Secondary hyperparathyroidism
Tertiary hyperparathyroidism
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Vitamin toxicity
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Vitamin A toxicity
Vitamin D toxicity
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Other disorders
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Hyperthyroidism
Humoral hypercalcemia of malignancy (ie, hypercalcemia of cancer in the absence of bone metastases)
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Excessive GI Ca absorption, intake, or both
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Sarcoidosis and other granulomatous diseases
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Berylliosis
Coccidioidomycosis
Histoplasmosis
Leprosy
Silicosis
TB
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Other disorders
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Milk-alkali syndrome
Vitamin D toxicity
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Elevated plasma protein concentration
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Uncertain mechanism
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Drugs
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Lithium toxicity
Theophylline toxicity
Thiazide treatment
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Endocrine dysfunction
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Addison's disease
Cushing's disease, postoperative
Myxedema
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Other disorders
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Aluminum-induced osteomalacia
Idiopathic infantile hypercalcemia
Neuroleptic malignant syndrome
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Artifactual
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Exposure of blood to contaminated glassware
Prolonged venous stasis as blood sample was obtained
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Pathophysiology
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, particularly among patients who are not hospitalized. 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 85% of patients with primary hyperparathyroidism, although it is sometimes difficult to distinguish an adenoma from a normal gland. About 15% of cases are due to hyperplasia of ≥ 2 glands. Parathyroid cancer occurs in < 1% 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 concentrations of plasma Ca being needed to inhibit PTH secretion. Subsequent PTH secretion induces renal phosphate (PO4) excretion. Persistent hypercalcemia (usually asymptomatic), often from an early age; normal to slightly elevated concentrations of PTH; hypocalciuria; and hypermagnesemia occur. 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 most commonly in advanced chronic kidney disease when decreased formation of active vitamin D in the kidneys and other factors lead to hypocalcemia and chronic stimulation of PTH secretion. Hyperphosphatemia that develops in response to chronic kidney disease also contributes. Once established, hypercalcemia or 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, usually 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 multiple myeloma, but also certain lymphomas and lymphosarcomas, cause hypercalcemia by elaborating a group of cytokines that stimulate osteoclasts to resorb bone, resulting in osteolytic lesions, diffuse osteopenia, or both. Hypercalcemia may result from local elaboration of osteoclast-activating cytokines or prostaglandins, direct bone resorption by the metastatic tumor cells, or both.
Vitamin
D toxicity can be caused by high concentrations of endogenous 1,25(OH)2D. Although plasma concentrations are low in most patients with solid tumors, patients with lymphoma and T-cell leukemia sometimes have elevated concentrations due to dysregulation of the 1-α-hydroxylase enzyme present in tumor cells. 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
disorders, such as sarcoidosis, TB, leprosy, berylliosis, histoplasmosis, and coccidioidomycosis, lead 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 concentrations 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 concentrations occur in some patients with hypercalcemia and leprosy.
Immobilization, particularly complete prolonged bed rest in patients at risk (see Table 9: 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. Young adults with several bone fractures and people with Paget's disease of bone are particularly prone to hypercalcemia when at bed rest.
Idiopathic
infantile hypercalcemia (Williams syndrome—see Table 2: 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. 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) can cause emotional lability, confusion, delirium, psychosis, stupor, and coma. Hypercalcemia may cause neuromuscular symptoms, including 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 plasma Ca concentration > 10.4 mg/dL (> 2.60 mmol/L) or ionized plasma Ca > 5.2 mg/dL (> 1.30 mmol/L). The condition is frequently discovered during routine laboratory screening. Plasma Ca can be artifactually elevated (see Table 10: Fluid and Electrolyte Metabolism: Laboratory and Clinical Findings in Some Disorders Causing Hypercalcemia). Hypercalcemia can also be masked by low serum protein. When protein and albumin are abnormal and when ionized hypercalcemia is suspected because of clinical findings (eg, because of symptoms of hypercalcemia), ionized plasma Ca should be measured.
Initial evaluation:
Initial evaluation should include a review of the history, particularly of past plasma Ca concentration; physical examination; a chest x-ray; and laboratory studies, including electrolytes, BUN, creatinine, ionized Ca, PO4, alkaline phosphatase, and serum protein immunoelectrophoresis. The cause is apparent from clinical data and results of these tests in ≥ 95% of patients. Patients without an obvious cause of hypercalcemia after this evaluation should undergo measurement of intact PTH and 24-h urinary Ca. When hyperparathyroidism is suspected, PO4 renal excretion is often measured.
Asymptomatic hypercalcemia that has been present for years or is present in several family members raises the possibility of FHH. Primary hyperparathyroidism generally presents late in life but can be present for several years before symptoms occur. When no cause is obvious, concentrations of plasma Ca < 11 mg/dL (< 2.75 mmol/L) suggest hyperparathyroidism or other nonmalignant causes, whereas concentration > 13 mg/dL (> 3.25 mmol/L) suggest cancer.
Measurement of intact PTH levels help differentiate PTH-mediated hypercalcemia (eg, caused by hyperparathyroidism or FHH), in which PTH levels are high or high-normal, from most other (PTH-independent) causes. In PTH-independent causes, levels are usually < 20 pg/mL.
The chest x-ray is particularly helpful, revealing most granulomatous disorders, 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.
Chest and bone (eg, skull, extremity) 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, bone x-rays are recommended only for symptomatic patients. X-rays typically show bone cysts, a heterogeneous appearance of the skull, and subperiosteal resorption of bone in the phalanges and distal clavicles.
Hyperparathyroidism:
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 concentration 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 elevation (ie, a high concentration in the absence of hypocalcemia) or an inappropriate high-normal concentration (ie, despite hypercalcemia), is diagnostic. Urinary Ca excretion is usually normal or high in hyperparathyroidism. Primary hyperparathyroidism is suggested by an absence of a family history of endocrine neoplasia, childhood neck irradiation, or other obvious cause. Chronic kidney disease suggests the presence of secondary hyperparathyroidism, but primary hyperparathyroidism can also be present. In patients with chronic kidney 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 done by experienced surgeons. Technetium-99 sestamibi, a newer radionuclide agent for parathyroid imaging, is more sensitive and specific than older 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 several imaging studies (MRI, CT, or high-resolution ultrasound in addition to technetium-99 sestamibi) before repeat parathyroidectomy is sometimes necessary.
Cancer:
A plasma Ca > 13 mg/dL (> 3.00 mmol/L) suggests some cause of hypercalcemia other than hyperparathyroidism. Urinary Ca excretion is usually normal or high in cancer. 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 humoral hypercalcemia of cancer from primary hyperparathyroidism. Humoral hypercalcemia of cancer can also be diagnosed by detection of PTH-related peptide in plasma.
Multiple myeloma is suggested by simultaneous anemia, azotemia, and hypercalcemia . or by the presence of a monoclonal gammopathy. Myeloma is confirmed by bone marrow examination.
FHH:
FHH should be considered in patients with hypercalcemia and elevated or high-normal intact PTH levels. 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.
Milk-alkali
syndrome:
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 when the plasma Ca concentration rapidly returns to normal when Ca and alkali ingestion stops, although renal insufficiency can persist when nephrocalcinosis is present. Circulating PTH usually is suppressed.
Other causes:
In hypercalcemia from sarcoidosis, other granulomatous disorders, and some lymphomas, plasma concentration of 1,25(OH)2D may be elevated. Vitamin D toxicity is also characterized by elevated 1,25(OH)2D concentration. In other endocrine causes of hypercalcemia, such as thyrotoxicosis and Addison's disease, typical laboratory findings of the underlying disorder help establish the diagnosis. When Paget's disease is suspected, plain x-rays (see Paget's Disease of Bone) are done first and may show characteristic abnormalities.
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Table 10
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Laboratory and Clinical
Findings in Some Disorders Causing Hypercalcemia
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Cause
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Findings
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Primary hyperparathyroidism
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Plasma Ca < 12 mg/dL
Ionized plasma Ca > 5.2 mg/dL
Low plasma PO4 (particularly with high renal PO4 excretion)
High alkaline phosphatase (often)
Inappropriately high PTH
Normal or high urinary Ca excretion
No family history of endocrine neoplasia, no neck irradiation during childhood, nor other obvious cause of hyperparathyroidism (typically)
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Secondary hyperparathyroidism
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Plasma Ca < 12 mg/dL
Ionized plasma Ca > 5.2 mg/dL
High plasma PO4 (particularly with high renal PO4 excretion)
High alkaline phosphatase (often)
Inappropriately high PTH
Normal or high urinary Ca excretion
Chronic kidney disease (typically)
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Humoral hypercalcemia of cancer
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Plasma Ca > 12 mg/dL
Low PTH
Normal or low PO4
Possibly metabolic alkalosis, hypochloremia, and hypoalbuminemia
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Familial hypocalciuric hypercalcemia
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Ratio of Ca clearance to creatinine clearance of < 1%
Hypermagnesemia (often)
High or normal PTH
Onset at young age
Hypercalcemia without hypercalciuria in patients and family members
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Milk-alkali syndrome
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No hypercalciuria
Metabolic alkalosis
Azotemia (occasionally)
Low PTH (usually)
Normalization of plasma Ca when Ca and alkali ingestion stops
High intake of Ca antacids (typically)
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PO4
= phosphate; PTH = parathyroid hormone.
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Treatment
There are 4 main strategies for lowering plasma Ca:
The treatment used depends on both the degree and the cause of hypercalcemia.
Mild 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 disorder is treated. When 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 IV as needed. Plasma Ca begins to decrease in 2 to 4 h and falls to near-normal within 24 h.
Moderate hypercalcemia:
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 is done for mild hypercalcemia or, depending on its cause, agents that decrease bone resorption (usually bisphosphonates, calcitonin , or infrequently plicamycin or gallium nitrate), corticosteroids, or chloroquine .
Bisphosphonates inhibit osteoclasts. They are usually the drugs of choice for cancer-associated hypercalcemia. 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 very effectively for an average of > 40 days. Ibandronate 4 to 6 mg IV can be given for cancer-associated hypercalcemia; it is effective for about 14 days. 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 dose is 20 mg/kg po once/day, but the dose must be reduced when GFR is low. Repetitive use of IV bisphosphonates to treat hypercalcemia associated with metastatic bone disease or myeloma has been associated with osteonecrosis of the jaw. Some reports suggest this may be more common with zoledronate. Renal toxicity has been reported in patients receiving zoledronate. Oral bisphosphonates (eg, alendronate or risedronate ) can be given to maintain Ca in the normal range but are not generally used for treating hypercalcemia acutely.
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 with the development of tachyphylaxis (often after about 48 h), 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. Should calcitonin stop working, it can be stopped for 2 days (while prednisone is continued) and then resumed.
Corticosteroids (eg, prednisone 20 to 40 mg po once/day) can help control hypercalcemia as adjunctive therapy 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 concentration in patients with sarcoidosis. Routine ophthalmologic surveillance (eg, retinal examinations every 6 to 12 mo) is mandatory to detect dose-related retinal damage.
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 rarely used 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.
Severe hypercalcemia:
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. 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.
Hyperparathyroidism:
Treatment for hyperparathyroidism depends on severity.
Patients with asymptomatic
primary hyperparathyroidism with no indications for surgery may be treated conservatively with methods to ensure that plasma Ca concentrations remain low. Patients should remain active (ie, avoid immobilization that could exacerbate hypercalcemia), follow a low-Ca diet, drink plenty of fluids to minimize the chance of nephrolithiasis, and avoid drugs that can raise plasma Ca, such as thiazide diuretics. Plasma Ca and renal function are monitored every 6 mo. Bone density is monitored every 12 mo. However, subclinical bone disease, hypertension, and longevity are concerns. Osteoporosis is treated with bisphosphonates.
Surgery is indicated for patients with symptomatic or progressive hypoparathyroidism. The indications for surgery in patients with asymptomatic, primary hyperparathyroidism are controversial. Surgical parathyroidectomy improves bone density and may have modest effects on some quality of life symptoms, but most patients do not have progressive deterioration in biochemical abnormalities or bone density. Still, concerns about hypertension and longevity remain. Many experts recommend surgery in the following circumstances:
Surgery consists of removal of adenomatous glands. PTH concentration can be measured before and after removal of the presumed abnormal gland using rapid assays. A fall of 50% or more 10 min after removal of the adenoma indicates successful treatment. In patients with disease of > 1 gland, several glands are removed, and often a small portion of a normal-appearing parathyroid gland is reimplanted in the belly of the sternocleidomastoid muscle or subcutaneously in the forearm to prevent hypoparathyroidism. Parathyroid tissue is also occasionally preserved using cryopreservation to allow for later autologous transplantation in case persistent hypoparathyroidism develops.
When hyperparathyroidism is mild, the plasma Ca concentration drops to just below normal within 24 to 48 h after surgery; plasma Ca must be monitored. In patients with severe osteitis fibrosa cystica, prolonged, symptomatic hypocalcemia may occur postoperatively unless 10 to 20 g elemental Ca is given in the days before surgery. Even with preoperative Ca administration, large doses of Ca and vitamin D may be required (see Fluid and Electrolyte Metabolism: Treatment) while bone Ca is repleted.
Hyperparathyroidism
in renal failure is usually secondary. Measures used for treatment can also be used for prevention. One aim is to prevent hyperphosphatemia. Treatment combines dietary PO4 restriction and PO4-binding agents, such as Ca carbonate or sevelamer . Despite the use of PO4 binders, dietary restriction of PO4 is needed. Aluminum-containing compounds have been used to limit PO4 concentration, but they should be avoided, especially in patients receiving long-term dialysis, to prevent aluminum accumulation in bone resulting in severe osteomalacia. Vitamin D administration is potentially hazardous in renal failure because it can increase PO4 absorption and contribute to hypercalcemia; administration requires frequent monitoring of Ca and PO4. Treatment should be limited to patients with any of the following:
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 concentration of 1,25(OH)2D directly suppresses PTH release. Simple osteomalacia may respond to 0.25 to 0.5 μg once/day of oral calcitriol , whereas correction of postparathyroidectomy hypocalcemia may require prolonged administration of as much as 2 μg of calcitriol once/day and ≥ 2 g of elemental Ca/day The calcimimetic, cinacalcet , modulates the set point of the Ca-sensing receptor on parathyroid cells and decreases PTH concentration in dialysis patients without increasing plasma Ca. In patients with osteomalacia caused by having taken large amounts of aluminum-containing PO4 binders, removal of aluminum with deferoxamine is necessary before improvement in bone lesions occurs with calcitriol .
FHH:
Although FHH results from histologically abnormal parathyroid tissue, the response to subtotal parathyroidectomy is unsatisfactory. Because overt clinical manifestations are rare, drug therapy is not routinely indicated.
Last full review/revision May 2009 by James L. Lewis, III, MD
Content last modified May 2009
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