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MAY 1, 2003 / VOLUME 67, NUMBER 9 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 1959

other inorganic molecules. Low albumin lev-els can affect the total serum calcium level.Directly measuring the free calcium level ismore convenient and accurate, but the follow-ing formula can be used to calculate the cor-rected total serum calcium level:

Corrected calcium = (4.0 g per dL [plasma albumin]) 0.8 + [serum calcium]

Parathyroid hormone (PTH), 1,25-dihy-droxyvitamin D3 (calcitriol), and calcitonincontrol calcium homeostasis in the body(Table 1). Increased bone resorption, increasedgastrointestinal absorption of calcium, anddecreased renal excretion of calcium causehypercalcemia. Normal serum calcium levelsare 8 to 10 mg per dL (2.0 to 2.5 mmol per L,Figure 1), although the exact range can varyamong laboratories. Normal ionized calciumlevels are 4 to 5.6 mg per dL (1 to 1.4 mmol perL). Hypercalcemia is considered mild if thetotal serum calcium level is between 10.5 and12 mg per dL (2.63 and 3 mmol per L).5 Levelshigher than 14 mg per dL (3.5 mmol per L)can be life threatening.

PTH is an 84-amino acid hormone pro-duced by the four pea-sized parathyroid glandsposterior to the thyroid gland. In response tolow serum calcium levels, PTH raises calcium

Hypercalcemia is a disordercommonly encountered byprimary care physicians.Approximately one in 500patients who are treated in a

general medicine clinic have undiagnosed pri-mary hyperparathyroidism, the leading causeof hypercalcemia.1-4 The diagnosis of hyper-calcemia most often is made incidentallywhen a high calcium level is detected in bloodsamples. The principal challenges in the man-agement of hypercalcemia are distinguishingprimary hyperparathyroidism from condi-tions that will not respond to parathyroidec-tomy and knowing when it is appropriate torefer the patient for surgery. It is essential thatphysicians know how to evaluate and opti-mally manage patients with hypercalcemia,because treatment and prognosis vary accord-ing to the underlying disorder.

Pathophysiology of HypercalcemiaThe skeleton contains 98 percent of total

body calcium; the remaining 2 percent circu-lates throughout the body. One half of circu-lating calcium is free (ionized) calcium, theonly form that has physiologic effects. Theremainder is bound to albumin, globulin, and

Hypercalcemia is a disorder commonly encountered by primary care physicians. The diag-nosis often is made incidentally in asymptomatic patients. Clinical manifestations affect theneuromuscular, gastrointestinal, renal, skeletal, and cardiovascular systems. The most com-mon causes of hypercalcemia are primary hyperparathyroidism and malignancy. Someother important causes of hypercalcemia are medications and familial hypocalciuric hyper-calcemia. An initial diagnostic work-up should include measurement of intact parathyroidhormone, and any medications that are likely to be causative should be discontinued.Parathyroid hormone is suppressed in malignancy-associated hypercalcemia and elevatedin primary hyperparathyroidism. It is essential to exclude other causes before consideringparathyroid surgery, and patients should be referred for parathyroidectomy only if theymeet certain criteria. Many patients with primary hyperparathyroidism have a benigncourse and do not need surgery. Hypercalcemic crisis is a life-threatening emergency.Aggressive intravenous rehydration is the mainstay of management in severe hypercal-cemia, and antiresorptive agents, such as calcitonin and bisphosphonates, frequently canalleviate the clinical manifestations of hypercalcemic disorders. (Am Fam Physician2003;67:1959-66. Copyright 2003 American Academy of Family Physicians)

A Practical Approach to HypercalcemiaMARY F. CARROLL, M.D., Eastern New Mexico Medical Center, Roswell, New MexicoDAVID S. SCHADE, M.D., University of New Mexico School of Medicine and Health Sciences Center,Albuquerque, New Mexico

See page 1853 fordefinitions of strength-of-evidence levels.

levels by accelerating osteoclastic bone resorp-tion and increasing renal tubular resorption ofcalcium. It also increases calcitriol, which indi-rectly raises serum calcium levels. PTH causesphosphate loss through the kidneys. Thus, inpatients with PTH-mediated hypercalcemia,serum phosphate levels tend to be low.

Vitamin D is a steroid hormone that isobtained through the diet or produced by theaction of sunlight on vitamin D precursors inthe skin. Calcitriol, the active form of vitaminD, is derived from successive hydroxylation of

the precursor cholecalciferol, first in the liver(25-hydroxylation), then in the kidneys (1-hydroxylation). Adequate vitamin D is nec-essary for bone formation. However, the prin-cipal target for vitamin D is the gut, where itincreases the absorption of calcium and phos-phate. Thus, in vitamin D-mediated hypercal-cemia, serum phosphate levels tend to be high.

Calcitonin is a 32-amino acid hormone pro-duced by the parafollicular C cells of the thy-roid. Calcitonin is a weak inhibitor of osteoclastactivation and opposes the effects of PTH onthe kidneys, thereby promoting calcium andphosphate excretion. Calcitonin levels might beelevated in pregnant patients and in patientswith medullary carcinoma of the thyroid.However, there are no direct clinical sequelae,and serum calcium levels usually are normal.

PTH-related peptide (PTHrP) is the princi-pal mediator in hypercalcemia associated withsolid tumors.6 PTHrP is homologous with PTHat the amino terminus, the region that com-prises the receptor-binding domain. PTHrPbinds the PTH receptor and mimics the bio-logic effects of PTH on bones and the kidneys.

Clinical Manifestations of HypercalcemiaThe optimal concentration of serum ionized

calcium is essential for normal cellular func-tion. Hypercalcemia leads to hyperpolariza-tion of cell membranes. Patients with levels ofcalcium between 10.5 and 12 mg per dL can beasymptomatic.7 When the serum calcium levelrises above this stage, multisystem manifesta-tions become apparent (Table 2). This constel-lation of symptoms has led to the mnemonicStones, bones, abdominal moans, and psychic

1960 AMERICAN FAMILY PHYSICIAN www.aafp.org/afp VOLUME 67, NUMBER 9 / MAY 1, 2003

TABLE 1

Actions of the Hormones Involved in Calcium Homeostasis

Hormone Effect on bones Effect on gut Effect on kidneys

Parathyroid hormone Ca++, Supports osteoclast Indirect effects via Supports Ca++ resorption PO4 levels in blood resorption calcitriol from and PO4 excretion, activates

1-hydroxylation 1-hydroxylation

Calcitriol (vitamin D) Ca++, No direct effects Ca++ and PO4 No direct effectsPO4 levels in blood Supports osteoblasts absorption

Calcitonin causes Ca++, PO4 Inhibits osteoclast No direct effects Promotes Ca++ and PO4levels in blood when resorption excretionhypercalcemia is present

Ca++ = calcium; PO4 = phosphate radical.

FIGURE 1. Spectrum of hypercalcemia indicated by serum total and ionized calcium levels.

Spectrum of Hypercalcemia

Ionized serum calcium level, mg/dL (mmol/L)

4 (1) 5.6 (1.4) 8 (2) 10 (2.5) 12 (3)

Normocalcemia

Mild hypercalcemia

Moderatehypercalcemia

Hypercalcemiccrisis

Total serum calcium level, mg/dL (mmol/L)

8 (2) 10 (2.5) 12 (3) 14 (3.5) 16 (4)

groans, which is used to recall the signs andsymptoms of hypercalcemia, particularly as aresult of primary hyperparathyroidism.

Neuromuscular effects include impairedconcentration, confusion, corneal calcifica-tion, fatigue, and muscle weakness.8 Nausea,abdominal pain, anorexia, constipation, and,rarely, peptic ulcer disease or pancreatitis areamong the gastrointestinal manifestations.The most important renal effects are polydip-sia and polyuria resulting from nephrogenicdiabetes insipidus, and nephrolithiasis result-ing from hypercalciuria. Other renal effectsinclude dehydration and nephrocalcinosis.Cardiovascular effects include hypertension,vascular calcification, and a shortened QTinterval on the electrocardiogram. Cardiacarrhythmias are rare. Bone pain can occur inpatients with hyperparathyroidism or malig-nancy. Osteoporosis of cortical bone, such asthe wrist, is mainly associated with primaryhyperparathyroidism.9 Excess PTH also canresult in subperiosteal resorption, leading toosteitis fibrosa cystica with bone cysts andbrown tumors of the long bones.

Differential Diagnosis for HypercalcemiaPrimary hyperparathyroidism and malig-

nancy account for more than 90 percent ofhypercalcemia cases. These conditions must bedifferentiated early to provide the patient withoptimal treatment and accurate prognosis.Humoral hypercalcemia of malignancy impliesa very limited life expectancyoften only a mat-ter of weeks. On the other hand, primary hyper-parathyroidism has a relatively benign course.

The causes of hypercalcemia can be dividedinto seven categories: hyperparathyroidism,vitamin D-related causes, malignancy, med-ications, other endocrine disorders, geneticdisorders, and miscellaneous causes (Table 3).Evaluation of a patient with hypercalcemia(Figure 2) should include a careful history andphysical examination focusing on clinicalmanifestations of hypercalcemia, risk factorsfor malignancy, causative medications, and afamily history of hypercalcemia-associatedconditions (e.g., kidney stones).


TABLE 2

Clinical Manifestations of Hypercalcemia

Renal stonesNephrolithiasisNephrogenic diabetes insipidusDehydrationNephrocalcinosis

Skeleton bonesBone painArthritisOsteoporosisOsteitis fibrosa cystica in

hyperparathyroidism (subperiostealresorption, bone cysts)

Gastrointestinal abdominalmoans

Nausea, vomitingAnorexia, weight lossConstipationAbdominal painPancreatitisPeptic ulcer disease

Neuromuscular psychic groansImpaired concentration and memoryConfusion, stupor, comaLethargy and fatigueMuscle weaknessCorneal calcification (band

keratopathy)

CardiovascularHypertensionShortened QT interval on

electrocardiogramCardiac arrhythmiasVascular calcification

OtherItchingKeratitis, conjunctivitis

TABLE 3

Causes of Hypercalcemia

Parathyroid hormone-relatedPrimary hyperparathyroidism*

Sporadic, familial, associated with multiple endocrine neoplasia I or II

Tertiary hyperparathyroidism Associated with chronic renal failure

or vitamin D deficiency Vitamin D-related Vitamin D intoxication

Usually 25-hydroxyvitamin D2 in over-the-counter supplements

Granulomatous disease sarcoidosis, berylliosis, tuberculosis

Hodgkins lymphoma

Malignancy Humoral hypercalcemia of

malignancy* (mediated by PTHrP)Solid tumors, especially lung,

head, and neck squamous cancers, renal cell tumors

Local osteolysis* (mediated by cytokines) multiple myeloma, breast cancer

PTHrP = parathyroid hormone-related peptide.

*The most common causes of hypercalcemia.

Medications Thiazide diuretics (usually mild)* Lithium Milk-alkali syndrome (from calcium

antacids) Vitamin A intoxication (including

analogs used to treat acne)

Other endocrine disorders Hyperthyroidism Adrenal insufficiency Acromegaly Pheochromocytoma

Genetic disorders Familial hypocalciuric hypercalcemia:

mutated calcium-sensing receptor

Other Immobilization, with high bone

turnover (e.g., Pagets disease, bedridden child)

Recovery phase of rhabdomyolysis

HYPERPARATHYROIDISM

Increased screening of calcium levels andwide availability of reliable assays for intact PTHlevels have led to more frequent and earlierdiagnoses of primary hyperparathyroidism. In80 percent of cases, a single parathyroid ade-noma is responsible. However, hyperpara-

thyroidism also can result from hyperplasia ofthe parathyroid glands or, rarely, parathyroidcarcinoma. In primary or tertiary hyper-parathyroidism, PTH levels are normal or highin the setting of hypercalcemia (Figure 3).

In many patients, primary hyperparathy-roidism progresses very slowly. Patientsshould be considered for parathyroidectomy


FIGURE 2. Diagnostic algorithm for the evaluation of hypercalcemia. Primary hyperparathy-roidism and malignancy account for more than 90 percent of cases. Intact PTH will be suppressedin cases of malignancy-associated hypercalcemia, except for the extremely rare parathyroid car-cinoma. The physician can conclude diagnostic testing and treat the causative disorder once afinal diagnosis step has been reached. (Ca++ = calcium; OTC = over-the-counter; PTH = parathy-roid hormone; PTHrP = parathyroid hormone-related peptide; TSH = thyroid-stimulating hor-mone; T4 = free thyroxine; MRI = magnetic resonance imaging.)

Evaluation of Hypercalcemia

Familial hypocalciurichypercalcemia

Primary or tertiary hyperparathyroidism

Stop causative medications if possible, and recheckcalcium level.

Hypercalcemia detectedTotal Ca++ >10.5 mg/dL (2.63 mmol/L) or ionized Ca++ >5.6 mg/dL (1.4 mmol/L)

Symptom-guided malignancy work-upSolid tumors

PTHrP: adeno and squamous cancer (e.g., lung tumor)

Alkaline phosphatase: bone lysis (e.g., breast tumor)

Hematologic malignancies Positive myeloma screen: multiple myeloma Calcitriol: lymphoma, granulomatous diseases

Careful history and physical examination focusing on: Clinical features of hypercalcemia (see Table 2) Possible causative diseases (see Table 3) Possible causative medications,

including OTC (see Table 3)

Check 24-hour urinary Ca++ level

If malignancy work-up is negative

Suppressed Normal or high

Measure intact PTH level.

Test for other endocrinopathies (considerreferral to endocrinologist) Hyperthyroidism: TSH, free T4 Adrenal insufficiency: cortisol Acromegaly: insulin-like growth

factor 1, pituitary MRI

Low Normal or high

If surgery indicated (see Table 4)

Consider parathyroidsestamibi scan.

Parathyroidectomy

only if they meet criteria recommended by theNational Institutes of Health ConsensusDevelopment Conference (Table 4).10 [Evi-dence level C, consensus opinion] The diseasewill progress in approximately one fourth ofpatients who do not undergo surgery.11 Pre-operative nuclear imaging of the parathyroidswith a sestamibi scan (Figure 4) allows the sur-geon to perform unilateral neck dissection,which results in reduced operative time andless morbidity.12 Risks of parathyroid surgeryinclude permanent hypoparathyroidism anddamage to the recurrent laryngeal nerve.

Chronic renal failure generally causeshypocalcemia. If untreated, prolonged highphosphate and low vitamin D levels can leadto increased PTH secretion and subsequenthypercalcemia. This is termed tertiary hyper-parathyroidism.

VITAMIN D-MEDIATED CAUSESThe most commonly available vitamin D

supplements consist of 25-hydroxyvitaminD2. In suspected overdose of over-the-countervitamin D, the level of 25-hydroxyvitamin D3(not 1,25-dihydroxyvitamin D3) should bemeasured. Macrophages can cause granu-loma-forming (i.e., sarcoidosis, tuberculosis,Hodgkins lymphoma) increased extra-renalconversion of 25-hydroxyvitamin D3 to cal-citriol. PTH levels are suppressed, and levels of1,25-dihydroxyvitamin D3 are elevated.Hypercalcemia mediated by excessive vitaminD responds to a short course of glucocorti-coids if the underlying disease is treated.

HYPERCALCEMIA OF MALIGNANCY

Hypercalcemia of malignancy occurs in sev-eral settings.13 It is mediated most commonlyby systemic PTHrP in patients with solidtumors. This is known as the humoral hyper-calcemia of malignancy. PTHrP mimics thebone and renal effects of PTH. In contrast toprimary hyperparathyroidism, the humoralhypercalcemia of malignancy is associatedwith suppressed PTH levels and normal cal-citriol levels. Extensive bone lysis also cancause malignancy-associated hypercalcemia.


FIGURE 3. Representative serum calcium and PTH levels in patients withcalcium disorders. The four differently shaped panels depict where theserum calcium level will plot in relation to the PTH level in various con-ditions. In primary hyperparathyroidism, a high PTH level correlateswith a high calcium level. In malignancy-associated hypercalcemia, PTHis suppressed. (PTH = parathyroid hormone)

Representative Normogram for Interpreting Serum Intact PTH Levels

Total serum calcium level, mg/dL (mmol/L)

6 (1.5) 8 (2) 10 (2.5) 12 (3) 14 (3.5) 16 (4)

Inta

ct P

TH (

pg

/mL)

500

200

150

100

50

Hypopara-thyroidism

Normal

Malignancy

Primary hyperparathyroidism

TABLE 4

Criteria for Surgery in Primary Hyperparathyroidism*

Serum total calcium level > 12 mg per dL (3 mmol per L) at any timeHyperparathyroid crisis (discrete episode of life-threatening hypercalcemia)Marked hypercalciuria (urinary calcium excretion more than 400 mg per day)NephrolithiasisImpaired renal functionOsteitis fibrosa cysticaReduced cortical bone density (measure with dual x-ray absorptiometry or

similar technique)Bone mass more than two standard deviations below age-matched controls

(Z score less than 2)Classic neuromuscular symptoms

Proximal muscle weakness and atrophy, hyperreflexia, and gait disturbanceAge younger than 50

*Guidelines from the National Institutes of Health Consensus DevelopmentConference.

Information from NIH conference: diagnosis and management of asymptomaticprimary hyperparathyroidism: consensus development conference statement.Ann Intern Med 1991;114:593-7.

Multiple myeloma and metastatic breast can-cer can present in this way. In osteolytic hyper-calcemia, the alkaline phosphatase level is usu-ally markedly elevated. Hodgkins lymphomacauses hypercalcemia through increased pro-duction of calcitriol.

MEDICATIONS

Thiazide diuretics increase renal calciumresorption and cause mild hypercalcemia thatshould resolve when the medication is discon-tinued. Thiazide diuretic therapy can unmaskmany cases of primary hyperparathyroidism.Consumption of large amounts of calciumcarbonate via calcium-containing antacidscan lead to hypercalcemia, alkalosis, and renalinsufficiencyan uncommon disordertermed milk-alkali syndrome.14 Lithium usecan cause hypercalcemia by increasing the setpoint of PTH,15 requiring a higher serum cal-

cium level to switch off PTH secretion. Largedoses of vitamin A and its analogs can causehypercalcemia, which appears to be mediatedthrough increased bone resorption.

OTHER ENDOCRINE DISORDERS

Thyrotoxicosis-induced bone resorption canresult in mild hypercalcemia. Volume expan-sion and glucocorticoid replacement can cor-rect the hypercalcemia that occasionally occursin patients with adrenal insufficiency. Pheo-chromocytoma is thought to cause hypercal-cemia through the production of PTHrP.Pheochromocytoma may be associated withprimary hyperparathyroidism as part of type 1multiple endocrine neoplasia syndrome.

FAMILIAL HYPOCALCIURIC HYPERCALCEMIA

Familial hypocalciuric hypercalcemia16

(FHH) is an autosomal-dominant conditionwith virtually 100 percent penetrance. Mostcases are caused by a mutation in the calcium-sensing receptor gene. Patients have moderatehypercalcemia from an early age but relativelylow urinary calcium excretion. PTH levels canbe normal or only mildly elevated despite thehypercalcemia. This mild elevation can lead toan erroneous diagnosis of primary hyper-parathyroidism. The conditions can be differ-entiated by use of a 24-hour urinary collectionfor calcium; calcium levels will be high or nor-mal in patients with hyperparathyroidism andlow in patients with FHH. Parathyroidectomyis not beneficial in patients with FHH.

MISCELLANEOUS CAUSES

In conditions of high bone turnover, such asPagets disease and normal growth in children,immobilization can cause hypercalcemia.Hyper-calcemia also can occur in the recovery phase ofrhabdomyolysis-induced renal injury, when cal-cium deposited in soft tissue is mobilized.

Treatment of HypercalcemiaAsymptomatic patients with mild hypercal-

cemia generally do not benefit from normal-ization of their serum calcium levels. Patientswith calcium levels greater than 14 mg per dL


The Authors

MARY F. CARROLL, M.D., is director of endocrinology and metabolism at Eastern NewMexico Medical Center, Roswell. She graduated from Trinity College in Dublin, Ireland,and completed a residency in internal medicine and a fellowship in endocrinology andmetabolism at the University of New Mexico School of Medicine in Albuquerque.

DAVID S. SCHADE, M.D., is professor of medicine and chief of endocrinology andmetabolism at the University of New Mexico School of Medicine and Health SciencesCenter. He graduated from Washington University School of Medicine in St. Louis andcompleted a residency in internal medicine and a fellowship in endocrinology andmetabolism at the University of New Mexico School of Medicine.

Address correspondence to David S. Schade, M.D., University of New Mexico HealthSciences Center, Department of Internal Medicine/5-ACC, Division of Endocrinology,2211 Lomas Blvd. NE, Albuquerque, NM 87131 ([email protected]). Reprintsare not available from the authors.

FIGURE 4. Parathyroid sestamibi nuclear scan showing normal uptakein the salivary glands and thyroid, and an abnormal focus inferior tothe left lobe consistent with a left inferior parathyroid adenoma. Theadenoma was successfully removed following a unilateral neck dissec-tion in a 66-year-old woman who presented in a hyperparathyroidstorm with a serum calcium level of 16.4 mg per dL (4.1 mmol per L).

Salivary glands

Right and left lobes of thyroid gland

Left inferior parathyroid gland

. .

.

..

or symptomatic patients with calcium levelsgreater than 12 mg per dL (Table 5) should beimmediately and aggressively treated.17 Thesafest and most effective treatment of hyper-calcemic crisis is saline rehydration followedby furosemide (Lasix) diuresis, calcitonin, andbisphosphonates.

HYDRATION AND DIURESIS

In patients with mild hypercalcemia, ade-quate hydration should be encouraged andimmobilization discouraged. In symptomaticpatients, a loop diuretic (e.g., furosemide) canbe prescribed. Recent evidence suggests thatestrogen-replacement therapy might be bene-ficial in postmenopausal women with pri-mary hyperparathyroidism.18 [Evidence levelB, lower-quality randomized controlled trial]

In patients with severe hypercalcemia, themainstay of management is aggressive intra-venous rehydration. Normal saline should beused to achieve a urine output of 200 mL per

hour. Only when the intravascular volume hasbeen restored should a loop diuretic be usedin low dosages (e.g., furosemide, 10 to 20 mg)to further lower the serum calcium level ifnecessary.

PHARMACOLOGIC AGENTS

In malignancy-associated hypercalcemia,intravenous pamidronate (Aredia), 60 to 90mg, can be given by four-hour infusion.13 Thisagent often will normalize the serum calciumlevel, but peak effects do not occur until 48 to72 hours after infusion. Caution must be usedwith bisphosphonates19 in patients with renal


TABLE 5

Pharmacologic Options for the Treatment of Hypercalcemia

Agent Mode of action Indication in hypercalcemia Cautions

Normal saline 2 to 4 L IV Enhances filtration and Severe Ca++ > 14 mg per dL May exacerbate heart failure in daily for 1 to 3 days excretion of Ca++ (3.5 mmol per L) elderly patients

Moderate Ca++ with Lowers Ca++ by 1 to 3 mg per dL symptoms (0.25 to 0.75 mmol per L)

Furosemide (Lasix) 10 to Inhibits calcium resorption Following aggressive K+, dehydration if used before 20 mg IV as necessary in the distal renal tubule rehydration intravascular volume is restored

Bisphosphonates Inhibits osteoclast action Hypercalcemia of malignancy Nephrotoxicity, Ca++, PO4, Pamidronate (Aredia), 60 to and bone resorption rebound Ca++ in

90 mg IV over 4 hours hyperparathyroidismZoledronic acid (Zometa), Maximal effects at 72 hours

4 mg IV over 15 minutes

Calcitonin (Calcimar or Inhibits bone resorption, Initial treatment (after Rebound Ca++ after 24 hours, Miacalcin) 4 to 8 IU per augments Ca++ excretion rehydration) in severe Ca++ vomiting, cramps, flushingkg IM or SQ every 6 hours Rapid Ca++ within 2 to 6 hoursfor 24 hours

Glucocorticoids Inhibits vitamin D conversion Vitamin D intoxication, Immune suppression, myopathyHydrocortisone, 200 mg to calcitriol hematologic malignancies,

IV daily for 3 days granulomatous disease

Plicamycin (Mithracin), 25 mcg Cytotoxic to osteoclasts Rarely used in severe Ca++ Marrow, hepatic, renal toxicityper kg per day IV over 6 hours for 3 to 8 doses

Gallium nitrate (Ganite) Inhibits osteoclast action Rarely used in severe Ca++ Renal and marrow toxicity100 to 200 mg per m2 IV over 24 hours for 5 days

IV = intravenously; Ca++ = calcium; = increase; = decrease; K+ = potassium; PO4 = phosphate radical; IM = intramuscularly; SQ =subcutaneously.

Patients with calcium levels greater than 14 mg per dL (3.5 mmol per L) or symptomatic patients with calcium levelsgreater than 12 mg per dL (3 mmol per L) should be immedi-ately and aggressively treated.

Hypercalcemia

impairment. In severe hypercalcemia refrac-tory to saline diuresis, calcitonin (Calcimar,Miacalcin) can be given every six hours. Thistreatment has a rapid onset but short durationof effect, and patients develop tolerance to thecalcium-lowering effect. Other antiresorptiveagents that are used occasionally include pli-camycin (Mithracin) and gallium nitrate(Ganite). In hypercalcemia mediated by vita-min D and in hematologic malignancies (e.g.,myeloma, lymphoma), glucocorticoids are thefirst line of therapy after fluids.

DIALYSIS

In cases of resistant, life-threatening hyper-calcemia, hemodialysis against a low-calciumdialysate is more effective than peritoneal dial-ysis in lowering serum calcium levels. Therapyfor the underlying condition should be insti-tuted as soon as possible. Consultation withan endocrinologist is recommended.

SURGERY

In cases of hypercalcemic crisis resultingfrom primary hyperparathyroidism, urgentparathyroidectomy is potentially curative.20

The authors thank Carolyn King for assistance in thepreparation of this manuscript.

The authors indicate that they do not have any con-flicts of interest. Sources of funding: none reported.

REFERENCES

1. Silverberg SJ, Fitzpatrick LA, Bilezikian JP. Hyper-parathyroidism. In: Becker KL, ed. Principles andpractice of endocrinology and metabolism. 2d ed.Philadelphia: Lippincott, 1995:512-9.

2. Bringhurst FR, Demay MB, Kronenberg HM. Hor-mones and disorders of mineral metabolism. In:Wilson JD, ed. Williams Textbook of endocrinology.9th ed. philadelphia: Saunders, 1998:1155-1209.

3. Wermers RA, Khosla S, Atkinson EJ, Hodgson SF,OFallon WM, Melton LJ 3d. The rise and fall of pri-mary hyperparathyroidism: a population-basedstudy in Rochester, Minnesota, 1965-1992. AnnIntern Med 1997;126:433-40.

4. Al Zahrani A, Levine MA. Primary hyperparathy-roidism. Lancet 1997;349:1233-8.

5. Bushinsky DA, Monk RD. Electrolyte quintet: cal-cium. Lancet 1998;352:306-11.

6. Strewler GJ. The physiology of parathyroid hormone-related protein. N Engl J Med 2000;342:177-85.

7. Shane E. Hypercalcemia: pathogenesis, clinicalmanifestations, differential diagnosis, and man-agement. In: Favus MJ, ed. Primer on the metabolicbone diseases and disorders of mineral metabo-lism. 4th ed. Philadelphia: Lippincott, Williams &Wilkins, 1999:183-7.

8. Solomon BL, Schaaf M, Smallridge RC. Psychologicsymptoms before and after parathyroid surgery.Am J Med 1994;96:101-6.

9. Abdelhadi M, Nordenstrom J. Bone mineral recov-ery after parathyroidectomy in patients with pri-mary and renal hyperparathyroidism. J ClinEndocrinol Metab 1998;83:3845-51.

10. NIH conference: diagnosis and management ofasymptomatic primary hyperparathyroidism: con-sensus development conference statement. AnnIntern Med 1991;114:593-7.

11. Silverberg SJ, Shane E, Jacobs TP, Siris E, BilezikianJP. A 10-year prospective study of primary hyper-parathyroidism with or without parathyroidsurgery. N Engl J Med 1999;341:1249-55.

12. Gupta VK, Yeh KA, Burke GJ, Wei JP. 99m-tech-netium sestamibi localized solitary parathyroid ade-noma as an indication for limited unilateral surgicalexploration. Am J Surg 1998;176:409-12.

13. Mundy GR, Guise TA. Hypercalcemia of malig-nancy. Am J Med 1997;103:134-45.

14. Orwoll ES. The milk-alkali syndrome: current con-cepts. Ann Intern Med 1982;97:242-8.

15. Mallette LE, Eichhorn E. Effects of lithium carbon-ate on human calcium metabolism. Arch InternMed 1986;146:770-6.

16. Marx SJ. Familial hypocalciuric hypercalcemia. In:Favus MJ ed. Primer on the metabolic bone diseasesand disorders of mineral metabolism. 4th ed. Philadel-phia: Lippincott, Williams & Wilkins, 1999:195-8.

17. Ziegler R. Hypercalcemic crisis. J Am Soc Nephrol2001;12(suppl 17):S3-9.

18. Orr-Walker BJ, Evans MC, Clearwater JM, Horne A,Grey AB, Reid IR. Effects of hormone replacementtherapy on bone mineral density in postmeno-pausal women with primary hyperparathyroidism:four-year follow-up and comparison with healthypostmenopausal women. Arch Intern Med 2000;160;2161-6.

19. Lourwood DL. The pharmacology and therapeuticutility of bisphosphonates. Pharmacotherapy 1998;18:779-89.

20. Fitzpatrick LA, Bilezikian JP. Acute primary hyper-parathyroidism. Am J Med 1987;82:275-82.


Recent evidence suggests that estrogen-replacement therapymight be beneficial in postmenopausal women with primaryhyperparathyroidism.

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