A Practical Approach to Hypercalcemia

1 MAY1, 2003 / VOLUME67, inorganic molecules. Low albumin lev-els can affect the total serum calcium 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 = ( g per dL [plasma albumin]) + [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.

2 Normal serum calcium levelsare 8 to 10 mg per dL ( to mmol per L,Figure 1),although the exact range can varyamong laboratories. Normal ionized calciumlevels are 4 to mg per dL (1 to mmol perL). Hypercalcemia is considered mild if thetotal serum calcium level is between and12 mg per dL ( and 3 mmol per L).5 Levelshigher than 14 mg per dL ( mmol per L)can be life 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 calciumHypercalcemia is a disordercommonly encountered byprimary care one in 500patients who are treated in ageneral medicine clinic have undiagnosed pri-mary hyperparathyroidism , the leading causeof diagnosis of hyper-calcemia most often is made incidentallywhen a high calcium level is detected in bloodsamples.

3 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 of HypercalcemiaThe skeleton contains 98 percent of totalbody 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.

4 Theremainder is bound to albumin, globulin, andHypercalcemia 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 hormone is suppressed in malignancy-associated Hypercalcemia and elevatedin primary hyperparathyroidism .

5 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 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.)

6 Copyright 2003 American Academy of Family Physicians)A Practical Approach to HypercalcemiaMARY F. CARROLL, , Eastern New Mexico Medical Center, Roswell, New MexicoDAVID S. SCHADE, , University of New Mexico School of Medicine and Health Sciences Center,Albuquerque, New MexicoSee page 1853 fordefinitions of strength-of-evidence 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 D is a steroid hormone that isobtained through the diet or produced by theaction of sunlight on vitamin D precursors inthe skin.

7 Calcitriol, the active form of vitaminD,is derived from successive hydroxylation ofthe 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 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.

8 Calcitonin levels might beelevated in pregnant patients and in patientswith medullary carcinoma of the ,there are no direct clinical sequelae,and serum calcium levels usually are peptide (PTHrP) is the princi-pal mediator in Hypercalcemia associated withsolid 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 Manifestations of HypercalcemiaThe optimal concentration of serum ionizedcalcium is essential for normal cellular func-tion.

9 Hypercalcemia leads to hyperpolariza-tion of cell membranes. Patients with levels ofcalcium between and 12 mg per dL can the serum calcium levelrises above this stage, multisystem manifesta-tions become apparent (Table 2).This constel-lation of symptoms has led to the mnemonic Stones, bones, abdominal moans, and , NUMBER9 / MAY1, 2003 TABLE 1 Actions of the Hormones Involved in Calcium HomeostasisHormoneEffect on bonesEffect on gutEffect on kidneysParathyroid hormone Ca++, Supports osteoclast Indirect effects via Supports Ca++resorption PO4levels in bloodresorption calcitriol from and PO4excretion, activates 1-hydroxylation1-hydroxylationCalcitriol (vitamin D)

10 Ca++, No direct effects Ca++and PO4No direct effects PO4levels in bloodSupports osteoblastsabsorptionCalcitonin causes Ca++, PO4 Inhibits osteoclast No direct effectsPromotes Ca++and PO4levels in blood when resorptionexcretionhypercalcemia is presentCa++= calcium; PO4= phosphate 1. Spectrum of Hypercalcemia indicated by serum total and ionized calcium of HypercalcemiaIonized serum calcium level, mg/dL (mmol/L)4 (1) ( )8 (2)10 ( )12 (3)NormocalcemiaMild hypercalcemiaModeratehypercalcemiaHyperc alcemiccrisisTotal serum calcium level, mg/dL (mmol/L)8 (2)10 ( )12 (3)14 ( )16 (4)groans, which is used to recall the signs andsymptoms of Hypercalcemia , particularly as aresult of primary effects include impairedconcentration, confusion, corneal calcifica-tion, fatigue, and muscle ,abdominal pain, anorexia, constipation, and,rarely, peptic ulcer disease or pancreatitis areamong the gastrointestinal most important renal effects are polydip-sia and polyuria resulting from nephrogenicdiabetes insipidus, and nephrolithiasis result-ing from hypercalciuria.