Introduction

Hypercalcemia, defined as a total serum calcium concentration greater than 2.5 mmol/l (10.2 mg/dl), or a serum ionized calcium concentration greater than 1.3 mmol/l (5.3 mg/dl), results from an imbalance between calcium influx (from bone resorption and gastrointestinal absorption) and efflux (by renal excretion). Calcium has widespread metabolic and electrophysiological roles; hence there are a variety of clinical presentations of hypercalcemia ranging from asymptomatic individuals to those in the coma of hypercalcemic crisis (Ti.bJe.1.). Most of the symptoms and signs are non-specific and are present with all etiologies of hypercalcemia. Relatively more intense symptoms are described with higher serum concentrations of calcium and with a more acute onset of hypercalcemia. The incidence of hypercalcemia is approximately 400 new cases per million population per year, but may exceed 3 per cent of the hospital population. Most of these are mild episodes, and the incidence of severe hypercalcemia, arbitrarily defined as serum calcium greater than 3.5 mmol/l or 14 mg/dl ( KayeJ995), is not known. More detailed discussions are given by Payne.elal (1973), Benabe ..a.Q,d..,Ma.^[ilD®z:Ma,l.doO§do..i,19.9.4), and Strewler„aod.., Rosenblatt.., i.1.9.,9..5)..

CcJr.ï mMU OqpnKOT. <rp*»'*d runVxy W*ytr. iyirpn M^nofi^ Hna. aypof. cortlaoii

HU rttafflrvrtftUi pnnnu mraHPY IwOWM. ibjuxd dt*p Itreto rakon

Hrfiefc I. -fWii ÛÎ wmi en eCi Rtrtjl PïiHMl hjpWUfKmc ili a s > s I nai hwwrit. BUM. mm imww.

WtAtr. imnini

Ûi tM ■ lia -d kfrttafolip. !shk : a c^u to ff 4 bAiHHi b^Tf-d-äoiM

Table 1 Symptoms and signs of hypercalcemia.

In blood, calcium has three forms: 45 per cent is present as the free divalent cation, 45 per cent is bound to serum proteins (principally albumin), and 10 per cent is complexed with anions such as citrate or phosphate. The concentration of free calcium ions in plasma is near saturation, as defined by the solubility product constant for calcium phosphate; hence tissue calcification may be seen in chronic hypercalcemia.

Variation in serum albumin concentration causes a corresponding change in total serum calcium concentration. By adjustment of the measured total serum calcium concentration one can normalize this result to allow interpretation based on the usual laboratory reference range. Empirical formulas to achieve this correction are available:

cEimxivcl | Or * (mmol 111 = ni lmmj i td [Cj1' immul I )| —

corrected |Ca?* {nip 4]) [ = me*$ufled Kji+ (mfltfl)] -

Critically ill patients frequently have reduced serum albumin concentrations and consequently may have low total serum calcium concentrations. Indeed, ionized hypercalcemia may be overlooked in the presence of a low total serum calcium concentration associated with a reduced serum albumin concentration.

Measurement of ionized serum calcium concentration may be carried out using an ion selective electrode, and the result needs no correction based on the serum albumin concentration. The normal range for serum ionized calcium concentration is 1.1 to 1.3 mmol/l (4.6-5.3 mg/dl).

Acute alkalemia increases calcium binding to serum albumin and reduces the concentration of free ionized calcium; such alkalemia may be seen, for example, in iatrogenic hyperventilation in the management of the patient with raised intracranial pressure. Acute acidemia has the opposite effect. Usually, pH-induced changes in serum ionized calcium concentration are small.

It should be noted that hypercalcemia does not present with coagulopathy, even though calcium has a vital role in blood coagulation. Etiology and diagnosis

The causes of hypercalcemia are listed in Table.., 2. Hyperparathyroidism and malignancy together constitute approximately 80 per cent of the hospital caseload.

Table 2 Etiology of hypercalcemia

Hypercalcemia occurs in approximately 10 per cent of cancer patients, most commonly those with lung, breast, kidney, prostate, or hematological malignancies (including multiple myeloma). The source of the calcium is the skeleton, secondary to either osteolytic bony metastases or humoral factors (paraneoplastic hypercalcemia) such as parathyroid hormone (PTH), PTH-like substance, prostaglandins, 1,25-dihydroxyvitamin D, or cytokines (including interleukins 1a and 6, and tumor necrosis factor). The malignancy is only occasionally occult once hypercalcemia is evident, and prognosis is poor with only 30 per cent surviving for 1 year. An exception to this rule is multiple myeloma which presents with hypercalcemia, where there may be a more chronic course.

Primary hyperparathyroidism increases calcium concentration secondary to an increase in bone resorption and in absorption of calcium from the gastrointestinal tract and renal tubular fluid. The patient may be hypophosphatemic, since PTH enhances renal phosphate excretion; PTH-induced bicarbonate wasting may also lead to a hyperchloremic acidosis. Hyperparathyroidism is usually due to a single adenoma (80 per cent); 1 to 3 per cent present with carcinoma, and the rest have multiglandular benign disease. Rarely, hyperparathyroidism may be part of the multiple endocrine neoplasia syndrome. Bone disease is now a rare feature of hyperparathyroidism; indeed the majority of patients are asymptomatic.

Chronic immobilization, which is a common characteristic of the critically ill patient, may lead to marked skeletal calcium liberation. The degree of hypercalcemia may be particularly dramatic where high rates of bone turnover are present, such as in Paget's disease or thyrotoxicosis.

Hypercalcemia is seen in up to a third of patients in the diuretic phase of acute renal failure, particularly acute renal failure secondary to rhabdomyolysis. Following successful renal transplantation for chronic renal failure, mild hypercalcemia may be seen in up to a third of patients; the condition resolves spontaneously within 2 years.

A variety of other critically ill patients become hypercalcemic. The condition seems to be multifactorial and has been reported in 15 per cent of surgical critical care patients (F.o.rst,e.Leí.a( 1985); associated factors include systemic inflammatory response syndrome, multiple transfusions, parenteral hyperalimentation, renal failure, and dialysis. These patients have elevated serum PTH concentrations, and it is suggested that parathyroid hypertrophy follows repeated hypocalcemic episodes and the gland displays autonomous PTH secretion at a later stage.

The cause of hypercalcemia in a particular instance is often clear. A concise history and full physical examination is essential. Particular attention should be given to drug and vitamin intake, calcium supplements, any family history of hypercalcemia, and signs or symptoms attributable to malignancy. Investigations should include a chest radiograph, a 12-lead electrocardiogram, serum PTH concentration, serum electrolyte and cortisol concentrations, and thyroid function tests. Serum and urine electrophoresis is carried out to identify multiple myeloma, the most common occult malignancy to cause hypercalcemia. A bone scan will identify osteolytic metastases in malignant hypercalcemia. This strategy will elucidate the etiology in the large majority of patients. A physician with experience in this area should be involved early in the patient's course.

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