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Q1: What is the cause of the apparent resistance to bisphosphonates?
The non-suppressed serum intact parathyroid hormone during hypercalcaemia should suggest the possibility of coexisting primary hyperparathyroidism, although this is usually responsive to calcium reducing therapeutic measures. Both oral and intravenous routes of bisphosphonate administration proved ineffective in inducing eucalcaemia and excludes malabsorption as a cause. The possibility of an artifactual cause for hypercalcaemia must be considered.
Q2: What further investigations for hypercalcaemia should be undertaken?
Ionised calcium should be measured on an anaerobically collected heparinised plasma sample to exclude primary hyperparathyroidism and confirm the presence of abnormal calcium binding globulins.
Q3: What are the causes of hypercalcaemia in myeloma?
See table 1.
The plasma ionised calcium in this man on oral clodronate was found to be 1.10 mmol/l (reference range 1.13–1.32) when a simultaneous corrected calcium was 3.03 mmol/l excluding primary hyperparathyroidism and confirming the existence of abnormal calcium binding globulins. Concordance of measured total calcium between cresolphthalein complexone (in house laboratory method) and atomic absorption spectrophotometry confirmed the validity of the in-house measurement. A fasting urine sample revealed very low calcium excretion consistent with a low filterable (includes ionised) calcium (ratio of calcium and creatinine clearance was 0.001). In retrospect it was clear that our patient did not reliably exhibit renal impairment or symptoms such as polyuria and polydipsia at the time of recognition of hypercalcaemia, undoubtedly attributable to non-raised ionised calcium.
Hypercalcaemia in myeloma, generally due to bone resorption, is associated both with renal failure as well as a poor prognosis.7 Factors leading to hypercalcaemia in myeloma are shown in table 1. Abnormal calcium binding globulins, bound to variable regions of Fab regions of the immunoglobulin molecule, have been described in myeloma previously and are considered to be very rare. Prompt recognition prevents inappropriate calcium reducing treatment and false attribution of a poor prognosis in such cases. Of course, it must be remembered that genuine hypercalcaemia may be superimposed on the artifactual and greatly complicate the metabolic picture. Resistance to calcium reducing measures alerted us to the possibility of calcium binding proteins in this patient with myeloma. In centres where ionised calcium is not routinely measured the artifactual nature of hypercalcaemia may be suspected when such resistance to calcium reducing measures is encountered.
Calcium in the blood is found in a bound state (approximately 40%; mainly bound to albumin in health), in a complex with citrate and other anions (<10%), as well as in an ionised form (approximately 50%).8 Only the ionised calcium controls and influences crucial biological processes such as neuromuscular transmission and excitability. Thus, changes in serum protein levels or acid-base status will affect the relationship between ionised and total calcium. Despite this total plasma calcium, adjusted to plasma albumin (adjusted or corrected serum calcium (mmol/l) = measured calcium concentration ± 0.02 for every g/l of albumin above or below an arbitrary figure respectively such as 42 g/l in our laboratory), remains the most commonly measured index even in hypoalbuminaemia and paraproteinaemias. Although ionised calcium can be measured easily using ion selective electrodes, it is impractical to measure ionised calcium in all situations requiring calcium measurement as specimens must be obtained anaerobically to minimise changes in specimen pH.
Approaches to correction, described above, attempt to estimate the ionised calcium by adjusting for interindividual and intraindividual variation in albumin or total protein concentrations. Such “corrections” invoke the use of equations incorporating the mean of the affinity of albumin or total proteins for calcium.9 10 Correction allows both the comparison of an individual calcium result with a reference range as well as the monitoring of calcium in the same person from day to day, minimising artifactual changes due to haemoconcentration (due to tourniquet effect) or haemodilution factors (intravenous fluid therapy). However, such “correction” is misleading when binding proteins with abnormally high affinities are present as in our case.
Correction factors employed to produce total serum calcium are crude estimates of the biologically important ionised calcium. Resistance to therapeutic attempts to reduce circulating calcium concentrations, especially when symptoms and signs of significant hypercalcaemia are absent, should lead to suspicion of the presence of calcium binding globulins in myeloma.
Hypercalcaemia due to abnormal calcium binding globulins in myeloma.