CME Endocrinology on regional fat distribution, insulin sensi- Hypercalcaemia of calcium in the blood is therefore tivity, and cardiovascular risk factors in exquisitely sensitive to changes in both hypopituitary adults. J Clin Endocrinol renal function and tubular handling of Metab 1995;80:153–9. 2 12 Bulow B, Hagmar L, Mikoczy Z, Nordstrom Peter Selby MA MD FRCP, Consultant calcium. CH, Erfurth EM. Increased cerebrovascular Physician, Manchester Royal Infirmary; In most cases of hypercalcaemia a new mortality in patients with hypopituitarism. Honorary Senior Lecturer, University of steady state is reached in which calcium Clin Endocrinol (Oxf) 1997;46:75–81. Manchester, Department of Medicine, entering the circulation is balanced by 13 Fowelin J, Attrall S, Lager I, Bengtsson BA. Manchester Royal Infirmary that leaving it; this results in a stable Effects of treatment with recombinant human growth hormone on insulin sensi- situation in which the plasma calcium tivity and glucose metabolism in adults Clin Med 2003;3:19–22 remains at a relatively constant level. with growth hormone deficiency. However, when the hypercalcaemia is Metabolism 1993;42:1443–7. sufficient to impair renal function, either 14 Rosen T, Bengtsson BA, Bennmarker H, Hypercalcaemia is one of the more directly or as a result of dehydration, Feldt-Rasmussen U et al. The influence of GH deficiency, GH replacement therapy common metabolic abnormalities seen calcium excretion is impaired and the and other aspects of hypopituitarism on in hospital practice; it occurs in approxi- plasma calcium level increases. This fracture rate and bone mineral density. J mately 5% of hospital inpatients. 1 results in further worsening of renal Bone Miner Res 2001;16:398–405. Hypercalcaemia results from an im- function, with consequent elevation of 15 Drake WM, Howell SJ, Monson JP, Shalet balance between the amount of calcium plasma calcium. This vicious circle is SM. Optimising GH therapy in adults and children. Review. KIMS Study Group and entering the plasma from the gastro- termed ‘disequilibrium hypercalcaemia’ the KIMS International Board. Pharmacia intestinal tract or as a result of bone and can rapidly lead to circulatory and Upjohn International Metabolic resorption and the amount being lost collapse if not treated with the Database. Endocr Rev 2001;22:425–50. from the circulation through the urine or appropriate degree of urgency. 16 Monson JP, Abs R, Bengtsson BA, into newly formed bone. The overall Bennmarker H, et al. Growth hormone deficiency and replacement in elderly fluxes in each of these systems are of a Causes of hypercalcaemia hypopituitary adults. Clin Endocrinol (Oxf) similar magnitude (Fig1), but the net 2000;53:281–9. loss of calcium in the urine is the result Most cases of hypercalcaemia in clinical 17 Hernberg-Stahl E, Luger A, Abs R, of most of the filtered calcium being practice will be the result of either Bengtsson BA et al. Healthcare consump- reabsorbed within the tubules. The level primary hyperparathyroidism or malig- tion decreases in parallel with improve- ments in quality of life during GH replacement in hypopituitary adults with Fig 1. Diagram indicating normal daily calcium fluxes in an adult. GH deficiency. J Clin Endocrinol Metab 2001;86:5277–81. Diet 20 mmol/day Absorption Formation 11 mmmol/day 6 mmol/day Plasma calcium Gut 2.4 mmol/l Bone Secretion Resorption 5 mmmol/day 6 mmol/day Filtered Reabsorbed 200 mmol/day 194 mmol/day Faeces 14 mmol/day Kidney Urine 6 mmol/day Clinical Medicine Vol 3No 1January/February 2003 19 CME Endocrinology nant disease. Less frequently, vitaminD Table 1. Causes of hypercalcaemia. intoxication or familial hypocalciuric Common Parathyroid dependent Primary hyperparathyroidism hypercalcaemia are encountered as Tertiary hyperparathyroidism causes of raised calcium levels. Most of Malignancy Humoral hypercalcaemia the other recognised causes of hypercal- Direct bone involvement: multiple myeloma caemia are rarely seen in clinical practice bone metastases (Table 1). Less common Vitamin D intoxication Familial hypocalciuric hypercalcaemia (abnormal sensing of calcium level) Diagnosis Sarcoidosis and other granulomatous diseases (increased activation of vitamin D) Clinical examination Uncommon Thiazide diuretics The clinical features of hypercalcaemia Lithium therapy Immobilisation are usually of little diagnostic value as (particularly where there is increased bone turnover, eg Paget’s disease) they are rarely sufficiently specific to Hyperparathyroidism allow differentiation from other condi- Milk-alkali syndrome tions. Nevertheless, clinical history and Renal failure examination are an important part of the Addison’s disease Vitamin A intoxication assessment of any patient with hyper- calcaemia. In addition to seeking the classical symptoms of the metabolic Investigation this is familial hypocalciuric hyper- disorder (polyuria, polydipsia, vomiting, calcaemia (FHH) which results from an constipation and abdominal pain), it is The diagnosis of hypercalcaemia itself is inactivating mutation of the calcium also important to ascertain whether there usually straightforward. Although sensing receptor. This causes the body to is any evidence of end-organ damage. emphasis has been placed upon the behave as if the calcium level is lower This might be suspected from a history importance of measuring plasma than it actually is. As a result, there may suggesting renal stones or acute pancre- calcium in the fasting state without be elevated or high-normal PTH concen- atitis. Bone involvement by either hyper- venous stasis, neither of these precau- trations despite hypercalcaemia. FHH parathyroidism or malignant disease is tions exerts a major influence on the level does not respond to parathyroidectomy, suggested by the presence of skeletal of measured plasma calcium. However, so this is an important differential pain. If it is possible to determine that as calcium in the blood is approximately diagnosis to exclude when such surgery is the hypercalcaemia is long-standing, 50% bound to plasma proteins, it is being considered. this is an important pointer in favour important to correct the measured value of hyperparathyroidism or other for any abnormality of the protein level. 3 benign conditions. A drug history will Clearance ratio of calcium to help exclude vitaminD intoxication. creatinine Parathyroid hormone level Although thiazide diuretics are The generally accepted method of frequently cited as a cause of hyper- The most important investigation for diagnosing FHH is to measure the calcaemia, it is more usual that they elucidating the cause of hypercalcaemia clearance ratio of calcium to creatinine. bring mild pre-existing hypercalcaemia is measurement of plasma parathyroid This involves measuring calcium and to light. hormone (PTH) level. Unlike plasma creatinine in both plasma and urine calcium levels, this is influenced by food following an overnight fast. The Physical examination and should therefore be measured after clearance ratio is calculated as follows: an overnight fast. It is also important to Physical examination is usually un- take blood for the measurement of PTH _____________Calcium (urine) x_____________creatinine (plasma)___ rewarding in establishing the diagnosis of before any attempt has been made to Creatinine (urine) x calcium (plasma) hypercalcaemia but may give some clues treat the plasma calcium because a fall in In hypocalciuric hypercalcaemia the towards any underlying malignant calcium can trigger PTH release, leading ratio is lower than 0.01, and in primary process. In patients with marked hyper- to the erroneous conclusion that the hyperparathyroidism generally higher calcaemia (plasma calcium 3 mmol/l), hypercalcaemia is PTH-dependent. than 0.02. it is important to make an assessment of PTH concentrations in the upper part the state of hydration. Any suggestion of of the normal range in the presence of Vitamin D metabolites salt and water depletion might indicate hypercalcaemia are usually indicative of the presence of disequilibrium hyper- parathyroid-dependent hypercalcaemia In rare cases of vitaminD activation such calcaemia and the need for urgent rehy- (primary or tertiary hyperpara- as sarcoidosis, it may be useful to mea- dration to prevent rapid deterioration. thyroidism). An important exception to sure the level of vitaminD metabolites. 20 Clinical Medicine Vol 3No 1January/February 2003 CME Endocrinology In other cases of hypercalcaemia it is gen- Key Points erally sufficient to perform the standard investigations for the suspected under- The kidney is the most important organ for plasma calcium regulation lying disease. Primary hyperparathyroidism and malignancy are the most common causes of hypercalcaemia Renal tract Primary hyperparathyroidism is diagnosed on biochemistry, not by imaging Assessment of the impact of chronic hypercalcaemia on the body involves Dehydration in a hypercalcaemic patient is potentially life-threatening examining the renal tract and skeleton. Severe hypercalcaemia is initially treated by rehydration; bisphosphonates can be The presence of renal stones is most used when volume replete readily sought using ultrasonography. Some indication of kidney damage is Not all patients with primary hyperparathyroidism require parathyroidectomy given by 24-hour urine calcium excretion; values above 10 mmol/day are KEY WORDS: bisphosphonates, calcium regulation, humoral hypercalcaemia of malignancy, hypercalcaemia, parathyroidectomy, primary hyperparathyroidism