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on regional fat distribution, insulin sensi- Hypercalcaemia of 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 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 circulator y 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 (Fig 1), 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 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 encountere d as Tertiary hyperparathyroidism causes of raised calcium levels. Most of Humoral hypercalcaemia the other recognised causes of hypercal- Direct bone involvement: caemia are rarely seen in clinical practice • bone metastases (Table 1). • Less common intoxication Familial hypocalciuric hypercalcaemia (abnormal sensing of calcium level) Diagnosis and other granulomatous diseases (increased activation of vitamin D) Clinical examination Uncommon The clinical features of hypercalcaemia 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 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 (, , , calcaemia (FHH) which results from an and ), 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 hypercalcae mia is long-standi ng, 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 vitamin D intoxication. creatinine 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 examinati on 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 underlyin g 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; 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 associated with a substantial risk of such complications. aspect of management is vigorous re- muscular injection. It is often poorly The skeleton hydration, using saline to restore the tolerated, with side effects such as extracellular volume and to obviate the flushing and . Some cases of Overt hyperparathyroid bone disease is risk of disequilibrium hypercalcaemia. resistant hypercalcaemia will respond to rare, but mild hyperparathyroidism is Some authors suggest using frusemide to corticosteroid therapy; this needs to be not infrequently associated with osteo- increase renal clearance of calcium. given in high doses (egprednisolone porosis. Bone density measuremen ts There is no evidence for its long-term 40 mg/day). should be part of the assessment of effectiveness and, since diuretics worsen hyperparathyroid patients. the risk of dehydration, frusemide is best Stable asymptomatic reserved for those patients who retain hypercalcaemia Parathyroid glands fluid during rehydration. Intravenous bisphosphonates should With stable asymptomatic hypercalcaemia Scanning of the parathyroid glands may be given when the patient has been re- there is sufficient time to establish the be ordered as a precursor to surgery. hydrated. They are generally well diagnosis of the cause before starting This can be undertaken using computed tolerated, but a minority of patients may treatment. The cause will usually be pri- tomography, ultrasonography or scinti- develop increased bone pain or a tran- mary hyperparathyroidism. graphy using technetium-labelled sient pyrexia and flu-like symptoms. sestamibi. None of the available tech- Rarer complications include rashes and niques has sufficient sensitivity or speci- Parathyroidectomy iritis. ficity to allow it to be used as a means Most patients will respond to intra- There is still disagreement as to the place of diagnosing hyperparathyroidism. venous bisphosphonates. For those who of parathyroidectomy. Some argue that do not, treatment with may be in the absence of surgical contraindica- Management helpful. It may need to be given in high tions the majority of patients should be doses (up to 400 IU) by six-hourly intra- offered surgery, whilst others reserve With plasma calcium concentra tions below 3 mmol/l the risk of significant 4 symptoms of hypercalcaemia is low. The Table 2. Indications for surgery in primary hyperparathyroidism. higher the calcium rises above this level Definite High serum calcium the more likely it is both that symptoms Previous disequilibrium hypercalcaemia will be present and that there may be Impaired renal function Renal stones acute metabolic consequences which need urgent treatment. High urinary calcium excretion (>10mmol/ 24h) Reduced density Severe symptomatic hypercalcaemia Relative Concomitant illness Difficulty of follow-up In many instances severe symptomatic Younger patients (<50years) Peptic ulcer disease hypercalcaemia will need to be treated Psychiatric complications before a definitive underlying diagnosis Patient preference is establishe d. The most important

Clinical Medicine Vol 3No 1January/February 2003 21 CME Endocrinology operation for those with symptoms or in edn. Kelseyville, CA: American Society for whom there is evidence of tissue damage Bone and Mineral Research, 1990:62–4. by the hypercalcaemia. This situation is 4NIH Conference. Diagnosis and manage- ment of asymptomatic primary hyper- unlikely to change until a prospective parathyroidism: consensus development study of parathyroidectomy is under- conference statement. Review. Ann Intern taken. Previous attempts to do this have Med 1991;114:593–7. all failed. The most widely accepted 5Bilezikian JP, Potts JT Jr, El-Hajj Fuleihan G, indications for parathyroidectomy were Kleerekoper M, et al. Summary statement from a workshop on asymptomatic hyper- established by a National Institutes of parathyroidism. J Bone Miner Res 2002; Health consensus development confer- 17(Suppl 2):N2–N11. ence in 1990, and modified in 2002. 5 6Davies M, Fraser WD, Hosking DJ. These are summarised in T able2. Management of primary hyperpara- 57 However, these recommendatio ns are thyroidism. Clin Endocrinol 2002; : 145–55. not evidenced based and have been criti- 7Silverberg SJ, Shane E, Jacobs TP, Siris E, cised for this. In the UK, the Bone and Bilezikian JP. A 10-year prospective study of Tooth Society has recently developed primary with or without parathyroid evidenced-based guidelines for the man- surgery. N Engl J Med 1999;341:1249–55. agement of hyperparathyroidism. 6 These 8Miccoli P, Berti P. Minimally invasive parathyroid surgery. Best Pract Res Clin are less likely to lead to surgical interven- Endocrinol Metab 2001;15:139–47. tion in any specific patient, but the 9Orr-Walker BJ, Evans MC, Clearwater JM, overall indicatio ns for surgery are Horne A et al. Effects of hormone replace- broadly similar (see Table 2). ment therapy on bone mineral density in Parathyroidectomy leads to normalisa- postmenopausal women with primary hyperparathyroidism: four-year follow-up tion of plasma calcium in most patients and comparison with healthy post- and is also associated with an increase in menopausal women. Arch Intern Med 2000; bone density. 7 However, the effect of 160:2161–6. surgery on the other complications of 10 Rossini M, Gatti D, Isaia G, Sartori L et al. hyperparathyroidism is less clear-cut. Effects of oral alendronate in elderly patients with osteoporosis and mild Minimally invasive surgical procedures primary hyperparathyroidism. J Bone Miner may make operative treatment more Res 2001;16:113–9. acceptable in the future. 8

Medical therapy

In patients with mild disease or those with strong contraindications to surgery it is possible to consider medical therapy of hyperparathyroidism. Hormone replacement therapy is associated with a modest reduction in plasma and urine calcium together with preservation of bone density. 9 Although bisphos- phonates are associated with preserva- tion of bone mass, they do not appear to have a significant effect upon the plasma calcium level in the long term. 10

References

1Burt ME, Brennan MF. Incidence of hyper- calcemia and malignant neoplasm. Arch Surg 1980;115:704–7. 2Selby PL. Normal calcium homeostasis. Clin Rev Bone Miner Metab 2002;1:3–9. 3Portale AA. Blood calcium, phosphorus and magnesium. In: Favus MJ (ed). Primer on the metabolic bone diseases and disorders , 1st

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