EM guidemap - Hypercalcemia

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Introduction

Risk factors for hypercalcemia

History of the presenting illness

Examination

Diagnostic testing

Medical decision-making and treatment

Appendix
Introduction

- hypercalcemia is defined as a serum calcium > 10.5 mg/dl and severe hypercalemia is defined as a serum calcium > 14 mg/dl (> 3.5 mmol/L)

- a hypercalcemic crises is present when severe neurological symptoms or cardiac arrhythmias are present in a patient with a serum calcium > 14 mg/dl (> 3.5 mmol/L) or when the serum calcium is > 16 mg/dl (> 4 mmol/L)

- the most common cause of hypercalcemia is primary hyperparathyroidism, and malignancy is the second most common cause - together they account for > 90% of cases; however, malignancy accounts for the majority of cases of severe hypercalcemia and hypercalcemic crises

- primary hyperparathyroidism rarely produces severe hypercalcemia and/or a hypercalcemic crises, unless renal insufficiency +/- dehydration is superimposed on the underlying hyperparathyroidism

- primary hyperparthyroidism usually results in mild/moderate long-standing hypercalcemia, which is often asymptomatic and a diagnosis is only made when a serum calcium level is incidently found to be elevated => an elevated serum parathyroid hormone level (PTH) confirms the diagnosis

- primary hyperparthyroidism may also be discovered during the workup of a patient with nephrolithiasis or PUD or pancreatitis

- primary hyperparathyroidism also produces hypertension and soft tissue calcifications and band keratopathy and rarely causes osteitis fibrosa cystica

(the incidence of these complications has declined over the years because routine blood testing detects cases of hyperparathyroidic hypercalcemia before the patient becomes symptomatic, and these complications are rarely found in other causes of hypercalcemia other than hyperparathyroidism)

- primary hyperparathyroidism is usually secondary to a parathyroid adenoma (85%), parathyroid hyperplasia (15%) and rarely due to a parathyroid carcinoma (< 1%)

- primary hyerparathyroidism is rarely associated with the multiple endocrine neoplasia syndrome (95% incidence in MEN type I - tumors of the pituatry, parathyroids and pancreatic islets cells; 5% incidence in MEN type II - hyperparathyroidism and medullary thyroid carcinoma and pheochromocytoma)

- primary hyerparathyroidism produces an elevated serum PTH, which distinguishes it from all other causes of hypercalcemia (where the serum PTH is normal-low)

- most patients with severe hypercalcemia have an underlying malignancy, which is usually manifest rather than occult, and most of these patients have end-stage malignant disease with a very poor prognosis => they usually present to the ED severely dehydrated, with a markedly altered mental status +/- renal insufficiency - their altered mental status is often presumed to be due to another cause until their serum calcium levels are found to be markedly elevated

(mandatory measurement of the serum calcium is recommended in all patients with a known malignancy if they present to the ED with altered mental status or unusual weakness/fatigue, especially if they have other suggestive hypercalcemic symptoms such as constipation and nausea/anorexia)

- certain malignancies very rarely cause hypercalemia even in the presence of widespread metastasis eg. prostrate cancer, gastric cancer and colorectal cancer

- pathophysiologically, hypercalcemia is almost always caused by diseases that increase bone osteoclastic activity and bone re-absorption to a degree that exceeds the kidney's ability to handle the increased calcium load (+/- decreased renal excretion secondary to renal insufficiency and/or dehydration), and hypercalcemia is rarely secondary to increased gastro-intestinal absorption alone

- malignancy increases osteoclastic activity by two mechanisms - production of a PTH-like substance called PTH-related protein = PTHrP (humoral hypercalcemia of malignancy - HHM - 80% of cases) and due to local osteoclastic activity secondary to bone metastasis (local osteolytic hypercalcemia of malignancy - 20% of cases), although there is no correlation between the extent of the metastasis and the severity of the hypercalcemia

(there can be an overlap of these two mechanisms because certain tumors produce both local osteolytic hypercalemia secondary to bone metastasis and also produce PTHrP; hypercalcemia is very rarely the result of increased calcitrol production by certain lymphomas => increased GIT absorption of calcium)

- hypercalcemia may also rarely be due to increased gastro-intestinal absorption of calcium secondary to vitamin D intoxication or the milk alkali syndrome; the milk alkali sydrome is becoming more common in recent years because of the increased use of calcium supplements + calcium carbonate antacids  +/- thiazide diuretics

(rarer cause of increased GIT absorption of calcium include sarcoidosis and iatrogenic vitamin A intoxication and calcitrol-secreting lymphomas)

- suspect underlying primary hyperparathyroidism in a hypercalcemic patient taking thiazide diuretics if there are no other risk factors - thiazide diuretics alone should not cause significant hypercalcemia in the absence of renal insufficiency or other risk factors

- hypercalcemia itself may produce renal insufficiency by a number of mechanisms => medullary damage and impairment of renal concentrating ability is common (initially results in polyuria, and potassium/magnesium wasting)  => eventually hypercalcemia causes severely impaired GFR which parallels (and compounds) the degree of hypercalcemia

(correction of the hypercalcemia causes a rapid improvement in GFR and a secondary hypercalciuria, which helps attenuate the hypercalcemia)

- hypercalcemia also produces gastro-intestinal symptoms - anorexia, nausea, vomiting and constipation

(decreased fluid intake due to anorexia and nausea/vomiting + any associated  renal impairment => increased hypercalcemia)

- hypercalcemia causes neuro-psychiatric symptoms - fatigue, lethargy, poor concentration, depression => obtundation => coma

(the severity of symptoms do not correlate with the serum calcium level, and may be affected by the rapidity of onset of the hypercalcemia and other superadded  factors)

- hypercalcemia occasionally causes cardiovascular complications - bradyarrhythmias and heart block and cardiac arrest (and tachyarrhythmias in digoxin-toxic patients)

Risk factors for hypercalcemia

Hyperparathyroidism

Malignancy (in rough order of frequency) Granulomatous disease (in rough order of frequency) Non-parathyroid endocrine disorders Vitamin D intoxication

Vitamin A intoxication

Mild alkali syndrome

Chronic renal insufficiency, or dialysis patients taking vitamin D replacement therapy

Recovery phase of rhabdomyolysis-induced renal insufficiency

AIDS

Drugs

Familial hypocalciuric hypercalcemia

Immobilisation and high bone turnover

History of the present illness

- a hypercalcemic crises with symptoms of progressive dehydration (thirst, weakness), renal insufficiency (decreased urine output) and altered mental status (obtundation) may be the presenting symptom-complex in a patient with a known malignancy

- the symptoms of hypercalcemia may also masquerade as those of the underlying malignancy or its narcotic therapy eg. weight loss, anorexia, nausea, muscle weakness, constipation, fatigue, lethargy, impaired concentration and disorientation

- abdominal pain may be secondary to PUD or pancreatitis or renal colic in patients with primary hyperparathyroidism

- a previous history of renal nephrolithiasis or PUD suggests primary hyperparathyroidism

- a family history of hypercalcemia suggests familial hypocalciuric hypercalcemia in a young patient

- consider the possibility of surreptitious calcium ingestion and/or vitamin D/A intoxication in the health-food addict, or when unexplained hypercalcemia is found

Examination

- the examination is very rarely useful in determing the etiological cause of the hypercalcemia

- signs of dehydration are very common in patients with a hypercalcemic crises, especially in patients with advanced/end-stage malignancy

- the blood pressure can be elevated (if intravascular volume is maintained) or normal (in the presence of total body volume depletion)

(hypercalcemia causes increased vascular tone, which may mask the degree of dehydration and  the true extent of volume depletion)

- bradycardia may reflect heart block or bradyarrhythmias

- a neck mass may be secondary to a parathyroid adenoma, or primary malignancy, or secondary metastatic lympadenopathy

 - a breast mass could be a malignant tumor

- a rectal exam to check for fecal impaction is useful in a patient with constipation or abdominal pain/distension

- altered mental status (cognitive difficulties, apathy, lethargy) is common, but it is difficult to seperate the signs of hypercalcemic encephalopathy from those of a paraneoplastic or other secondary metabolic encephalopathy

(it is better to err on the side of caution and pursue other diagnostic possibilities - instead of simply assuming that the altered mental status is due to hypercalcemia - especially if the serum calcium is only slightly elevated)

Diagnostic testing

- a serum calcium, electrolytes, magnesium, BUN and creatinine should routinely be ordered

- a significant amount of calcium is bound to serum albumin (~ 40%) or complexed to anions eg. bicarbonate, citrate, sulphate, phosphate and lactate (~ 10%) and is therefore not functionally active; measurement of the serum ionised calcium (if available) is a more accurate reflection of the true state of hypercalemia

- if it is not possible to obtain a serum ionised calcium level, then you have to take into account the effect of changes in the serum albumin on the serum calcium level

For every 1g increase in the serum albumin > 4g/dl => subtract 0.8 mg/dl (0.2 mmol/L) from the measured serum calcium to obtain a corrected value

For every 1g decrease in the serum albumin level below 4g/dl => add 0.8 mg/dl (0.2 mmol/L) to the measured serum calcium level to obtain a corrected serum calcium level

(many patients with hypercalcemia have end-stage malignant disease and their serum albumin level may be low secondary to poor nutrition and severe liver disease => their measured serum calcium may be normal although their ionised serum calcium levels are elevated)

- a serum phosphate and alkaline phosphatase has no real utility in the diagnostic differentiation of the different causes of hypercalcemia

- urinary cyclic AMP levels are no longer measured because serum PTH measurements are more accurate and discriminatory

- the serum PTH and serum PTHrP are extremely useful, but they are not usually available in the ED setting and they are often performed by off-site reference or research laboratories

- a serum calcitriol (1, 25 (OH) 2 D assay) level is selectively ordered when both the PTH and PTHrP are low and the diagnosis of sarcoidosis or a calcitriol-secreting lymphoma is being considered - levels are increased

- a serum 25 (OH) D assay is elevated in hypervitaminosis D

- an urinary calcium level only needs to be measured when familial hypocalciuric hypercalcemia is being considered - the level is low while it is usually normal/elevated in primary hyperparathyroidism

- skeletal surveys, mammograms and bone scans are selectively ordered when an occult malignancy is suspected - especially if the PTHrP is elevated in the absence of overt malignancy

- an X-ray of the hands can be performed to detect osteitis fibrosa cystica, which is only seen in long-standing hypercalcemia due to primary hyperparathyroidism

(osteitis fibrosa cystica is rarely seen in the absence of vitamin D deficiency, which is rare in a modern society where vitamin D supplementation of food products is a widespread phenomenon)

- urine for Bence-Jones protein can be ordered prn if myeloma is suspected

- an ECG may demonstrate a shortened QT interval and bradyarrhythmias

- a routine chest X-ray may show evidence of granulomatous disease or malignancy

Medical decision-making

- the first decision that has to be made is whether emergent treatment of the hypercalcemia is necessary

- emergent treatment of hypercalcemia is necessary if the patient is significantly symptomatic with a serum calcium in the range of 12 - 14 mg/dl (3.0 - 3.5 mmol/L) or if the serum calcium is > 14 mg/dl (> 3.5 mmol/L) in the absence of symptoms

- the first step in the management of severe hypercalcemia is hydration with isotonic saline

- specific therapy to inhibit osteoclastic bone resorption is indicated if the hypercalcemia is severe or if the hypercalcemia does not respond promptly to saline/fluid loading

- specific therapy should be given immediately if the serum calcium is life-threatening (> 16 mg/dl, > 4.0 mmol/L) or if the patient is unequivocally symptomatic with severe neurologic symptoms and/or cardiac arrhythmias (hypercalcemic crises) => saline loading + calcitonin + biphosphonate therapy

(if the patient has known end-stage malignant disease and the entire clinical history is known to the treating physician, it may be more appropriate and kind not to intervene at all and allow nature to takes its course)

- calcitonin is only used in patients with severe hypercalcemia + severe symptoms as a temporising measure until a more long-lasting effect can be achieved with biphosphonates or plicamycin, and calcitonin is not necessary if symptoms are moderate

- biphosphonates will decrease the serum calcium to normal levels, but they have a delayed effect (~ 48 hours)  and they are mainly used for the more definitive managment of severe hypercalcemia

- biphosphonates can be given after saline loading (without any calcitonin) if the stable patient has only moderate symptoms, or if the asymptomatic patient with severe hypercalcemia does not respond to saline loading

(plicamycin can also be used and it acts more rapidly than biphosphonates, but it is more toxic)

- any drug aggravating hypercalcemia (thiazides, aminophylline) should be promptly discontinued

- if the patient is asymptomatic and the serum calcium is only mildly elevated (10.5 - 12 mg/dl) => the patient can be referred to the family doctor for further workup

(see the appendix for an approach to the workup of mild hypercalcemia)

Saline/fluid hydration

- the rate of saline hydration depends on the severity of the hypercalcemia, the extent of the dehydration and the tolerance of the cardiovascular system to volume expansion

- an appropriate starting infusion rate of normal saline could be 300 - 500ml/hour => tapering to 200 - 250 ml/hour when the ECF volume deficit is partially corrected => tapering to 100 - 200 ml/hour (after the fluid deficit has been fully corrected) to ensure a continuous saline-induced diuresis

- the initial rate of administration may be limited by the cardiovascular stability of the patient - elderly patients with marginal cardiac function may not tolerate aggressive fluid therapy

- usually 2 - 4 litres of fluid needs to be administered within the first 24 hours

- furosemide (lasix) should only be used after volume expansion has been achieved and the amount of furosemide required depends on the ability of the patient to handle the fluid load => patients with cardiovascular impairment require more aggressive furosemide therapy (20 - 40 mg bid - qid), while no/small amounts of furosemide may be necessary in young patients who have a prompt diuresis in response to saline fluid loading

(administration of furosemide prior to adequate volume expansion => increased potential fluid deficit - because furosemide has a profound natriuretic effect and a lesser calciuretic effect => decreased renal perfusion => worsening hypercalcemia)

- saline/fluid therapy should decrease the serum calcium by 1.5 - 3 mg/dl (0.25 - 0.75 mmol/L) in 1 - 2 days

- saline therapy is clearly ineffective in renal failure patients, and dialysis with low/zero calcium dialysates should be promptly instituted

- potassium and magnesium replacement therapy may be necessary if the patient has a brisk diuresis

Biphosphonates

- have become the drugs-of-choice in the targeted inhibition of osteoclastic bone resorption

- the po absorption of these compounds is very poor and they should be administered by IV infusion

- an effect is seen within 1 - 2 days but the nadir effect is delayed 3 - 7 days

- side-effects are not serious and include mild fever, hypomagnesemia and hypophosphatemia

Etidronate

- given as a 7.5mg/kg IV infusion over 4 - 24 hours every day for 4 consecutive days

- the serum calcium should fall by day 2 and reach a nadir by day 7, and the nadir should be in the normal range in 60 - 100% of patients

- the drug does not have  to be given for a full 4 days if the serum falls rapidly (> 3 mg/dl) or if the serum calcium normalises in the first two days of therapy (continued etidronate theray may result in hypocalcemia)

Pamidronate

- the most potent biphosphonate presently available

- a single dose of 60 mg over > 4 hours is adequate for a serum calcium < 14 mg/dl (< 3.5 mmol/L), while 90 mg infused over 24 hours is used for severe hypercalcemia > 14 mg/dl

- the serum calcium will always fall to normal within one week of therapy in all patients

- pamridonate does not worsen renal function if administered over several hours and is less nephrotoxic than etidronate

 (vigorous saline hydration should always accompany biphosphonate therapy)

Calcitonin

- calcitonin is not a potent drug, but is has no serious side-effects and it can be safely used in patients with renal insufficiency

- calcitonin decreases bone resorption and also increases the urinary clearance of calcium

- calcitonin is used if a rapid decrease in the serum calcium is required because of severe symptoms or if the serum calcium is > 16 mg/dl (> 4 mol/L), but calcitonin does not decrease the calcium level to normal and its effect is modest - tachyphylaxis often occurs after a few days

- salmom-calcitonin is given in a dose of 4 units/kg sc/IV every 12 hours, while the dose of synthetic human calcitonin is 0.5 mg sc daily

- an effect will be seen within a few hours and the nadir of its effect is seen in 12 - 24 hours, although subsequent rebound hypercalcemia will occur if long-lasting biphophonates are not concurrently given

- calcitonin has potent analgesic properties and may help alleviate bone pain in cancer patients with bone metastasis

- salmon-calcitonin is more potent than human-calcitonin, although rare allergic reactions suggest that an initial skin test with 1 unit of salmon-calcitonin is advisable prior to the adminstration of the full dose

- glucocorticoids may potentiate the action of calcitonin in patients with granulomatous diseases and decrease the "escape" phenomenon whereby the anti-hypercalcemic effect of calcitonin wanes over several days

Plicamycin (Mitharmycin)

- decreases bone resorption

- given IV in a dose of 25mcg/kg over a period of 4 - 6 hours

- the dose can be repeated q 24 - 48 hours prn

- an effect is seen within 12 - 24 hours with a maximal effect in 48 - 72 hours

- potentially toxic and may cause an elevation in liver enzymes, impairment of renal function and thrombocytopenia => contra-indications include hepatic or renal dysfunction or any coagulopathy

- although plicamycin is more rapidly-acting than biphosphonates, biphosphonates are often preferred because plicamycin has a potentially greater risk of adverse side-effects

Gallium nitrate

- binds to bone mineral and decreases bone resorption by an unknown mechanism

- given as a continuous IV infusion (100 - 200 mg/square meter/day) for 5 days

- takes several days before a nadir is reached and lasts a week

- side-effects are severe and include nephrotoxicicty, hypophosphatemia and anemia

- contra-indicated in patients with renal insufficiency

- its role in therapy is not clearly defined - considering that equally potent, but safer, biphosphonate therapy is available

Glucocorticoids

- only effective in certain hematogenous malignancies (lymphoma or myeloma) or in granulomatous diseases such as sarcoidosis and in vitamin D intoxication

- given IV in a dose of 200 - 300mg/day of hydrocortisone (or its equivalent) for 3 - 5 days

- it only has a modest effect, which is delayed a few days

Phosphate

- IV phosphate is contra-indicated in the therapy of severe hypercalcemia because it precipitates with calcium in the soft tissues, blood vessels, lungs and kidneys and may precipitate severe organ damage

Hemodialysis

- used in patients with renal failure

- is more effective when using a low-calcium/zero-calcium dialysate

Appendix

Work-up of a patient with asymptomatic, mild hypercalcemia

- contact the patient's family doctor to discuss which preliminary tests to order and to arrange follow-up of the test results => document follow-up plan on the chart and send a copy of the chart to the patient's family doctor

- a reasonable initial diagnostic test would include a serum PTH to differentiate hyperparathyroidism from other causes of hypercalcemia

- if the patient looks cachetic and has a history of weight loss, night sweats or fever => consider occult cancer or  a granulomatous disease => chest X-ray +/- PPD +/- serum PTHrP

- skeletal surveys, mammograms and other diagnostic cancer testing should be performed prn

- testing for other endocrine disorders (hyperthyroidism, pheochromocytoma, addison's disease, acromegaly) will depend on clinical presentation and clinical suspicion

- hypervitaminosis D and A are uncommon and testing should only be performed prn

Clinical indications for surgery in patients with primary hyperparathyroidism

Medical management of primary hyperparathyroidism

- patients who are not treated surgically should be followed up at 6 monthly intervals

- medical therapy with drugs to lower the serum calcium have not been shown to affect the eventual outcome

- estrogens (premarin 1.25mg/day) preserve bone mass in post-menopausal females

- patients should ensure that they remain well-hydrated by drinking 2 - 3 litres of fluid daily, and they should also ingest 8 - 10 g of salt daily

- dietary restriction of calcium is not necesssary

- oral phosphate should rarely be used because of the risk of metastatic calcifications and decreased renal function, and should only be used if the serum phosphate is low and significant hypercalcemia is present

Medical management of hypercalcemia in cancer patients

- ensure adequate daily fluid intake of 2 - 3 litres per day + 8 - 10g of salt/day

- pamridonate can be used prn every few weeks to keep the serum calcium in the normal range

- prednisone (20 - 50 mg bid) is only useful in certain malignancies eg. multiple myeloma and certain lymphomas

Medical management of hypercalcemia in sarcoidosis

- a low dose of prednisone (10 - 20 mg/day) is usually adequate