Hypercalcemia PDF

  Hypercalcemia Glenn Mat n Key Points The skeleton is the major store of calcium. conveniently divided into those associated Approximately 99% of total body calcium with an elevated or inappropriately normal...

  Hypercalcemia Glenn Mat n Key Points The skeleton is the major store of calcium. conveniently divided into those associated Approximately 99% of total body calcium with an elevated or inappropriately normal (1 kg) is found in bone. Most of the remainder PTH level, and those where PTH output is is located in the intracellular compartment appropriately suppressed. with only a small amount present in extra- In an ambulatory population, primary cellular uid. hyperparathyroidism (PHPT) accounts for The free (ionized) calcium is the physiologi- the vast majority of detected hypercalcemia cally important ion and is tightly regulated. (>90%). Calcium homeostasis is directly or indirectly Hypercalcemia of malignancy (HCM) com- regulated by vitamin D metabolites and plicates 5–30% of malignancies and is the parathyroid hormone (PTH) via the kidney, commonest cause of inpatient hypercal- intestine, and bone. cemic crises (>50%). PTH is secreted by the chief cells of the The nal common pathway for many types parathyroid glands. A unique calcium recep- of severe hypercalcemia is increased mobi- tor on the cell membrane (extracellular lization of calcium from bone due in part calcium-sensing receptor [CaSR]) responds to activation of osteoclasts by RANK/RANKL rapidly to changes in serum ionized calcium. pathway. Hypercalcemia (serum calcium >10.5 mg/dL For treatment of severe hypercalcemia, the [2.6 mmol/L], measured on at least two underlying cause should be identi ed and occasions) a ects about 0.5% of hospital- multitargeted therapies should be started as ized patients and is usually well tolerated soon as possible. if adjusted calcium (i.e., corrected for albu- The cornerstone of acute management of min concentration) levels are 10.5 mg/ ment with only a small amount present dL [2.6 mmol/L], measured on at least two in extracellular uid (ECF). Calcium home- occasions) a ects about 0.5% of hospital- ostasis is tightly regulated through multi- ized patients and is usually well tolerated if ple interactions between the dietary intake adjusted calcium (ACa) (i.e., corrected for of bone minerals and the serum levels albumin concentration) levels are 12 mg/dL (3.0 mmol/L) homeostatic mechanisms have become over- is associated with nephrogenic diabetes whelmed by a speci c pathological process. insipidus (DI), increasingly severe volume PTH is secreted by the chief cells of the contraction, neurological, cardiac, and parathyroid glands (four glands classically gastrointestinal dysfunction, and requires located on or near the posterior surface of urgent treatment to prevent life-threatening the thyroid gland). A unique calcium recep- consequences. The term “hypercalcemic tor on the cell membrane (the extracellular crisis” is frequently used to describe the calcium-sensing receptor [CaSR]) responds severely compromised patient with pro- rapidly to changes in serum free (ionized) cal- found volume depletion, altered sensorium, cium (10,11). When the free (ionized) cal- which may be manifest as coma, cardiac cium is high, appropriate inhibition of PTH decompensation (including dysrhythmias), synthesis and release occurs, while a decrease and abdominal pain that may mimic an in free (ionized) calcium prompts a rapid acute surgical abdomen (2). Hypercal- adaptive increase in PTH release (Figure 24- cemic crises usually occur when ACa levels 1). The main function of PTH is to main- >14 mg/dL (3.5 mmol/L) (3). Hypercalcemia tain the calcium concentration of the ECF by of malignancy is the commonest cause of promoting the release of calcium from bone inpatient hypercalcemic crises (>50%) and by osteoclast resorption, increasing the acti- complicates 5–30% of malignancies (4). vation of 25-hydroxyvitamin D (25-(OH)D, Severe hypercalcemia requires urgent calcidiol) to 1,25-dihydroxyvitamin D (1,25- treatment (5). Although there are multiple, (OH)2D, calcitriol), which increases the cal- overlapping causes of calcium imbalance, cium absorption from the intestine plus sen- much of the acute management is generic, sitizes bone to the resorptive actions of PTH, logical and intuitive. However, making a and stimulates calcium conservation by the correct diagnosis remains important for kidney while increasing phosphate excretion the quality of management and long-term (which prevents calcium phosphate salt for- outcomes (6). mation in the ECF) (Figure 24-1) (7). At least one of the following mechanisms is involved in the pathophysiology of hyper- Pathophysiology calcemia: (a) increased intestinal calcium absorption; (b) increased bone resorption; Calcium is ingested in the diet, absorbed and (c) increased renal calcium reabsorption from the intestine, ltered in the glomeru- or decreased calcium excretion. Hyper- lus of the kidney, reabsorbed in the renal calcemia often results when the in ux of tubules, and eliminated in the urine (1,7). calcium into the ECF compartment from the Approximately 99% of total body calcium skeleton, intestine, or kidney is greater than  Glenn Mat n  Calcitonin X Bone Thyroid Gut ↓Plasma calcium 1,25-dihydroxyvitamin D Parathyroid 25-dihydroxyvitamin D Kidneys ↑Parathyroid Parathyroid hormone hormone Figure - Parathyroid hormone (PTH) response to a fall in free (ionized) calcium. A decrease in free (ionized) calcium is detected by the calcium-sensing receptor (CaSR) on the chief cells of the parathyroid gland to stimulate PTH release and synthesis. PTH acts on the osteoblasts and osteoclasts promoting calcium release via bone resorption; on the kidneys promoting calcium reabsorption and 1,25-(OH)2D (calcitriol) production which stimulates calcium absorption via the intestine, thus increasing circulating ionized calcium. the e ux as, for example, when excessive ltration rate (GFR) severely limit the ability resorption of bone mineral occurs in malig- of the kidneys to excrete calcium. If contin- nancy. Hypercalciuria often develops in such ued calcium mobilization from bone occurs, situations. When the capacity of the kidney hypercalcemia can rapidly increase. The to excrete ltered calcium is exceeded, patient becomes progressively worse until hypercalcemia develops; where renal fail- hypercalcemia is treated and the vicious cycle ure is present and calcium excretion is is broken. This chain of events highlights the decreased, hypocalciuria may paradoxically extreme importance of volume resuscitation be present. Hypercalcemia can be caused in the management of hypercalcemia (12). by increased intestinal absorption (e.g., vita- Hypercalcemia predominantly results min D intoxication [rare]); increased renal from increased mobilization of calcium retention (e.g., thiazide diuretics); increased from bone. The nal common pathway for skeletal resorption (e.g., immobilization); or increased bone resorption is activation of a combination of mechanisms (e.g., primary one of the key signaling pathways, known hyperparathyroidism [PHPT]). When the as the RANK/RANKL/OPG system (13). 24 h urinary calcium concentration exceeds RANK (receptor activator of nuclear factor– 400 mg/dL (10 mmol/L) (plasma concentra- κB) is a membrane protein expressed on tion approximately 12 mg/dL [3.0 mmol/L]), the surface of osteoclasts. Its ligand (RANK nephrogenic DI results with impaired ligand, or RANKL) is found on the surface urine concentrating ability due to e ects of osteoblasts (also on stromal and T cells). on vasopressin binding, with aquaporin Binding of RANK to RANKL activates downregulation, and altered renal interstitial osteoclasts. Osteoprotegerin (OPG, liter- sodium concentration. Volume depletion can ally means “bone protector”) is a cytokine also result from associated vomiting. The (a member of the tumor necrosis factor resultant intravascular volume contraction [TNF] receptor superfamily) and a RANK and subsequent reduction in glomerular homolog that can inhibit the production and  Hypercalcemia maturation of osteoclasts by acting as a hypercalcemia in >20% cases). FHH1 is the decoy receptor blocking the interaction of most common type (∼65% of all FHH cases) RANK with its ligand RANKL. Activation and is caused by an inactivating mutation in of RANK by RANKL is increased in many the CaSR. Reduced sensing of extracellular causes of severe hypercalcemia. Knowledge calcium leads to a rise in PTH levels, result- of this pathway has resulted in the devel- ing in hypercalcemia without hypercalciuria opment of a new therapy (i.e., denosumab, (hypocalciuria is seen in 95% of cases). Bio- which prevents RANKL activating RANK on chemically, it can look very similar to PHPT, osteoclasts) for hypercalcemia (14–16) and distinguished only by a lower fractional some metabolic bone diseases. excretion of urine calcium (FeCA) and the absence of clinical complications. In an ambulatory population, PHPT Etiology accounts for the vast majority of detected hypercalcemia (>90%) (7,21–23). PHPT The two most common causes of hyper- is often characterized by increased secre- calcemia are PHPT and malignancy. PHPT tion of PTH that results in hypercalcemia. tends to be more common in outpatient Inappropriate autonomous PTH secre- settings, whereas malignancy is most com- tion is found in the context of parathyroid monly seen in inpatients (17,18). Vitamin adenomas which may be solitary (80% to D (cholecalciferol or ergocalciferol) or vita- 85% of cases) or multiple (7). Parathyroid min D analog therapy has become one adenomas are most commonly sporadic of the most common causes of hypercal- but may be part of an endocrine neoplastic cemia detected in laboratory practice (vita- syndrome especially if numerous or found min D toxicity is de ned as hypercalcemia in the young, such as multiple endocrine and serum 25-(OH)D >250 nmol/L [su - neoplasia (MEN) type 1 (MEN1); MEN2A cient is >50 nmol/L], with hypercalciuria (MEN2); and MEN4. Hereditary forms of and suppressed PTH) (19). Together, these PHPT occur in 5–10% overall, including causes account for 90–95% of all cases of syndromic (i.e., associated with other glands hypercalcemia. and systems) and non-syndromic types, but The causes of hypercalcemia can be con- can be even higher in younger patients or veniently divided into those associated with with atypical features (e.g., age less than an elevated or inappropriately normal PTH 45 years, multi-gland involvement, parathy- level (PTH increases hydroxylation of vita- roid carcinoma). Parathyroid hyperplasia min D to its active form in the kidneys and without an obvious physiological stimulus increases bone resorption resulting in hyper- can also occur, and usually involves all four calcemia), and those where PTH output is glands (∼15% of PHPT). Rarely, parathyroid appropriately suppressed (Table 24-1) (20). carcinoma may occur (80%); or direct destruction of cemia are more evident in patients with bone, either in myeloma or lytic metastatic HHM because the plasma calcium increases disease (∼20%). Increased calcitriol produc- rapidly and often reaches concentrations tion due to increased 1α-hydroxylase activity higher than those usually seen in PHPT. in some lymphomas, and ectopic PTH Hematological malignancies such as multiple are rare and account 80%) is induced peptides, which can include PTHrP.  Hypercalcemia Increased expression of 1α-hydroxylase (26). A number of endocrinopathies are asso- by lymphoproliferative tissues including ciated with hypercalcemia. Hypercalcemia in lymphoma occasionally results in clinically thyrotoxicosis is postulated to be secondary signi cant hypercalcemia as a result of to increased bone resorption (27,28). Volume signi cantly increased synthesis of 1,25 depletion in Addison’s disease is claimed to dihydroxyvitamin D (25). Between 5% and promote hypercalcemia. PTHrP secretion 15% of patients with hypercalcemia and by pheochromocytomas occasionally results malignancy have coexisting PHPT. in clinically signi cant hypercalcemia. The A number of administered drugs can very rare vasoactive intestinal peptide (VIP) cause hypercalcemia. Thiazide diuretics secreting tumor, VIPoma, is associated reduce renal calcium excretion, increase with hypercalcemia possibly through VIP renal calcium reabsorption and, as a result, mediated stimulation of the PTH receptor. mild hypercalcemia is frequently seen, and they can unmask PHPT. The e ect of lithium is discussed above. Calcium (± vitamin D) Diagnostic Considerations supplementation rarely causes hypercal- cemia if normal physiological mechanisms of Calcium status is more accurately deter- calcium regulation are intact. In milk-alkali mined by measuring free (ionized) cal- syndrome, a high intake of milk or calcium cium, the tightly regulated, biologically active carbonate (used to treat dyspepsia or more species. Interpretation of the total serum cal- commonly now osteoporosis) may lead to cium value is complicated by its association hypercalcemia mediated by the high cal- with protein and inorganic and organic ions. cium intake plus metabolic alkalosis, which Interpretation of free calcium concentration augments calcium reabsorption in the distal is less complicated, provided the specimen tubule. This usually occurs in the presence of has been properly obtained, handled, and renal impairment and reducing GFR, which analyzed. decreases calcium excretion, thus increasing Severe hypercalcemia is de ned as a total serum ACa. Hypercalcemia in the context of serum calcium >14 mg/dL (3.5 mmol/L) vitamin D intoxication is recognized but rare (29). Some 40% of total serum calcium is (8,19), but treatment with vitamin D analogs protein bound with the majority bound to (alfacalcidol, calcitriol) especially in CKD albumin, while 50% is ionized and active. and osteoporosis is increasingly recognized Albumin concentrations should therefore be as a cause of hypercalcemia (26). Hypercal- considered when assessing hypercalcemia, cemia is of particular concern in individuals and most laboratories provide a calcium level treated with large doses of parent vitamin D adjusted for the prevailing albumin (ACa). (ergo- or cholecalciferol), which can accumu- However, in states of acute albumin uctua- late in large amounts in fat stores and, when tions such as sepsis, infections and in many released, can result in prolonged hypercal- emergency situations, measurement of ion- cemia. Prolonged immobilization (including ized calcium may be a more reliable assess- the post-acute care setting) may be associated ment of calcium status (although alkalosis with hypercalcemia due to a marked increase increases binding to albumin and therefore in bone resorption. Patients with underlying decreases free calcium levels). Overall free high bone turnover states are at particular (ionized) calcium measurement may be more risk (e.g., active polyostotic Paget’s disease). useful than total calcium determination in Granuloma-associated macrophages occa- hospitalized patients. The reference interval sionally express 1α-hydroxylase with conse- of free calcium (in adults) has been reported quent increased conversion to active 1,25- as 4.6–5.3 mg/dL (1.15–1.33 mmol/L). (OH)2D (calcitriol), and hypercalcemia will Hypercalcemia is de ned >5.4 mg/dL complicate over 10% of cases of sarcoidosis (1.34 mmol/L) when measuring free calcium.  Glenn Mat n  Severe hypercalcemia, suspected clinically con rmed or suspected diagnosis of lympho- or detected biochemically, should prompt proliferative disorders. Thyroid disease and immediate treatment. The rst step in the acute adrenal insu ciency should be inves- evaluation of hypercalcemia which must tigated if clinical manifestations are present be performed prior to commencing any (Table 24-2). FeCa (fractional excretion of treatment is to obtain samples for PTH calcium) is used to di erentiate between measurement to establish whether the PHPT and FHH, but the de nitive diagnosis hypercalcemia is PTH dependent (30). of FHH requires genetic testing (11). Next PTH can be unstable in serum and there- generation genetic sequencing for hereditary fore blood samples should be taken in the forms of PHPT is now cheaper and more appropriate preservative and delivered to the widely available. PTHrP can be measured but laboratory promptly. The “intact” molecule adds little to the management if malignancy (PTH [1-84]) is now assayed routinely and associated hypercalcemia is already obvious. was thought to have eliminated the problems Other investigations should be directed by of measured bio-inactive C-terminal frag- the clinical situation and include electrocar- ments (especially in patients with impaired diogram (ECG) and imaging tests as required renal function). It has become clear that the (Table 24-2). “intact” assays measure some PTH fragments (particularly PTH (7-84)) which are biologi- cally inactive but accumulate with impaired Clinical Signs and Features renal function. The percentage of PTH (7- 84) fragments increase proportionally with Most patients with mild hypercalcemia are decreasing renal function. New “whole” PTH asymptomatic and hypercalcemia is an inci- assays have been developed that do not cross- dental nding on blood testing (including react with the PTH (7-84) fragment, but these 80% of PHPT patients). However, severe have not been shown to be o er any major hypercalcemia is usually symptomatic and clinical usefulness when investigating cal- symptoms can vary from malaise to severe cium abnormalities compared to the “intact” dehydration and coma (Table 24-3). In prac- assays. It should be remembered that PHPT tice, most cases of severe, acute hypercal- is a common condition and is therefore occa- cemia are due to cancer, though excess intake sionally (5–15% of patients with HCM) the of calcium-containing products elicits a simi- cause of hypercalcemia in patients with con- lar biochemical picture with suppressed PTH current cancer (24,29). and biochemical alkalosis. Other tests include measurement of cre- A history of smoking, persistent cough, atinine and calculation of estimated GFR hemoptysis, and weight loss suggests lung (eGFR). Renal function may be abnormal cancer as the most likely underlying diagno- due to dehydration or may indicate THPT. sis. Back pain can be due to bone metastases, Raised alkaline phosphatase is associated myeloma, osteoporotic fracture, vitamin D with osteoblastic bone metastases, but de ciency or, rarely, Paget’s disease, but can also with vitamin D de ciency and acute also be unrelated (e.g., due to degenerative fracture. Full (complete) blood count may disease). Night sweats and lymphadenopa- point to hematological disorders such as thy may be suggestive of lymphoma or lymphoma, whereas serum electrophoresis tuberculosis. If the patient is known to is used to diagnose myeloma. Levels of blood have cancer, then hypercalcemia is most markers such as 1,25-(OH)2D (calcitriol) likely malignancy-related, but other causes, and angiotensin converting enzyme (ACE) particularly PHPT, should be ruled out. may be raised in sarcoidosis. Assessment of Long-standing, relatively asymptomatic calcitriol level is also required if the patient hypercalcemia is usually most likely due is receiving vitamin D analogs, or has a to PHPT, but the diagnosis should always  Hypercalcemia Table - Investigation of hypercalcemia (22) Routine investigations Specific investigations Corrected (ACa) or free (ionized) calcium; Blood lm/markers – lymphoma phosphate – low phosphate suggests PHPT Serum and urine electrophoresis – myeloma or PTHrP related CXR/chest CT scan – lung cancer or Urea (BUN)/creatinine – raised due to granulomatous disease dehydration or acute kidney injury (AKI) or Bone scan/MRI – bone metastases suggests THPT; eGFR 400 mg/dL [10 mmol/L) – or THPT PHPT*; or hypocalciuria (e.g., FHH) Thyroid function tests – thyrotoxicosis Spot urine calcium and creatinine to calculate Cortisol level/Short ACTH stimulation test – calcium:creatinine clearance ratio – FHH acute adrenal insu ciency (0.015) familial causes (e.g., FHH, MEN) X-ray hands – periosteal calci cation due to vitamin A toxicity Vitamin A /theophylline level – toxicity * Indications for surgery in PHPT include age >50 and any one of ACa >1 mg/dL (0.25 mmol/L) above ULN; eGFR 400 mg/day (10 mmol/day). PHPT = primary hyperparathyroidism; THPT = tertiary hyperparathyroidism; PTH = parathyroid hormone; PTHrP = parathyroid hormone-related peptide; ACE = angiotensin converting enzyme; MEN = multiple endocrine neoplasia; FHH = familial hypocalciuric hypercalcemia; ACTH = adrenocorticotropic hormone; BUN = blood urea nitrogen Table - Assessment of the hypercalcemic patient Features of hypercalcemia Features of the underlying cause Malaise, fatigue, lethargy Lymphadenopathy – cancer, lymphoma or Anorexia, nausea, vomiting, weight loss tuberculosis Mental status change: depression, confusion, coma Clubbing, chest dullness, hemoptysis – lung Bone pain cancer Polydipsia and polyuria Abdominal masses, visceromegaly – solid organ Abdominal pain suggestive of pancreatitis/peptic malignancy or lymphoma ulcer/re ux/renal calculi Neck mass – cancer (including parathyroid) or Features of bowel distension due to fecal impaction goitre (constipation) Tachycardia, goitre, sweating - thyrotoxicosis Fracture due to osteoporosis in PHPT or Hyperpigmentation and hypotension – malignancy Addison’s disease Metastatic calci cation End-stage CKD/dialysis – THPT ECG changes: short QT interval Syndromic features – MEN1; MEN2A (MEN2); MEN4; Hyperparathyroid Jaw tumor syndrome PHPT = primary hyperparathyroidism; THPT = tertiary hyperparathyroidism; MEN = multiple endocrine neoplasia; CKD = chronic kidney disease.  Glenn Mat n  be con rmed. Family history may indicate volunteered by the patient. While the di er- genetic causes (which constitute 5–10% ential diagnosis of hypercalcemia is broad, a PHPT) such as FHH, MEN syndromes or nding of ACa increased to the extent that familial hyperparathyroidism-jaw tumor overt symptoms are present nearly always syndrome. Thiazide diuretics, lithium, indicates either PHPT or malignancy. Acute calcium (including antacids), vitamin D onset of hypercalcemia and rapidly increas- supplements and high-dose vitamin A ing calcium strongly favors a diagnosis of supplements may promote hypercalcemia neoplastic disease, although sudden volume that is typically reversible on stopping the contraction secondary to diarrhea, vomiting, medication. surgery, or immobilization can dangerously Examination of patients with hypercal- exacerbate pre-existing hypercalcemia. cemia should explore the e ects of hyper- As a consequence of hypercalcemia- calcemia itself as well as search for the induced nephrogenic DI, the initial symp- underlying cause. Features of severe hyper- toms relate to polyuria and the resultant calcemia usually a ect multiple organ sys- adaptive increased thirst. Neurological dys- tems (Table 24-3). Patients with chronic function, secondary to the central neuronal hypercalcemia may present with renal failure, depressant e ect of increased calcium, is renal stones, or osteoporotic fractures. Palpa- prominent and may manifest as confusion, ble masses (including breast exam), enlarged drowsiness, agitation, stupor, or coma. lymph nodes, or visceromegaly on abdominal Myopathy is occasionally seen. Hypertension examination, point toward malignancy as a as a consequence of calcium-mediated vaso- likely cause. Finger clubbing, cough, hemop- constriction can occur in chronic disease but tysis, and pleural e usions suggest lung can- is less likely in the acute volume contracted cer. Back pain, leg weakness, and spinal ten- state. Bradyarrhythmias or heart block are derness indicate spinal disease (including frequently seen in severe hypercalcemia, possibility of spinal cord compression, which however, and relate to detrimental e ects on is an oncologic emergency), which may be the cardiac action potential as a consequence metastases from a di erent site. If features of increased extracellular calcium. Gastroin- of thyrotoxicosis or adrenal insu ciency are testinal symptoms resulting in part from present, they should be considered as a possi- reduced smooth muscle contraction include ble etiology. Granulomatous diseases usually constipation, nausea, anorexia, vomiting, produce signs in the chest or bowel, but other and abdominal pain, which are often severe. organ systems may also be a ected. Renal stones and pancreatitis can occur. The The symptoms and signs of hypercalcemia term “hypercalcemic crisis” is frequently predominantly relate to the rapidity of onset used to describe the severely compromised or chronicity of the abnormality and the patient with profound volume depletion, and e ects on volume contraction that accom- altered sensorium, which may be manifest as pany increased ACa, and the neuromus- coma, cardiac decompensation, and abdom- cular dysfunction that occurs. Aside from inal pain, that may mimic an acute abdomen underlying speci c features (i.e., bone pain (2). in metastatic neoplastic disease), the symp- The diagnosis of hypercalcemic crisis can toms can be the same irrespective of the eti- sometimes be di cult to make clinically ology, and relate more to the level of hyper- when associated with malignancy. This is calcemia. Overt symptoms are unlikely to because the patient may already be debili- occur if the ACa is 3.5 mmol/L or 14 mg/dL) IV 0.9% saline 500–1000 mL over 1 hour Consider furosemide Continue 0.9% saline if aggressive uid infusion (3–6 L/24 administration likely to hours) as per uid compromise cardiac assessment function Pamidronate 30–90 mg Zoledronate 4 mg in Ibandronate 2–6 mg in Clodronate 900–1500 in 50–250 ml 0.9% 100 ml 0.9% saline 100 ml 0.9% saline mg in 500 ml 0.9% saline over at least over 15 minutes IV over 15 minutes IV saline over 4 hours IV 90 minutes IV Consider complementary therapies in refractory hypercalcemia or in the context of speci c etiologies Calcitonin 100–200 Prednisone 40–60 Parathyroidectomy Denosumab units SC every mg/day PO or or 120 mg SC weekly for Hemodialysis 6 hours (± prednisone Hydrocortisone Cinacalcet 30–360 1 month and then monthly therapy) 150–300 mg/day IV mg/day PO Figure - An algorithm for the acute management of hypercalcemia. bone” syndrome). If the diagnosis is PHPT, clodronate. Zoledronate and pamidronate then surgical removal of parathyroid ade- are the most potent (zoledronate is 1000x noma(s) should be planned, ideally when the even more potent than pamidronate). Anal- patient is stabilized but occasionally emer- yses of randomized controlled trials (RCTs) gency surgery may be required (Figure 24-3). suggest a superior e ect of zoledronate over pamidronate in the management of HCM (normalizing ACa levels in 90% vs 70% using Calcium-Specific Therapy zoledronate compared with pamidronate Bisphosphonates respectively) (33). Intravenous bisphospho- Irrespective of the etiology, severe hypercal- nates (Table 24-4) should be administered as cemia predominantly results from increased soon as possible following rehydration (12 h) mobilization of calcium from bone. Bis- for severe hypercalcemia because there is phosphonate therapy directly addresses this latency until peak e ect of 2–4 days. The feature by inhibiting osteoclast activity (4,32). dose of pamidronate depends on the level of Several IV bisphosphonate formulations are hypercalcemia (i.e., 30 mg over 2 hours with available; in order of potency, the nitrogen- calcium 3 mg/dL Bisphosphonates should be particularly (0.75 mmol/L). They are used for at least avoided if parathyroid surgery is imminent 3–10 days, but depend on the underlying as their use can result in profound postop- condition. Glucocorticoids may also be use- erative hypocalcemia. Calcimimetics, such ful in HCM involving cytokine release (e.g., as cinacalcet, which activate CaSR, reduce some myelomas). An overall management PTH secretion and, subsequently, a decrease plan should be established in liaison with a in calcium levels may be a better option in hematologist for lymphoproliferative disor- these circumstances (21). ders and myeloma. Glucocorticoids may also be of value in treating other neoplastic prob- Calcitonin lems in addition to HCM (e.g., spinal cord Calcitonin acts by inhibiting osteoclast compression, brain metastases). Hydroxy- action and therefore calcium mobilization chloroquine may also be useful in sarcoid- from bone (34). It can be given as a subcuta- related hypercalcemia. neous (SC) or intramuscular (IM) injection (100–200 units every 6 h) or as an IV infu- Hemodialysis sion in emergencies (10 units/kg over 6 h). Hemodialysis against a low or calcium free A test dose (10–50 units) should precede a diasylate is e ective and should be consid- treatment as hypersensitivity reactions are ered in any patient already on dialysis ther- reported. Flushing, nausea, and vomiting can apy or with new onset oliguric renal failure occur as milder side-e ects. Tachyphylaxis (Figure 24-3 and Figure 24-4) (3). In refrac- is often seen with calcitonin administration tory hypercalcemia, it should be considered  Glenn Mat n  Figure - The e ect of PTHrP on the 3.8 response to bisphosphonate. Circulating PTHrP > 2.6 pmol/L parathyroid hormone-related peptide 3.6 PTHrP ⩽ 2.6 pmol/L (PTHrP) higher than 2.6 pmol/L (Nichols 3.4 Adjusted Ca mmol/L Institute Assay) signi cantly decreases the percentage of patients normalizing 3.2 adjusted calcium (ACa) and shortens the length of time of response to 60 mg 3.0 Pamidronate (APD) infusion. 2.8 2.6 2.4 2.2 -1 1 3 5 7 9 11 13 15 Day post APD lnfusion (60mg) as an additional therapy even in those with- severe encephalopathy when dialysis is not out underlying renal dysfunction. It is the immediately available. most potent and rapid means of decreasing ACa levels in severe hypercalcemia (i.e., 3– 5 mg/dL [0.75–1.25 mmol/L] decrease within Treatment of Precipitating Illness 2–4 h). After the acute treatment of severe hypercal- cemia (ACa can be decreased by 3–9 mg/dL Miscellaneous [0.7–2.2 mmol/L] within 24–48 h in most Medications that interfere with osteoclast patients), the underlying cause should be action and therefore bone resorption include established. Further therapy will be deter- gallium nitrate and mithramycin. These mined by the diagnosis. preparations are associated with signi cant side-e ects and are very rarely used. Gallium Parathyroid Disease nitrate appears to be at least as e ective as pamidronate in achieving decreases in All patients with underlying parathyroid ACa, but is limited by the long duration disease (e.g., parathyroid adenoma or car- of infusion with typical dosing 200 mg per cinoma), who present with hypercalcemic square meter of body surface administered crisis, should be considered for elective over 24 hours for 5 consecutive days (35). parathyroidectomy at the earliest safest Signi cant nephrotoxicity seen with rapid opportunity unless there is good reason infusions is ameliorated by the longer dura- not to (i.e., comorbidities, poor prognosis, tion of infusion (36). Onset is usually within non-localizable disease, or strong patient 4 days and duration of activity about 2 weeks. preference). Urgent parathyroidectomy can Mithramycin (plicamycin) is a tumoricidal be considered in all patients with hyperten- antibiotic that has signi cant renal and sive crises as a result of hyperparathyroidism hepatic toxicity. It is currently only available (37) or in cases of severe hypercalcemia for research purposes but has signi cant due to hyperparathyroidism refractory to hypocalcemic properties. medical treatment. However, initial curative Phosphate infusion e ciently reduces success rates di er only marginally between the serum calcium level within minutes elective and urgent cases, and long-term of administration, but the resultant tissue outcomes appear similar, therefore elective deposition of calcium phosphate makes surgery when the patient is stabilized may be it inappropriate for use in most hypercal- preferred in these circumstances (38). cemia cases. The only indications are for Alternatively, cinacalcet, a calcimimetic life-threatening cardiac arrhythmias or which activates the CaSR thereby reducing  Hypercalcemia PTH secretion, is in current use in treatment therapy, the o ending drug must be stopped of PHPT (including parathyroid carcinoma, and ACa monitored for 3–6 months. This and additionally PHPT deemed unsuitable may be particularly di cult in those on for surgery), SHPT and THPT (7,23). It lithium therapy. However, newer psy- decreases ACa signi cantly in most patients chotropic agents e ective in bipolar disease with PHPT, and in approximately two-thirds can e ect this change more safely than in the of those with parathyroid carcinoma (39,40). past. Drug cessation must also occur in the The use of cinacalcet in the management of more common scenario where a drug is felt to hypercalcemic crisis has not yet been the sub- have contributed to the hypercalcemic state ject of a RCT, but many case studies and (i.e., thiazide therapy in a patient with HCM), reports demonstrate safety and e ectiveness unless signi cant bene t to risk ratios can be of its application in the context of refrac- demonstrated. tory hyperparathyroid disease. It is com- menced at a dose of 30 mg once- or twice- daily orally and titrated to a maximum dose of 90 mg 6 hrly (180 mg per day in renal Emerging Treatments dialysis patients). ACa should be checked one week after starting treatment or after Osteoclast recruitment with resultant dose adjustments. Bisphosphonates may be bone resorption is in part mediated by the used in combination with cinacalcet (cinacal- RANK/RANKL system (13). Activation of cet alone does not improve bone mineral the RANK receptor located on immature density). Ethanol injection directly into the osteoclasts by osteoblast-derived RANKL parathyroid adenoma may be another option promotes maturation and di erentiation of if surgery is declined or contraindicated. the osteoclast. Denosumab, a monoclonal antibody which binds to RANKL, prevent- ing binding to the RANK receptor, has Treatment of Underlying Neoplastic been shown to decrease bone resorption in Disease metastatic bone disease and in osteoporo- De nitive treatment of a primary solid tumor sis with a good safety pro le (14). Recent with expression of PTHrP may prevent fur- reports have demonstrated the e cacy of ther hypercalcemic events. PTHrP secretion denosumab in patients with HCM who by a tumor signi cantly decreases bispho- have become “resistant” to bisphosphonates sphonate e cacy restoring normocalcemia (15,16). For example, in one study of bispho- and will result in earlier rebound hypercal- sphonate refractory HCM patients (n = 33, cemia (Figure 24-4). Occasionally patients baseline ACa 13.5 mg/dL [3.4 mmol/L]), with non-humoral hypercalcemia as a result administration of denosumab (120 mg SC of lytic bone metastases may nd improve- weekly for 4 weeks; and then monthly there- ment with radiation therapy directed at the after) resulted in a normalization in ACa in lesion. 64% of patients by, on average, day 9 (Day 50 ACa ∼10.2 mg/dL [2.4 mmol/L]) (16). Miscellaneous This has translated into a proposed regime Treatment of granulomatous disorders with of 120 mg weekly for one month followed standard therapy including glucocorticoids by monthly injections (which can be self- and immunosuppressants may reduce cir- administered). Onset is usually within 7–10 culating 1,25-(OH)2D (calcitriol) concen- days and duration of activity of 3–4 months. trations resulting in decreased ACa (26). Denosumab may also be of value in parathy- Hydroxychloroquine may also be useful in roid cancer with refractory hypercalcemia this setting. if adjuvant treatments such as chemother- On the rare occasions where severe hyper- apy and radiotherapy are declined or calcemia is felt to be secondary to drug ine ective (41).  Glenn Mat n  Case Study A 76-year-old man presents confused, with previous prostatectomy. Investigations reveal increased thirst, lower back and hip pain, PSA >100 ng/mL (normal 9.8 mg/dL been used in pregnancy). It is critical to (2.4 mmol/L) may be suggestive of hyper- measure intraoperative PTH levels to con- calcemia. Subsequently surgery for PHPT rm successful removal of abnormal parathy- (which is the major cause of hypercalcemia roid gland(s). Because of the short half-life in pregnancy) may also be warranted at lower of PTH (≤5 minutes), intraoperative determi- calcium levels than in non-pregnant patients nation of intact PTH can be used to assess (e.g., >11 mg/dL [2.75 mmol/L]). Surgery the completeness of parathyroidectomy and can be performed in any trimester but is to facilitate minimally invasive parathyroid preferred in the 2nd and has been associ- surgery, thereby improving cost-e ectiveness ated with decreased risk of fetal loss when and cosmetic outcomes. PTH is measured ACa >11.4 mg/dL (2.85 mmol/L). Maternal just before the incision and again at 20 min- issues with signi cant hypercalcemia include utes after resection of the hyperfunction- hyperemesis, PHPT-associated hypertension ing parathyroid tissue. The surgeon should and pre-eclampsia, nephrolithiasis, and pan- not massage the patient’s neck at baseline creatitis. In view of the young population (this can increase PTH) or following parathy- being a ected with PHPT, genetic causes roidectomy (when PTH can be released from such as MEN should be considered. Fetal injured parathyroid glands). A decline of 50% issues include intrauterine growth defect, in or more is usually considered indicative of utero fetal demise, and increased miscar- the removal of all hyperfunctioning tissue. riage. Tetany can occur in the neonatal period It is important to be aware that increased due to hypocalcemia. risk of PHPT may prevail for up to 5 years As with all comorbid conditions in post-operatively in this population, so regu- pregnancy, multidisciplinary team (MDT) lar screening is needed. management is critical; it is important to be aware that at least 2 lives are involved; prompt senior review should be available at Conclusions all times; and many standard of care inves- tigations (e.g., nuclear scans) and drugs (e.g., Severe hypercalcemia is an endocrine emer- bisphosphonate) may be contraindicated gency that requires prompt action to prevent or need to be modi ed or have not been severe neurological, cardiac, and renal conse- tested in the pregnant setting. The majority quences. The diagnosis should be considered of cases are asymptomatic (>80%). How- in any patient with known parathyroid ever, when treatment is warranted, medical disease or neoplasm who presents with acute management can be a reasonable approach deterioration, especially in the context of with increased hydration, IV phosphate, IV neurological dysfunction. The cornerstone magnesium sulfate, and calcitonin being well of management is to perform appropriate tolerated. Cinacalcet, although not approved investigations to make an accurate diagnosis;  Glenn Mat n  uid resuscitation; and the administration that a ect the RANKL system, are likely of calcium-speci c therapies such as bispho- to become more widely used in the future sphonates. Additional therapies, including although further studies are required to calcimimetics in certain situations and drugs de ne their role. References  Favus MJ, Goltzman D. Regulation of calcium-sensing receptor mutations. Best calcium and magnesium. In: Rosen CJ, ed. Pract Res Clin Rheumatol. 2008;22: Primer on the Metabolic Bone Diseases and 129–148. Disorders of Mineral Metabolism, 8 ed,  Hannan FM, Babinsky VN, Thakker RV. Washington, DC, American Society for Disorders of the calcium-sensing receptor Bone and Mineral Research, 2013; and partner proteins: insights into the 173–179. molecular basis of calcium homeostasis. J  Ahmad S, Kuraganti G, Steenkamp D. Mol Endocrinol. 2016;57: R127–R142. Hypercalcemic crisis: a clinical review. Am  Asam M, Pawlak A, Mat n G, Quinton R. J Med. 2015;128:239–245. Disorders of calcium homeostasis.  Walsh J, Gittoes N, Selby P, the Society for Foundation Years J. 2014;5;14–23. Endocrinology Clinical Committee.  Tanaka S, Nakamura K, Takahasi N, Suda Emergency Management of Acute T. Role of RANKL in physiological and Hypercalcaemia in Adult Patients (2016). pathological bone resorption and DOI: 10.1530/EC-16-0055. therapeutics targeting the RANKL–RANK  Sternlicht H, Glezerman IG. signaling system. Immunol Rev. Hypercalcemia of malignancy and new 2005;208;30–49. treatment options. Therapeutics Clin Risk  Body JJ, Lipton A, Gralow J, et al. E ects of Management. 2015;11:1779–1788. denosumab in patients with bone  Carroll R, Mat n G. Endocrine and metastases with and without previous metabolic emergencies: hypercalcaemia. bisphosphonate exposure. J Bone Miner Therap Advances Endocrinol Metab. Res. 2010;25;440–446. 2010;1:225–334.  Hu MI, Glezerman I, Leboulleux S, et al.  Schafer AL, Shoback D. Hypocalcemia: Denosumab for patients with persistent or de nition, etiology, pathogenesis, relapsed hypercalcemia of malignancy diagnosis, and management. In: Rosen CJ. despite recent bisphosphonate treatment. J ed., Primer on the Metabolic Bone Diseases Natl Cancer Inst. 2013;105(18):1417–1420. and Disorders of Mineral Metabolism, 8th  Hu MI, Glezerman I, Leboulleux S, et al. ed. Ames, Iowa: John Wiley & Sons, Inc., Denosumab for treatment of 2013. hypercalcemia of malignancy. J Clin  Fraser WD. Hyperparathyroidism. Lancet. Endocrinol Metab. 2014;99:3144–3152. 2009;11;374(9684):145–158.  Fenech, ME, Turner, JJO. Hypercalcaemia  Holick MF. Vitamin D de ciency. N Engl J and primary hyperparathyroidism. Med. 2007;357; 266–281. Medicine (United Kingdom). 2013;  Holick MF, Brinkley NC, Bischo -Ferrari 41/10(573–576):1357–3039, 1365–4357. HA, et al. Evaluation, treatment, and  Minisola S, Pepe J, Piemonte S, Cipriani C. prevention of vitamin D de ciency: an The diagnosis and management of Endocrine Society Clinical Practice hypercalcaemia. BMJ. 2015;350:h27323. Guideline. J Clin Endocrinol Metab. DOI:10.1136/bmj.h2723. 2011;96:1911–1930.  Munns CF, Shaw N, Kiely M, et al. Global  Egbuna OI, Brown EM. Hypercalcaemic consensus recommendations on and hypocalcaemic conditions due to prevention and management of nutritional  Hypercalcemia rickets. J Clin Endocrinol Metab. 2016;  Fraser WD, Logue FC, Gallacher SJ, et al. 101:394–415. Direct and indirect assessment of the  Endres, DB. Investigation of parathyroid hormone response to hypercalcemia. Clinical Biochemistry. pamidronate therapy in Paget’s Disease of 2012;45/12(954–963): 0009-9120, bone and hypercalcaemia of malignancy. 1873–2933. Bone & Mineral. 1991;2:113–121.  Marcocci C, Cetani F. Clinical practice:  LeGrand SB, Leskuski D, Zama I. Narrative primary hyperparathyroidism. N Engl J review: furosemide for hypercalcemia: an Med. 2011;365:2389–2397. unproven yet common practice. Ann Intern  Bilezikian JP, Brandi ML, Eastell R, et al. Med. 2008;149;259–263. Guidelines for the management of  Maraka S, Kennel KA. Bisphosphonates for asymptomatic primary the prevention and treatment of hyperparathyroidism: summary statement osteoporosis. BMJ. 2015;351:h3783. from the Fourth International Workshop. J  Major P, Lortholary A, Hon J, et al. Clin Endocrinol Metab. 2014;99: Zoledronic acid is superior to pamidronate 3561–3569. in the treatment of hypercalcemia of  Khan AA, Hanley DA, Rizzoli R, et al. malignancy: a pooled analysis of two Primary hyperparathyroidism: review and randomized, controlled clinical trials. J Clin recommendations on evaluation, diagnosis, Oncol. 2001;19;558–567. and management: a Canadian and  Chesnut CH, Azria M, Silverman S, iInternational consensus. Osteoporosis Int. Engelhardt M, Olson M, Mindeholm M. 2017;28:1–19. Salmon calcitonin: a review of current and  Fraser WD, Robinson J, Lawton R, et al. future therapeutic indications. Osteoporos Clinical and laboratory studies of new Int. 2008;19:479–491. immunoradiometric assay of parathyroid  Cvitkovic F, Armand J-P, Tubiana-Hulin hormone related protein. Clin Chem. M, Rossi J-F, Warrell R. Randomized, 1993;39:414–419. double-blind, phase ii trial of gallium  Hewison M, Burke F, Evans KN, et al. nitrate compared with pamidronate for Extra-renal 25-hydroxyvitamin acute control of cancer-related D3-1-hydroxylase in human health and hypercalcemia. Cancer J. 2006;12; disease. J Steroid Biochem. 47–53. 2007;103;316–321.  Chitambar CR. Medical applications and  Tebben PJ, Singh RJ, Kumar R. Vitamin toxicities of gallium compounds. Int J D-mediated hypercalcemia: mechanisms, Environ Res Public Health. diagnosis, and treatment. Endocrine Rev. 2010;7(5):2337–2361. 2016;37: 521–547.  Young WF, Calhour DA, Lenders JWM,  Fraser WD, Logue FC, MacRitchie K, et al. Stowasser M, Textor SC. Screening for Intact parathyroid hormone concentration endocrine hypertension: an Endocrine and cyclic AMP metabolism in thyroid Society Scienti c Statement. Endocr Rev. disease. Acta Endocrinology. 2017;38(2):103–122. DOI: 1991a;124:652–657. 10.1210/er.2017-00054.  Igbal AA, Burgess EH, Gallina DL, Nanes  Cannon J, Lew J, Solorzano J. MS, Cook CB. Hypercalcemia in Parathyroidectomy for hypercalcemic hyperthyroidism: patterns of serum crisis: 40 years’ experience and long-term calcium, parathyroid hormone, and outcomes. Surgery. 2010;148;807–813. 1,25-dihydroxyvitamin D3 levels during  Marcocci C, Chanson P, Shoback D, et al. management of thyrotoxicosis. Endocr Cinacalcet reduces serum calcium Pract. 2003;9:517–521. concentrations in patients with intractable  Stewart A. Hypercalcaemia associated with primary hyperparathyroidism. J Clin cancer. N Engl J Med. 2005;352:373–379. Endocr Metab. 2009;94;2766–2772.  Glenn Mat n   Silverberg SJ, Rubin MR, Faiman C, et al. with refractory hypercalcemia. QJ Med. Cinacalcet hydrochloride reduces the 2015;108:49–50. serum calcium concentration in inoperable  Rey E, Jacob CE, Koolian M, Morin F. parathyroid carcinoma. J Clin Endocr Hypercalcemia in pregnancy – a Metab. 2007;92;3803–3808. multifaceted challenge: case reports and  Tong CV, Hussein Z, Noor NM, et al. Use literature review. Clinical Case Reports. of denosumab in parathyroid carcinoma 2016;4:1001–1008.