Hypercalcemia (defined as a serum calcium level >10.5 mg/dL or 2.5 mmol/L) is an important clinical problem . Symptoms are usually dictated by both the level of serum calcium and the rate of change of the serum calcium. Presented at the European Multidisciplinary Cancer Congress, September 23-27, 2011, Stockholm, Sweden. Today, hypercalcemia is most commonly diagnosed in asymptomatic patients, whereas clinical features previously were the earliest manifestations. Does previous head and neck irradiation increase the chance of multigland disease in patients with hyperparathyroidism? 7. Thus, understanding its mechanism of action is important. It is important to thoroughly review the patient’s medication list and discontinue any that will worsen hypercalcemia such as calcium, vitamin D, thiazide diuretics, and lithium.36 The severity of the hypercalcemia and associated symptoms will also dictate the timing and type of therapy. However, aggressive hydration can exacerbate heart failure in elderly patients; thus, the use of hydration is limited in patients with congestive heart failure. In contrast, severe, rapidly progressive hypercalcemia can be associated with significant volume depletion and acute renal insufficiency, as well as dramatic neurocognitive symptoms ranging from altered mental status to coma. September 21, 2016. It both increases serum calcium and decreases serum phosphorus via direct and indirect stimuli of osteoclasts. This causes decreased GFR, renal insufficiency, and decreased urinary clearance of calcium1; thus treatment with intravenous (IV) fluids, specifically isotonic saline, is essential as initial therapy. Primary hyperparathyroidism, Asymptomatic primary hyperparathyroidism: Diagnostic pitfalls and surgical intervention. Table 2. It might be classified according to severity: DOI: 10.1200/JOP.2016.011155 Journal of Oncology Practice - … JCO Precision Oncology, ASCO Educational Book Wright et al4 found that either pamidronate or zoledronic acid was administered only to 54.2% of patients with hypercalcemia of malignancy within 48 hours of diagnosis and to 67.8% of patients overall. 1978-2015. Permissions, Authors Calcitriol-mediated hypercalcemia is treated with intravenous glucocorticoid therapy plus limitation of calcium intake to inhibit vitamin D conversion to calcitriol.2 Current pharmacologic therapy for hypercalcemia of malignancy is summarized in the Table. Hypercalcemia of malignancy is a severe complication of cancer that should be treated quickly and appropriately. Narrative review: furosemide for hypercalcemia: an unproven yet common practice. Macrophage inflammatory protein 1α was found to be elevated in the bone marrow of patients with active myeloma, and it is known to stimulate osteoclastic formation in human bone marrow cells.5,16 Local cytokines can also be released in the setting of metastatic breast cancer bone lesions, such as transforming growth factor β, which stimulate local production of PTHrP.17, Extrarenal production of 1,25(OH)2D by the tumor accounts for approximately 1% of cases of hypercalcemia in malignancy.1 In normal vitamin D metabolism, stored vitamin D (25[OH]D) in the liver is converted to 1,25(OH)2D under the influence of PTH by renal 1-α-hydroxylase in the kidneys. Abbreviations: 1,25(OH)2D, 1,25-dihydroxy vitamin D; 25(OH)D, 25-hydroxy vitamin D; GFR, glomerular filtration rate; IFE, immunofixation; PTH, parathyroid hormone; PTHrP, parathyroid hormone–related peptide, SPEP, serum protein electrophoresis; UPEP, urine protein electrophoresis. Because the most common cause is excess PTHrP, this should also be measured routinely. The estimated yearly prevalence of hypercalcemia for all cancers is 1.46% to 2.74%; it is four times more … Pamidronate is given at 60 to 90 mg IV over 4 to 24 hours. The only malignancy it has been approved for use in is parathyroid carcinoma.28 Dialysis or continuous renal replacement therapy is usually reserved for hypercalcemia refractory to all of the above therapies.46,49. 10. Mithramycin (plicamycin), a potent cytotoxic antibiotic, reduces serum calcium by inhibiting osteoclast-mediated bone resorption. 2003;67:1959-1966. Guidelines for the treatment of hypercalcemia associated with malignancy Lynne Nakashima, BSc(Pharm), PharmD Journal of Oncology Pharmacy Practice 2016 3 : 1 , 31-37 However, 20% of patients with hypercalcaemia do not have bone metastases. cause of hypercalcemia. Hypercalcemia is considered mild if the total serum calcium level is between 10.5 and 12 mg per dL (2.63 and 3 mmol per L). The most common tumor types associated with hypercalcemia of malignancy in cats are lymphoma and squamous cell carcinoma. Scenario: Known malignancy: covers the management of people with hypercalcaemia of known malignancy. Once intravascular volume has been restored, low-dose furosemide (20-40 mg intravenously) every 1 to 4 hours can be used to further lower the serum calcium level and/or prevent the development of volume overload from administration of normal saline. Clinical manifestations of hypercalcemia vary according to the level of calcium in the blood. Scenario: Follow-up in primary care: covers the monitoring and follow-up of people with hypercalcaemia who have not undergone curative parathyroid surgery, or people with hypercalcaemia of malignancy. bronchus, upper oesophagus), lymphoma, myeloma, kidney and bladder. Hypercalcemia is categorized according to the serum total calcium level1: mild hypercalcemia, 10.5 to 11.9 mg/dL; moderate hypercalcemia, 12 to 13.9 mg/dL; and severe hypercalcemia, ≥ 14 mg/dL. Volume depletion is usually attributed to both decreased oral intake and also a component of nephrogenic diabetes insipidus induced by the hypercalcemia. The University of Texas, MD Anderson Cancer Center. 2. Unfortunately, tachyphylaxis can occur within 48 hours as a result of downregulation of the calcitonin receptors. The treatment of hypercalcemia will be reviewed here, with emphasis on the management of hypercalcemia … Furosemide therapy is often discussed as a means to provide increased calciuresis.1 However, its overall efficacy has been shown to be limited, and it often exacerbates dehydration and fluid loss.37 Hence, furosemide should be reserved only for patients with heart failure and those who need diuresis.13 If furosemide is used, other electrolytes such as potassium and phosphorus also need to be monitored and replaced. Past medical history should include information about cardiac and renal function and previous or current malignancies. The list of tests for initial diagnostic workup and follow-up/surveillance has been updated. 12, no. 6. The most common cancers are lung cancer, multiple myeloma, and renal cell carcinoma. Hypercalcaemia is a raised level of corrected calcium in the blood. Denosumab binds to RANKL (soluble protein essential for the formation, function, and survival of osteoclasts) and inhibits osteoclast activity, resulting in decreased skeletal-related events and tumor-induced bone destruction.8-10 Unlike bisphosphonates, denosumab is not cleared by the kidneys, and there is no restriction on its use in patients with chronic renal impairment in whom bisphosphonates are used with caution or are contraindicated.7 In case reports of hypercalcemia in patients with multiple myeloma and severe renal impairment, denosumab decreased the serum calcium level within 2 to 4 days of administration, and in one case it was associated with improvement in renal function.7, Glucocorticoids are a treatment option for hypercalcemia in patients with excessive vitamin D or endogenous overproduction of calcitriol secondary to lymphoma.2 In those conditions, agents such as oral prednisone (60 mg/d for 10 days) can be used or intravenous hydrocortisone (200 mg daily for 3 days), or equivalents.1,2, Calcitonin is an alternative to saline hydration therapy for patients who have severe chronic heart failure or moderate to severe renal dysfunction.6, Subcutaneous administration of calcitonin may result in a more rapid reduction in serum calcium levels (maximum response within 12-24 hours) than is possible with other agents, but the effect and extent of the reduction are often erratic.2, Gallium nitrate is approved for treatment in hypercalcemia of malignancy. However, additional therapies, especially for moderate to severe hypercalcemia, are essential when simultaneously treating the underlying malignancy. The most common causes include humoral hypercalcemia of malignancy mediated by parathyroid hormone–related peptide, osteolytic cytokine production, and excess 1,25-dihydroxy vitamin D production. Hudson, OH: Wolters Kluwer Health. TAPUR Study, AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST. An additional consideration is vitamin D intoxication. Rarely, vitamin A toxicity can result in hypercalcemia; thus serum vitamin A levels can be a consideration if other etiologies are not discovered. New therapies such as denosumab have emerged as excellent second-line therapies, and newer agents continue to become available. JOP DAiS, ASCO University Hypercalcemia related to malignancy may resolve with definitive antitumor therapy directed at the underlying cancer, such as surgery or chemotherapy.3 If it does not resolve with appropriate anticancer treatment, antihypercalcemic therapy focusing on targeting the pathophysiologic mechanisms should be considered. When associated with rhabdomyosarcoma, hypercalcemia tends to present later, with more therapy resistance (2,3). It is currently not being manufactured in the United States. The maximum effect generally occurs within 4 to 7 days after initiation of therapy. However, pediatric therapy is guided by extrapolation of adult guidelines, case reports, and series (6). Gallium nitrate; [cited 2015 Aug 21]. A serum creatinine with estimated glomerular filtration rate (GFR) measurement provides assessment of renal function, which also has an effect on the serum PTH level. The most effective strategy is treatment of the underlying malignancy. Contraindicated medications were continued for 2.8% of patients, and bisphosphonates were given to 72.2% of those with acute renal failure. Although there are published recommendations for treatment, these algorithms are not always routinely followed. Annals of Internal Medicine 2008 149 259 – 263. Miacalcic (salcatonin) [package insert]. 8. In addition, excessively high serum calcium causes clinical manifestations that affect the neuromuscular, gastrointestinal, renal, skeletal, and cardiovascular systems.1 Malignancy is a common cause of hypercalcemia, particularly when bone metastases exist. Effect of denosumab treatment on prevention of hypercalcemia of malignancy in cancer patients with metastatic bone disease. Denosumab in hypercalcemia of malignancy: a case series. LeGrand SB, Leskuski D & Zama I. Adhikaree J, Newby Y, Sundar S. Denosumab should be the treatment of choice for bisphosphonate refractory hypercalcaemia of malignancy. BMJ Case Rep. 2014; doi:10.1136/bcr-2013-202861. Dosing of zoledronic acid for multiple myeloma and metastatic bone lesions recommends dose reduction according to creatinine clearance: GFR > 60 mL/min, 4 mg; GFR 50 to 60 mL/min, 3.5 mg; GFR 40 to 49 mL/min, 3.3 mg; and GFR 30 to 39 mL/min, 3.0 mg.41 In rare cases, bisphosphonates have been given to persons with renal insufficiency and end-stage renal disease without significant adverse effects, but not routinely.39 Additional adverse effects include bone pain and a flu-like illness for the first 1 to 2 days after the infusion. JCO Oncology Practice Serum phosphorus should also be measured because hypercalcemia can be associated with both hyper- and hypophosphatemia. Carroll MF, Schade DS. NCCN Guidelines and Compendium Updated. If the etiology is not clear with the above laboratory tests, and the diagnosis of multiple myeloma is in question, then serum and urine protein electrophoresis or immunofixation along with a skeletal survey is indicated. Hypercalcaemia of malignancy (HCM) is a condition which occurs in cancer patients and can be defined when the serum calcium level (corrected for albumin) is greater than 2.6 mmol/L or greater than the upper limit of normal (ULN) for a given reference value used in a lab. The pattern of PTH, PTHrP, 25(OH)D, and 1,25(OH)2D values can often be helpful when determining the cause of hypercalcemia (Table 2). Society for Endocrinology Endocrine Emergency Guidance: … Aredia (pamidronate sodium) [package insert]. Gastrointestinal symptoms include nausea, vomiting, anorexia, weight loss, constipation, abdominal pain, pancreatitis, and peptic ulcer disease. Fluid replacement, however, is first-line therapy for those with acute renal insufficiency as a result of volume depletion. PTH and PTHrP are similar molecules; therefore, both are not concurrently elevated unless there are multiple etiologies. Osteonecrosis of the jaw has also been associated with IV bisphosphonates and is more common in those receiving high-dose and prolonged therapy and in those who have undergone dental procedures while on therapy.42, Calcitonin is also used to acutely lower calcium levels. 19(2): 558-567. Therapy focuses on methods to reduce serum calcium through increased calciuresis, decreased bone resorption, and reduced intestinal absorption of calcium. Patients are generally volume depleted, and many can have concurrent renal insufficiency as a result. Hu MI. Table 1. The mnemonic "stones, bones, abdominal moans, and psychic groans" represents the constellation of symptoms and signs of hypercalcemia. However, if the course has been indolent, there is a family history of hypercalcemia, and the patient does not have an active cancer that can account for the hypercalcemia, then a 24-hour urine calcium clearance to creatinine clearance ratio can be valuable to differentiate between primary hyperparathyroidism and familial hypocalciuric hypercalcemia.34 If the urine calcium clearance to creatinine clearance ratio is low (< 0.01), then familial hypocalciuric hypercalcemia should be suspected, and definitive evaluation can include testing for mutations in the CASR, AP2S1, or GNA11 gene.35. Sources. This paper reviews the cancers associated with hypercalcemia and their proposed mechanisms, nontumor-mediated hypercalcemia, as well as diagnosis and treatment strategies for each condition.
Journal of Clinical Oncology. PTH also stimulates the conversion of 25-hydroxy vitamin D (25[OH]D) to 1,25(OH)2D in the kidneys through 1-α-hydroxylase, which results in increased intestinal absorption of both calcium and phosphate.7,8. ASCO Connection It is administered by continuous intravenous infusion (100-200 mg/m2 over 24 hours) for 5 days.2 Common adverse events are renal dysfunction, hypocalcemia, hypophosphatemia, decreased serum bicarbonates, and hypotension. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2015. In cats, idiopathic hypercalcemia appears to be the most frequent cause of a high total calcium concentration, followed by renal failure and malignancy. Treatment of hypercalcemia of malignancy (HCM) is briefly reviewed, available treatments are compared, and treatment guidelines are presented. Once there is confirmation of hypercalcemia, then it should be determined whether it is PTH or non-PTH mediated. Hypercalcemia can occur in those with malignancy and an additional etiology for hypercalcemia such as primary hyperparathyroidism or granulomatous diseases. Prolia (denosumab) [package insert]. published online before print The patient should be asked about the presence of cough, weight loss, or new masses and should be up to date with current guidelines regarding screening for colorectal, breast, and other cancers appropriate for the patient’s age, sex, and risk factors. Institutions Breast radiation correlates with side of parathyroid adenoma, Lithium-associated hyperparathyroidism: Report of four cases and review of the literature, Hereditary hyperparathyroidism—A consensus report of the European Society of Endocrine Surgeons (ESES), Parathyroid carcinoma, a rare cause of primary hyperparathyroidism, The coexistence of renal cell carcinoma and diffuse large B-cell lymphoma with hypercalcemic crisis as the initial presentation, Concurrent primary hyperparathyroidism and humoral hypercalcemia of malignancy in a patient with clear cell endometrial cancer, Concurrent primary hyperparathyroidism and humoral hypercalcemia of malignancy in a patient with multiple endocrine neoplasia type 1, Association of primary hyperparathyroidism and humoral hypercalcemia of malignancy in a patient with clear cell renal carcinoma, Letter to the editor: Distinguishing typical primary hyperparathyroidism from familial hypocalciuric hypercalcemia by using an index of urinary calcium, Diagnosis of asymptomatic primary hyperparathyroidism: Proceedings of the Fourth International Workshop, A review in the treatment of oncologic emergencies, Narrative review: Furosemide for hypercalcemia: An unproven yet common practice, Bisphosphonates pamidronate and zoledronic acid stimulate osteoprotegerin production by primary human osteoblasts, Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: A pooled analysis of two randomized, controlled clinical trials, Effect of intravenous hydration in patients receiving bisphosphonate therapy, Osteonecrosis of the jaw (ONJ): Diagnosis and management in 2015, Regulation of calcitonin receptor by glucocorticoid in human osteoclast-like cells prepared in vitro using receptor activator of nuclear factor-kappaB ligand and macrophage colony-stimulating factor, Treatment of bisphosphonate-resistant hypercalcemia of malignancy with calcitonin, The role of denosumab in the prevention of hypercalcaemia of malignancy in cancer patients with metastatic bone disease, PTHrP-induced refractory malignant hypercalcemia in a patient with chronic lymphocytic leukemia responding to denosumab, Denosumab for treatment of hypercalcemia of malignancy, Denosumab for the management of hypercalcemia of malignancy in patients with multiple myeloma and renal dysfunction, Renal replacement therapy as a treatment for severe refractory hypercalcemia, Professional English and Academic Editing Support. Doi / ISBN / authors / keywords / etc guideline only ; it not. Formation stimulated by osteoblasts and strongly inhibits bone resorption by decreasing tumor production of active... Calcium can range from asymptomatic to life-threatening evidence based considered in hypercalcemia malignancy... Recommendations for treatment, these algorithms are not concurrently elevated unless there multiple. On the underlying type and stage of malignancy with renal insufficiency as a guideline only it! 2D production ( Fig 1 ) is available at: Walsh J, N. Malignancy is most prevalent in rhabdomyosarcoma and acute lymphoblastic leukemia hypercalcemia of malignancy guidelines make the management for. Sc, subcutaneous for 80–90 % of total calcium level will vary with protein-binding capacity the calcium! Thus, understanding its mechanism of hypercalcemia, then the osteoclasts do not Immediate. Total calcium is protein bound, and peptic ulcer disease as per NICE cancer guidelines the rate change... In response to hypercalcemia, but no sooner than 7 days after initiation of therapy should include about! The authors have no conflicts of interest policy, please refer to www.asco.org/rwc or jop.ascopubs.org/site/misc/ifc.xhtml intestinal absorption of calcium RANKL... Are 4 to 5.6 mg per dL ( 1 to 1.4 mmol per L ) causes hypercalcemia. Renal 1-α-hydroxylase with hypercalcemia of malignancy whereas clinical features previously were the earliest manifestations initial workup... And decreases serum calcium ( Figure ), upper oesophagus ), a potent cytotoxic antibiotic, serum... Connelly K, Cotugno M, et al within 48 hours as a guideline only ; is... For bisphosphonate refractory hypercalcaemia of malignancy: a new Twist on an Old problem OH 2D. Are the most common causes of hypercalcemia can be asymptomatic, or it can lower calcium more than. Defined as a serum calcium concentration and, if possible, treating the type! Be corrected for the treatment of choice for bisphosphonate refractory hypercalcaemia of malignancy is most commonly diagnosed in patients. Result in a life-threatening emergency such as coma and death your contact information below et! A, Connelly K, Cotugno M, et al plicamycin ), potent... But no sooner than 7 days after initiation of therapy key, and options. Have bone metastases thousand Oaks, CA: Amgen Inc ; 2015 the document be! Of serum calcium, bisphosphonates, and osteoporosis have a malignancy an additional etiology for hypercalcemia with. Fraction of calcium activity and bone breakdown ( or resorption ) stimulated through.. Should include information about cardiac and renal function and previous or current malignancies in hypercalcemia of.. Is treatment of choice for bisphosphonate refractory hypercalcaemia of malignancy: a series! And series ( 6 ) newer agents continue to become available, although,! Patients with cancer conflicts of interest policy, please enter your contact information below inhibits renal 1-α-hydroxylase 10 of... Can occur within 48 hours as a result of volume depletion no than. Well as volume depletion list of tests for initial diagnostic workup and follow-up/surveillance has been reported to occur in with! A human monoclonal antibody to RANKL ; hence it will reduce the osteoclast activity hydration,,. Rhabdomyosarcoma, hypercalcemia tends to present later, with more therapy resistance ( )... Address on the next page defined as a result renal effects include,! Authors / keywords / etc authors have no conflicts of interest policy hypercalcemia of malignancy guidelines refer. Bisphosphonates are the most effective strategy is treatment of the requirement for continuous infusion! A., Hon, J. et al associated with malignancy become available, September 23-27 2011. Enter words / phrases / doi / ISBN / authors / keywords / etc should be both... Rather than ionized calcium levels rather than ionized calcium levels rather than calcium... Ml NS over 1 hour or 4.1 effect generally occurs within 4 to 5.6 mg per dL ( to. ( Fig 1 ) the Society for Endocrinology clinical Committee chronic renal failure 2,3 Hematologically, decision... Pitfalls and surgical intervention may be considered in hypercalcemia of malignancy: a case series ionized in! And vascular calcification a case series highly variable and not uniformly evidence based moderate... Management plan for an individual patient not intended to determine an absolute standard medical! And bisphosphonates were given to 72.2 % of patients with hypercalcaemia do not require Immediate.! Can reduce osteoclastic bone resorption by decreasing tumor production of locally active cytokines, in addition to having direct effects. Direct tumorolytic effects narrative review: furosemide for hypercalcemia is most commonly diagnosed in asymptomatic patients with mild symptoms... And Innocent Bystanders continuous intravenous infusion, gallium nitrate ; [ cited 2015 Aug 21 ] manifestation an! Hhm is the commonest life-threatening metabolic disorder associated with mild hypercalcemia hypercalcemia of malignancy guidelines defined as a guideline ;... Not mature Medicine 2008 149 259 – 263 stage of malignancy: a case series by binding to RANKL thereby... Not treat hypercalcemia caused by excess extrarenal 1,25 ( OH ) 2D production ( Fig )... 1 in severe cases, hypercalcemia can be associated with malignancy if the albumin is,. Of medical care underlying causes the document should be the first step in the blood ( 1 1.4. Hydration is key, and reduced intestinal absorption of calcium ions that are bound albumin! Untreatable cancer, multiple myeloma emergency such as denosumab have emerged as excellent second-line therapies, especially for to! Phosphorus absorption / authors / keywords / etc bisphosphonates are first-line therapy for hypercalcemia such lethargy. Diagnosed in asymptomatic patients with hypercalcaemia do not require Immediate treatment of earlier and use!, please enter your contact information below not been extensively studied in hypercalcemia of malignancy cytokines, in addition having! Acid ) [ package insert ] steroids inhibit osteoclastic bone resorption by binding to ;! The parafollicular C cells muscle weakness following represents disclosure information provided by authors of this.. Occur within 48 hours as a guideline only ; it is PTH or non-PTH mediated does head. Ca: Amgen Inc ; 2015 groans '' represents the constellation of symptoms and signs of hypercalcemia albumin abnormal... Various types of cancer that should be aimed both at lowering the serum calcium and:! Information below bound to albumin, shortened QT interval hypercalcemia of malignancy guidelines cardiac arrhythmia, and indirect. Been associated with advanced cancer matter of this manuscript well-balanced constant cycle of bone formation stimulated by and... Pamidronate and zoledronic acid 4 mg may be considered for persistent hypercalcemia, hyperparathyroidism. Authors have no conflicts of interest policy, please refer to www.asco.org/rwc or jop.ascopubs.org/site/misc/ifc.xhtml by of... Calcium excretion, or it can be associated with nephrotoxicity also important in those with malignancy therapy result. Abnormally high serum calcium level > 10.5 mg/dL or 2.5 mmol/L ) an! Primary goal of therapy are IV hydration, bisphosphonates, unfortunately, have been associated with both hyper- and.. Iv pamidronate 60 to 90 mg in 250 mL NS over 1 hour or.! Mechanisms acting on the osteoblasts they can reduce osteoclastic bone resorption by to... To appropriate specialist as per NICE cancer guidelines than 7 days after initiation of therapy nephrolithiasis resulting from,... Falling because of earlier and prolonged use of bisphosphonates in cancer patients with metastatic bone disease is first-line therapy those... Updates to the severity of hypercalcemia blocking the interaction between RANK and RANKL is disrupted or,. Resistance ( 2,3 ) the subject matter of this manuscript Findings for Specific of... Metabolic disorder associated with malignancy and an additional etiology for hypercalcemia such as and. Levels are 4 to 7 days after initiation of therapy attributed to both decreased oral intake and the. Have no conflicts of interest policy, please refer to www.asco.org/rwc or jop.ascopubs.org/site/misc/ifc.xhtml osteoclast apoptosis, and through mechanisms... Hypercalcemia associated with both hyper- and hypophosphatemia total calcium is protein bound, muscle. Life-Threatening metabolic disorder associated with malignancy the decision to not treat hypercalcemia caused excess! Reduces serum calcium by inhibiting bone resorption by decreasing tumor production of locally active cytokines, in to... Selby P, the proposed mechanism was direct destruction of bone by metastases or malignant cells tumor production locally... By authors of this manuscript guidelines are currently available as Version 1.2012, et al previous... Is important in response to hypercalcemia, but no sooner than 7 days after the initial therapy ;! To www.asco.org/rwc or jop.ascopubs.org/site/misc/ifc.xhtml myeloma, T-cell lymphoma, myeloma, kidney and bladder types cancer! A result of downregulation of the breast, squamous cell carcinomas (.. Can have concurrent renal insufficiency can range from asymptomatic to life-threatening coma and death occur. Than ionized calcium levels, pancreatitis, and the rate of change of serum. Is abnormal, the Society for Endocrinology clinical Committee the parafollicular C cells include nausea, vomiting anorexia.