Hypocalcemia in a Patient with Cancer

Kidney Case Conference: Nephrology Quiz and Questionnaire

Mitchell H. Rosner Clin J Am Soc Nephrol 12: 696–699, 2017. doi: https://doi.org/10.2215/CJN.13241216

Introduction A. Serum PTH-related protein For most American Society of Nephrology (ASN) B. Serum fibroblast growth factor-23 Kidney Week attendees, case-based clinical nephrol- C. Serum alkaline phosphatase Division of ogy talks are one of the most exciting venues. The D. Blood ionized calcium Nephrology, Nephrology Quiz and Questionnaire (NQQ) is the E. Urine calcium/creatinine University of Virginia essence of clinical nephrology and represents what Health System, fi ’ Charlottesville, drew all of us into the eld of nephrology. This year s Virginia NQQ in surprisingly temperate Chicago, with full- Discussion of Question 1 house attendance, was no exception. The expert dis- Answer: D (blood ionized calcium). This patient Correspondence: cussants prepared vignettes of puzzling patients, which presents with profound hypocalcemia, and it is impor- Dr.MitchellH.Rosner, illustrated some topical, challenging, or controversial tant to check the blood ionized calcium level to confirm Division of aspect of the diagnosis or management of key clinical Nephrology, and determine the severity of hypocalcemia. This is University of Virginia areas of nephrology. These eight interesting patients because of the inaccuracies of total serum calcium to Health System, were presented and eloquently discussed by our four determine the physiologically active ionized calcium Box 800133, expert ASN faculty. Subsequently, each discussant fraction, especially in the setting of low serum albumin Charlottesville, VA prepared a manuscript summarizing his or her case levels (as in this patient) or derangements of systemic 22908. Email: mhr9r@ virginia.edu discussions, which serves as the main text of this article pH. (Mark A. Perazella and Michael Choi, comoderators). Total serum calcium values can be significantly affected by the level of serum albumin, because a large Patient percentage (between 35% and 50%) of calcium is bound A 66-year-old man with metastatic prostate cancer by albumin (1). Thus, in a patient with low serum is admitted to the hospital with weakness, nausea, and albumin levels, the total serum calcium will not directly fl severe bone pain. He has known tumor metastases to re ect the physiologically active ionized (free) calcium the bone and liver, and he has failed therapy with (2). Various formulas, such as the formula proposed androgen deprivation treatment. by Payne et al. (3), have been proposed to derive a “ ” Three months ago, he was treated with zoledronic corrected serum calcium when serum albumin levels acid, which did not improve his bone pain. Twelve fall outside of the normal range. The methodologies fl days ago, he received subcutaneous injection therapy used in the development of these formulas are awed, with denosumab 120 mg in an effort to treat his bone and none were developed and validated in separate pain. Other medications include metoprolol 25 mg independent datasets (2). This is especially true for fi twice a day, furosemide 20 mg twice a day, occasional speci c patient populations (such as critically ill patients use of omeprazole 20 mg daily, and ibuprofen 400 mg or patients with ESRD), where the formulas have never fi three times a day. been con rmed (2,4,5). For example, Dickerson et al. (5) Physical examination was notable for a BP of 152/ examined the ability of eight correction formulas to 98 mmHg and the finding of moderate peripheral estimate ionized calcium and 15 correction formulas to edema bilaterally. The rest of his physical examination predict a corrected total calcium in critically ill trauma was unremarkable. Laboratory values are shown in patients and found that the mean sensitivity of the 23 fi Table 1. methods for diagnosing hypocalcemia (as veri ed by an 6 After you get these laboratory tests back, you go ionized calcium level) was 25% ( 32%) and that the fi 6 back and examine the patient but find that he does not speci city was 90% ( 18%). The percentage of false 6 have Chvostek or Trousseau signs. Other laboratory positives for assessing hypocalcemia was 10% ( 18%), tests are ordered: 25-hydroxyvitamin D is 9.8 ng/ml, and the mean percentage of false negatives was in- 6 1,25-dihydroxyvitamin D is 59 ng/ml, and parathy- ordinately high at 75% ( 32%) (5). roid hormone (PTH) is 560.3 pg/ml. There are also circumstances where the physiologically active calcium fraction can change, but the total serum calcium does not (1,6). This is most commonly Question 1 encountered with changes in systemic pH that affect What other laboratory tests would you want at this the binding of calcium to albumin, such that in the time? setting of metabolic acidosis, there is less binding of

Discussion of Question 2 Table 1. Laboratory values Answer: B (serum magnesium). Hypomagnesemia is a common etiology in patients with hypocalcemia, and thus, Laboratory Test Value measurement of serum magnesium levels and correction of Sodium, mEq/L 138 low levels should be a very early step in the search for a cause Potassium, mEq/L 4.3 (11). Several possible mechanisms have been identified to Bicarbonate, mEq/L 25 explain hypocalcemia seen in patients with deficient mag- Chloride, mEq/L 106 nesium levels (12,13). Because many patients with hypomag- BUN, mg/dl 18 nesemia have concomitant poor nutritional intake, this may Serum creatinine, mg/dl 1.1 be a factor (or at least permissive) in some patients, leading Calcium, mg/dl 4.9 to vitamin D and other electrolyte and mineral deficien- Phosphorus, mg/dl 3.9 cies. More important are the effects of magnesium on PTH Albumin, g/dl 2.4 secretion and/or synthesis (14). In patients with hypomagnesemia and hypocalcemia, PTH concentrations are calcium to albumin and a concomitant rise in the ionized either inappropriately normal or low, suggesting inhibi- level (the opposite occurs with acute respiratory alkalosis, tion of PTH secretion or synthesis. There is also evidence where the fall in ionized calcium can induce symptoms of for bone and kidney resistance to PTH as well as loss of a hypocalcemia, such as cramps and paresthesias). Clinically, PTH stimulation of 1- -hydroxylation of vitamin D in pa- – one area where this is important is in the care of patients tients with low serum magnesium levels (12 14). Typically, with CKD, in whom metabolic acidosis is prevalent, and patients with hypomagnesemia will only have transient rises thus, measurement of total serum calcium may underes- in serum calcium levels in response to calcium supplemen- timate the ionized calcium value and lead to treatment tation and require magnesium repletion for normalization of errors (7). the calcium level, which occurs over days (15). Thus, the gold standard for the determination of bi- Figure 1 depicts a common diagnostic algorithm for pa- ologically active calcium is the ionized value, and clinical tients presenting with hypocalcemia and starts with identi- fi decisions should ideally be made using this value. cation and treatment of hypomagnesemia. After this step, fi Patients with hypocalcemia may present with signs of etiologies of hypocalcemia can be classi ed according to the muscle irritability, such as Chvostek signs (twitching of the serum phosphorus and PTH levels. Those patients with low fi facial muscles in response to tapping over the area of the phosphorus levels often have vitamin D de ciency or re- facial nerve) or Trousseau signs (carpopedal spasm caused sistance as the etiology, and PTH levels are elevated. Those by inflating the BP cuff to a level above the systolic pressure patients with elevated phosphorus levels and hypocalcemia for 3 minutes). It is important to note that these signs are may have low or high PTH levels. High PTH levels are not reliable indicators of the severity of hypocalcemia (8). associated with either advanced CKD or PTH resistance Chvostek sign can be seen in other conditions, such as (pseudohypoparathyroidism), whereas low PTH levels are myxedema, scarlet fever, and whooping cough, and it is associated with various etiologies of hypoparathyroidism found in 25% of normal individuals and absent in nearly (including surgical removal of the glands, autoimmune de- 30% of patients with hypocalcemia (8). Trousseau sign is a struction, and genetic defects [X-linked or autosomal re- much more reliable indicator of hypocalcemia, and 94% of cessive hypoparathyroidism]). There are also various causes fi patients with hypocalcemia have positive sign (8). of hypocalcemia associated with speci c drugs (such as Theotheroptionsforanswerstothisquestionare cinacalcet, bisphosphonates, foscarnet, citrate, denosumab, incorrect for the following reasons. (1) PTH-related protein and others) and clinical contexts (such as sepsis, rhabdo- is useful in the diagnostic algorithm of patients presenting myolysis, and severe pancreatitis) that must be recognized. with hypercalcemia secondary to a paraneoplastic syn- Finally, some of the forms of gadolinium-based contrast drome. (2) Fibroblast growth factor-23 levels are elevated agents (gadodiamide and gadoversetamide) can interfere in patients with rare forms of isolated hypophosphatemia with the colorimetric assays for calcium used in many (tumor-induced osteomalacia) or patients with CKD (9). hospital laboratories and lead to a falsely low measured (3) Serum alkaline phosphatase levels may be elevated in calcium level if laboratory values are obtained shortly after states of increased bone turnover but are not diagnostic of administration of the agent (16). The other choices listed as any specificcondition.(4) Urine calcium/creatinine levels possible answers would not yield a diagnosis in this patient. can be helpful in the diagnosis of familial hypocalciuric In this case, the patient was treated with a combination hypercalcemia, where urine calcium excretion is low (10). of ergocalciferol 50,000 U every 7 days as well as 1,25- dihydroxycholecalciferol 1 mg daily and initially, intrave- nous doses of calcium gluconate followed by oral calcium Question 2 carbonate (6–8 g daily). His serum calcium level normal- What other test would you order in working through this ized over a 2-week period. patient’s hypocalcemia? Question 3 A. 24-hour Urine calcium What is the most likely etiology of this patient’shypo- B. Serum magnesium calcemia? C. Neck ultrasound D. Next sestamibi scan A. Pseudohypoparathyroidism E. Nuclear bone scan B. Vitamin D deficiency 698 Clinical Journal of the American Society of Nephrology

21 Figure 1. | Diagnostic algorithm for patients presenting with hypocalcemia. Mg ,magnesium;PO4, phosphorus; PTH, parathyroid hormone.

C. Denosumab reduced renal function have documented a potentially D. Furosemide higher incidence of hypocalcemia after treatment with E. Omeprazole denosumab in this group (21). Current recommendations for the use of denosumab stress calcium and activated vitamin D supplementation before and after the adminis- Discussion of Question 3 tration of denosumab to reduce the risk of hypocalcemia. Answer: C (denosumab). Given the clinical scenario and However, even with these measures, some patients will laboratory values (low calcium, normal phosphorus, elevated develop denosumab-induced hypocalcemia, and monitor- PTH, and low vitamin D levels), the most likely etiology for ing of serum calcium levels is recommended in all patients. ’ this patient s hypocalcemia is denosumab. Denosumab is Treatment of denosumab-induced hypocalcemia includes a fully humanized mAb that binds to and neutralizes the calcium and active vitamin D supplementation, which may k receptor activator of NF- B ligand (17). In so doing, osteoclast have to extend for several weeks, because the effects of activity rapidly declines after treatment with denosumab, denosumab are long acting (22). with subsequent reduction in osteoblast cell activity. Bone The other choices for this question are incorrect. Pseudo- remodeling can drop by over 80% from baseline within hypoparathyroidism is due to resistance to end organ effects weeks to months after treatment (17,18). Denosumab is of PTH and typically presents with low serum calcium and approved by the Food and Drug Administration for treat- high phosphorus levels accompanied by high PTH levels. It ment of men and postmenopausal women with osteoporosis is a rare and heterogeneous condition due to various defects who are at high risk for fracture, treatment to increase bone in stimulatory G proteins, and symptoms are generally first mass in men at risk for fracture who are receiving androgen seen in childhood (23). Both hypocalcemia and hypophos- deprivation therapy for prostate cancer, treatment to increase phatemia as well as low vitamin D levels characterize bone mass in women at risk for fracture who are receiving vitamin D deficiency. Furosemide and other loop diuretics adjuvant aromatase inhibitor therapy for breast cancer, and can lead to increases in urine calcium excretion but have not prevention of skeletal-related events in patients with bone been associated with severe hypocalcemia. Omeprazole and metastases from solid tumors and hypercalcemia due to other proton pump inhibitors can lead to hypomagnesemia malignancy refractory to bisphosphonates. and secondary hypocalcemia (24). Because of the mechanism of denosumab inhibiting bone remodeling, bone calcium release is markedly inhibited, Disclosures and hypocalcemia can be a consequence. Phase 3 trials of M.H.R. has consultancy agreements with Johnson and Johnson denosumab in patients with cancer and metastatic bone (New Brunswick, NJ), Abbvie (North Chicago, IL), and Otsuka lesions showed a 5.2% incidence of hypocalcemia, most of (Tokyo, Japan) and has received research funding from Otsuka and which was mild and asymptomatic, but 2% of cases were Kadmon (New York, NY). M.H.R. has received honoraria from the high-grade (19). Hypocalcemia was also seen in patients American Society of Nephrology (Washington, DC) and Baxter receiving denosumab for low bone density if they had Scientific(Deerfield, IL). M.H.R. is an advisor or member of the concomitant vitamin D deficiency and higher baseline bone Editorial Board of the American Journal of Kidney Disease and the turnover rates (20). Small trials in patients with severely Clinical Journal of the American Society of Nephrology. Clin J Am Soc Nephrol 12: 696–699, April, 2017 Hypocalcemia in a Patient with Cancer, Rosner 699

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