Hypercalcaemia caused by calcium sulfate beads

Background

There are several mechanisms through which calcium homeostasis can be disrupted. As such, derangements in calcium levels are a relatively common clinical conundrum for physicians. Both hypercalcaemia and hypocalcaemia can have significant clinical consequences if unrecognised or untreated; however, in this case report, we will discuss hypercalcaemia.

Roughly 90% of all cases of hypercalcaemia are related to primary hyperparathyroidism or related to malignancy.1–3 Determining if hypercalcaemia is parathyroid hormone (PTH) dependent or independent is a crucial first step in the diagnostic workup. In primary hyperparathyroidism, the rise in calcium is related to overproduction of PTH from the parathyroid gland.1 Primary hyperparathyroidism can be diagnosed in cases of hypercalcaemia when serum PTH is elevated.2 4 Although nearly any type of cancer can cause hypercalcaemia, there are few typical mechanisms for calcium elevation in malignancy —secretion of parathyroid-related hormone (PTHrP) and more rarely PTH from tumour cells, osteolytic metastasis causing bony breakdown and osteoclast activation, and secretion of calcitriol from tumour cells.3

Hypercalcaemia related to primary hyperparathyroidism and malignancy each have their own characteristic features. Typically, patients with primary hyperparathyroidism develop hypercalcaemia more gradually and are commonly asymptomatic.2 In hypercalcaemia driven by malignancy, elevations in serum calcium can be more abrupt, reach higher serum values and are typically more symptomatic.2 3 Additionally, in these cases, other symptoms of malignancy are typically present.3

Most cases of hypercalcaemia fall into one of these two categories. Having a stepwise approach to the workup and diagnosis of hypercalcaemia is crucial in identifying cases due to other causes. In this case, we will discuss a patient with acute onset hypercalcaemia after surgery and highlight the schema for workup of hypercalcaemia.

Case presentation

We present a woman in her 70s with a medical history significant for papillary thyroid cancer and post thyroidectomy complicated by metastasis to right femur, hypertension, hyperlipidaemia, type 2 diabetes, chronic kidney disease stage 3, status post right hip arthroplasty due to her bony metastasis as mentioned above. She was admitted from her orthopaedic clinic for concern for prosthetic joint infection with draining sinus tract despite 2 months of cefadroxil therapy. She underwent a revision of her total hip arthroplasty which included irrigation and debridement as well as insertion of biodegradable antibiotic beads and cement. During the procedure, 3 g of vancomycin mixed with cement along with rapid cure antibiotic beads was placed into the right hip capsule. The date of this procedure will be listed as postoperative day (POD) 0.

She was recovering well with no apparent postoperative complications until she was noted to have an acute rise in serum calcium on POD 3 (figure 1). As shown, the patient had no history of hypercalcaemia and developed a persistent elevation in serum calcium level (as well as associated elevations in ionised calcium, however, this measurement was not monitored regularly through the hospitalisation). It is important to note that despite elevated levels of calcium (peak of 14.4 mg/dL), the patient did not experience any change in mental status.

Investigations

The patient was treated with aggressive fluid resuscitation with normal saline running continuously at rates between 100 and 200 mL/hour throughout much of her postoperative course. Expert consultation from both nephrology and endocrinology was called on POD 5 and 7, respectively. On POD 6, the patient was treated with pamidronate and 3 days of calcitonin (figure 1).

Given the patients comorbid conditions listed above, a broad workup for hypercalcaemia was initiated. Results of various laboratory tests and their date of collection are noted on the graph. PTH was low at 21 pg/mL (laboratory reference range has normal 12–88). PTHrp was only mildly elevated which was difficult to interpret in the setting of prior malignancy and was felt to be unlikely to represent a source of hypercalcaemia. Vitamin 1,25 dihydroxy was normal at 25.3 pg/mL as was vitamin D 25 at 30.65 ng/mL. Subsequent ACE level was near normal. Serum and urine protein electrophoresis as well as free light chains were within normal limits. For treatment of this patient’s iatrogenic hypothyroidism from thyroidectomy, she was treated with levothyroxine 250 mcg daily and had thyroid levels checked before and after period of hypercalcaemia with TSH level of <0.03 mIU/L and Free T4 level of 0.76 and 1.1 ng/dL, respectively.

Given the extensive workup and hypercalcaemia that was refractory to typical treatment modalities, it was felt that the calcium sulfate-containing beads were the most likely culprit and were exacerbated by patients underlying renal function, immobility and recent surgery. Feasibility of removal of the beads was discussed with orthopaedic surgeon who felt that the benefit of such a procedure would not outweigh the risks, particularly as the patient was asymptomatic. An X-ray taken on POD 16 showed complete absorption of the beads (figure 2).

Differential diagnosis

Throughout this case, the differential remained broad. As previously mentioned, primary hyperparathyroidism and malignancy account for most cases of hypercalcaemia. Low PTH level effectively ruled out primary hyperparathyroidism as the cause. Malignancy was strongly suspected given the patient’s history of thyroid cancer with bony metastasis; however, low PTHrp, negative surgical biopsy and lack of other symptoms suggestive of active malignancy made this less likely. The low vitamin D (both 25 and 1,25) ruled out granulomatous diseases or lymphoma as well as vitamin D toxicity (the patient was instructed to stop vitamin D supplementation regardless).2 Serum and urine protein electrophoresis as well as kappa to lambda ratio were all within acceptable limits, which effectively ruled out multiple myeloma. Evaluation with positron emission tomography (PET) scan was considered given history of bone metastasis; however, following her resolution of hypercalcaemia was ultimately deferred after deliberation between primary and consulting teams. At this point, based on a diagnosis of exclusion, it was suspected that the antibiotic beads placed during the procedure was the most likely cause.

There were several patient factors that likely contributed to the degree of hypercalcaemia but were unlikely to represent the primary source of this derangement. The patient had a history of chronic kidney disease (CKD) which likely led to decreased calcium excretion of the antibiotic beads as they were absorbed—renal disease is actually listed as a warning for use on the Rapid Cure website.5 Additionally, postoperative immobilisation likely contributed to the rise in calcium. Hypercalcaemia from immobilisation is typically observed only in cases of severe and prolonged immobilisation primarily in patients with brain and spinal cord injury and elevations in serum calcium usually do not reach levels as high as observed in our case.6 Finally, the patient was also found to be in an exogenous hyperthyroid state with severely depressed thyroid stimulating hormone levels. Although hyperthyroidism can cause hypercalcaemia, it does not usually cause a rapid or significant elevation in serum calcium but certainly could exacerbate the hypercalcaemia seen in our case.1 7

Outcome and follow-up

Following improvement of serum calcium levels and after appropriate postoperative monitoring, the patient was discharged home. She was readmitted 2 months after hospital discharge due to recurrence of draining sinus tract and concern for recurrent prosthetic joint infection. Her admission and preoperative labs showed normal levels of serum calcium. She underwent another revision total hip arthroplasty with removal of the cement placed in the previous procedure. Her second operation was similar to her first including the placement of antibiotic-containing cement prior to closure. Notably, no calcium sulfate-containing antibiotic beads were used during this procedure. Postoperative calcium levels remained near the upper limit of normal and no periods of severe hypercalcaemia were observed.