Hypercalcemic crisis in a young woman

A 21-year-old woman was admitted to the hospital with acute onset nausea, vomiting and abdominal pain that she attributed to an alcohol binge.

On admission, her serum calcium was 16 mg/dL with a normal serum albumin of 4.2 g/dL and a low phosphate of 0.8 ng/dL. She had no prior history of hypercalcemia and no symptoms of hypercalcemia, except for intermittent constipation. She did not have a history of kidney stones, polyuria, peptic ulcer disease, pancreatitis or thyroid problems. Her four siblings were all healthy, and her family history was unremarkable. She was unemployed and frequently smoked marijuana and drank alcohol with weekend binges. She took no regular medications or supplements.

Devin Steenkamp

Stephanie L. Lee

Physical exam was unremarkable, except for signs of mild volume depletion. No neck masses were palpable clinically, and her thyroid exam was normal. She was lethargic and disinterested with blunted affect alternating with mild agitation.

Further laboratory testing revealed an elevated creatinine of 1.2 mg/dL and elevated alkaline phosphatase of 152 U/L with normal liver transaminase, lipase and amylase levels. Her intact parathyroid hormone (PTH) on admission was markedly elevated to 1,315 pg/mL, but when measured 3 days later, it was more than 2,500 pg/mL. Her 25-hydroxyvitamin D was low at 9.7 ng/mL. A diagnosis of primary hyperparathyroidism (PHP) was made, with a concomitant secondary PHP and vitamin D deficiency. Multiple endocrine neoplasia type 1 (PTH, pancreatic neuroendocrine or pituitary disease) was excluded by normal gastrin, serum free metanephrine, prolactin and thyroid-stimulating hormone levels.

A nuclear medicine thyroid/parathyroid scan revealed an abnormal focus of activity with slow wash-out kinetics abutting the inferior right thyroid lobe reaching the sternal notch that was compatible with a PTH adenoma (Figure 1). Neck ultrasound confirmed a 2.7-cm hypervascular mildly hypoechoic mass with well-defined margins and a polar feeding vessel with arcing internal vessels adjacent to the inferior pole of the thyroid, consistent with a right inferior extrathyroidal PTH adenoma (Figure 2).

Figure 1. Sestamibi thyroid-PTH scintigraphy scan: Anterioposterior planar view of the neck and mediastinum obtained at 5 minutes (EARLY) and 2 hours (LATE) after IV injection of 26.4 mCi of Tc-99m sestamibi. Both the thyroid (THY) and PTH adenoma (PTH) are seen on the EARLY image. Only the large PTH adenoma (PTH) is seen on the LATE image because the radioisotope persists in the PTH adenoma longer than the normal thyroid gland. Photos courtesy of: Stephanie L. Lee, MD, PhD

Figure 2. Ultrasound of the thyroid and PTH adenoma. A. Sagittal image shows the mildly hypoechoic PTH adenoma (PTH) abutting the inferior right thyroid lobe (THY). B. Doppler analysis of the sagittal image demonstrates the feeding blood vessel (arrow) to the superior apical pole of the PTH adenoma. C. Doppler analysis of the transverse (TRV) image demonstrating the intranodular arcing or arborization of the vessels from the feeding apical vessel (arrow) within the PTH adenoma.

Figure 3. Serum calcium during treatment of hypercalcemic crisis. The normal range for serum calcium is marked by the red box. The serum calcium level fell quickly with saline infusion (blue box), pamidronate 60 mg infusion (green arrow), calcitonin 240 U intramuscular twice daily (green box) and furosemide (F) 20 mg or 40 mg IV (red arrow) to less than 11.5 mg/dL within 48 hours after admission. The nadir after medical therapy was on the fifth day of admission. Postoperatively, the calcium became mildly low for a few days before returning to normal.

She was treated aggressively with IV normal saline and pamidronate, as well as intramuscular calcitonin. Her calcium levels improved to 11.4 mg/dL within 48 hours but started to climb to 12.5 mg/dL preoperatively (Figure 3). She also received three doses of IV furosemide after rehydration. She had a focused open parathyroidectomy, and a 3.8-cm brown-red right inferior PTH adenoma was removed. The mass was separate from the thyroid gland.

An intraoperative PTH (ioPTH) level was elevated at 4,560 pg/mL and fell after resection of the PTH adenoma to 299 pg/mL at 10 minutes and 237 pg/mL at 15 minutes. The > 50% decrease in ioPTH predicted surgical success. Typically, ioPTH levels are obtained centrally from the ipsilateral internal jugular vein (IJV). The ioPTH levels are higher than peripheral levels because the PTH adenoma typically drains into the IJV. Occasionally, the PTH adenoma will drain in to the thyrocervical vessels, resulting in IJV values similar to peripheral levels. Pathological examination revealed an 8.68-g PTH adenoma with no evidence of capsular or vascular invasion or tumor necrosis.

Her postoperative course was complicated by temporary hypocalcemia (7.3 mg/dL) on postoperative day 4, likely caused by “hungry bone syndrome” and vitamin D deficiency, which was corrected with oral calcium and temporary 1,25-dihydroxyvitamin D₃ treatment. At follow-up, her PTH level (69 pg/mL) and serum calcium levels (9.6 mg/dL) were normal (Figure 3).

Primary hyperparathyroidism caused by benign PTH adenoma is the most common cause of hypercalcemia in non-hospitalized patients; however, hypercalcemic crisis is a rare complication that warrants urgent medical care. Complications of severe hypercalcemia include nephrolithiasis, acute renal failure, nephrocalcinosis, acute pancreatitis and mental status changes, ranging from confusion and mood disturbances to fatal coma.

Hypercalcemic or PTH crisis is most often the result of acute decompensation of chronic hypercalcemia of PHP but is also associated with hypercalcemia of malignancy, PTH carcinoma and ectopic PTH adenomas. This condition is life-threatening and a true endocrine emergency. The major clinical hallmarks are calcium levels of more than 14 mg/dL, oliguria and altered mental status. PTH adenomas should be actively excluded, with surgical removal prioritized because it is curative. During the investigation of the etiology of severe hypercalcemia, it is critical that treatment be immediately initiated to decrease serum calcium levels by treatments that may include saline rehydration, saline diuresis with a loop diuretic (after rehydration), antiresorptive therapy with IV bisphosphonate and/or calcitonin therapy, and hemodialysis against a calcium-free dialysate.

This case describes many of the classic features associated with hypercalcemia and the numerous potential complications that may be anticipated before and after removal of the PTH adenoma. Interestingly, the patient’s postoperative ioPTH level fell by more than 90% during the surgery but did not normalize immediately. However, a few weeks later, the PTH normalized, indicating a possible lag-time due to secondary hyperparathyroidism because of her very low levels of vitamin D and her postoperative hypocalcemia.

The postoperative hungry bone syndrome occurs after removal of the PTH adenoma. The lowering of the PTH levels allows vigorous bone remineralization associated with low serum calcium, phosphorus and magnesium levels. This complication is associated with very high preoperative PTH levels and may be ameliorated with careful attention to normalize 25-hydroxyvitamin D status preoperatively, as well as calcium, magnesium and 1,25-dihydroxyvitamin D₃ supplementation after surgery.

Devin Steenkamp, MD, is a fellow in endocrinology in the section of endocrinology, diabetes and nutrition at Boston Medical Center. Stephanie L. Lee, MD, PhD, is director of the Thyroid Health Clinic at Boston Medical Center and associate professor of medicine at Boston University School of Medicine. She is also an Endocrine Today Editorial Board member.

For more information:

• Beck W. J Surg Res. 2011;doi:10.1016/j.jss.2011.04.010.
• Brasier AR. Am J Med. 1988;84:654-660.
• Kamaya A. Ultrasound Q. 2006;22:253-262.
• Ziegler R. J Am Soc Nephrol. 2001;12 Suppl 17:S3-S9.

Disclosure: Drs. Steenkamp and Lee report no relevant financial disclosures.