A 21-year-old woman presents with a history of recurrent renal stones. Her serum calcium level is 11.5 mg/dL (normal, 8.6 to 10.5 mg/dL); serum phosphorus, 2.4 mg/dL (2.5 to 4.8 mg/dL); intact parathyroid hormone (PTH), 198 pg/mL (7 to 53 pg/mL); and serum 25-hydroxyvitamin D [25(OH)D], 12.6 ng/mL (30 to 60 ng/mL). After six weeks of therapy with vitamin D (50,000 IU three times/week), the serum calcium level is 11 mg/dL; PTH, 164 pg/mL; and 25(OH)D, 28 ng/mL. With all lab results improved but still abnormal, what other information would be helpful?
With this particular case, the striking history is recurrent renal stones. Analysis of one of the stones to determine if they are calcium oxalate would be beneficial; however, a 24-hour urine calcium measurement would provide useful information about the potential cause of the renal stones. Vitamin D deficiency can cause mild hypercalcemia but can also mask underlying primary hyperparathyroidism—as it did in this case. A Tc-99 sestamibi parathyroid scan will often localize a parathyroid adenoma.
This patient’s 24-hour urine calcium was high, and her parathyroid scan suggested an adenoma in the left lower lobe of the thyroid. An experienced parathyroid surgeon was consulted, and surgical excision of a 1.5-cm parathyroid adenoma followed. The intraoperative PTH went from 183 to 39 pg/mL, and the intraoperative calcium from 11.6 to 9.2 mg/dL. There was no postoperative hypocalcemia.
Q: What is the differential diagnosis for hypercalcemia?
• Parathyroid adenoma or carcinoma
• Hypercalcemia of malignancy (eg, breast, lung, pancreas)
• Multiple myeloma
• Multiple endocrine neoplasia types 1 and 2
• Familial hypocalciuric hypercalcemia
• Excess 1,25 dihydroxy vitamin D [1,25(OH)2D] production: sarcoid or other granulomatous disorders, lymphomas
• Miscellaneous: immobilization, milk-alkali syndrome, and parenteral nutrition
• Drug-related: vitamin D deficiency or intoxication; use of thiazide diuretics or lithium
• Nonparathyroid endocrine causes: hyperthyroidism, pheochromocytoma, Addison’s disease, islet cell tumors
Q: What are the clinical manifestations of hypercalcemia?
Mild hypercalcemia is usually asymptomatic, especially if serum calcium is 10.5 to 11.5 mg/dL. Polyuria and polydypsia, renal stones, constipation, nausea, and weight loss are nonspecific symptoms. Decreased mental alertness and depression can be seen, especially if calcium is higher than 12 mg/dL. Bone pain, arthralgias, and decreased bone density can occur with longstanding hypercalcemia. ECG changes, including bradycardia, atrioventricular block, and short QT interval, are sometimes noted.
Q: What is the significance of familial hypocalciuric hypercalcemia (FHH)?
Patients with this genetic disorder, which involves mutated calcium-sensor receptors, often have a mildly elevated PTH but may have a normal PTH in the presence of hypercalcemia. A 24-hour urine calcium level below 100 mg is indicative of FHH.
A calcium/creatinine clearance ratio (calculated as urine calcium/serum calcium divided by urine creatinine/serum creatinine) of < 0.01 is suggestive of FHH, particularly if there is a family history of mild hypercalcemia.
An important point is that parathyroid surgery is ineffective in these patients, and they seldom develop clinical symptoms or stones.
Q: Often, hypercalcemia is identified through routine labs. What diagnostic studies should be obtained with the initial work-up?
Since it is not uncommon to discover mild hypercalcemia on routine labs, it may be prudent to simply recheck serum calcium before launching into an extensive work-up. A comprehensive metabolic panel will give you the calcium, albumin, and serum protein.
When serum albumin is reduced, a corrected calcium level is calculated by adding 0.8 mg/dL to the total calcium for every decrement of 1 g/dL in serum albumin below the reference value of 4 g/dL. Serum phosphate is often low, except in secondary hyperparathyroidism due to renal failure, in which case phosphate is high. Urine calcium excretion may be high or normal.
A 25(OH)D level should also be obtained, as vitamin D deficiency is a common cause of hypercalcemia. Adequate vitamin D replacement will often correct the hypercalcemia; however, vitamin D deficiency may be masking underlying primary hyperparathyroidism.
The PTH level will be high in primary hyperparathyroidism, although it is possible to have a normal intact PTH in patients who have had long-standing mild primary hyperparathyroidism. Secondary hyperparathyroidism due to vitamin D deficiency will also result in an elevated PTH.
A suppressed PTH level in the presence of severe hypercalcemia suggests nonparathyroid-mediated hypercalcemia, often due to malignancy. Hypercalcemia of malignancy is usually symptomatic and severe (≥ 15 mg/dL).
Q: What other nonroutine studies should be considered in the work-up?
A 24-hour urine for calcium, phosphorus, and creatinine clearance, as well as a DXA bone density test, are important for making treatment decisions. A Tc-99 sestamibi parathyroid scan is important to localize a parathyroid adenoma.
Ultrasound of the neck may help to localize an enlarged parathyroid gland, especially if the scan is negative or equivocal.
Q: What are the complications of untreated hypercalcemia?
These include renal stones and urinary tract infections; peptic ulcer; altered mental status; pancreatitis; and during pregnancy, neonatal hypocalcemia.
Q: What is the medical treatment for hypercalcemia?
For acute hypercalcemia, use IV fluids at a high rate, such as normal saline 2,000 cc/hr, unless contraindicated.
Bisphosphonates, such as IV zoledronic acid, are potent inhibitors of bone resorption of calcium and can temporarily treat hypercalcemia, especially in cases of malignancy or severe hyperparathyroidism. It is important to know that oral bisphosphonates are not effective in treating hypercalcemia.
Avoid thiazide diuretics, as well as vitamin A, vitamin D, and calcium supplements. Another caveat: In the face of vitamin D deficiency, correct the vitamin D level to 40 to 60 ng/dL. Patients with 1,25(OH)2D-mediated hypercalcemia should be treated with glucocorticoids (prednisone or IV hydrocortisone), as they decrease 1,25(OH)2D.
Cinacalcet is approved for treatment of secondary hyperparathyroidism due to chronic renal failure, parathyroid carcinoma, and severe hypercalcemia in patients with primary hyperparathyroidism who are unable to undergo parathyroidectomy. The mode of action of cinacalcet is by binding to the parathyroid glands’ extracellular calcium-sensing receptors (CaSRs) to increase their affinity for extracellular calcium and decrease PTH secretion production.
Q: What are the indications for surgical intervention?
Surgery is recommended for patients with kidney stones or bone disease or with notable symptoms; those who have osteoporosis (identified on DXA scan); patients younger than 50; and those with a glomerular filtration rate below 60 mL/min and calcium 1.0 mg/dL or more above the upper limit of normal. Surgical removal of a parathyroid adenoma usually results in a cure.
Q: What causes secondary hyperparathyroidism?
Chronic renal failure is usually the cause. Hyperphosphatemia and decreased 1,25(OH)2D produce a decrease in ionized calcium. The parathyroid glands are thus stimulated and enlarge.
Vitamin D deficiency is another common cause; it is corrected with adequate vitamin D replacement. Once the vitamin D level is corrected, additional calcium supplementation should be given.
Q: What is the prognosis of hypercalcemia?
Primary hyperparathyroidism is usually chronic and progressive unless surgically cured or medically corrected. The prognosis of hypercalcemia is directly related to the degree of renal impairment or the underlying cause, such as malignancy. The presence of pancreatitis increases the mortality rate.
Regular monitoring and follow-up are important, especially if there is a trend of worsening hypercalcemia and etiology has not been identified. Monitor calcium and albumin at least every three months and renal function at least every six months.
Furthermore, check the 24-hour urine calcium and order DXA bone density testing annually.
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