Most patients with PHPT are asymptomatic, although some eventually develop bone loss, nephrolithiasis, and renal colic.4,5 A 10-year prospective cohort study of patients with PHPT found that 21% of asymptomatic patients developed decreased bone density at one or more sites.6 None acquired kidney stones, but hypercalcemia and hypercalciuria did worsen in 10 of 52 patients. A guideline and a review on PHPT recommend measuring creatinine clearance and obtaining a bone densitometry study of the distal third of the radius, hip, and lumbar spine to assess for end-organ changes related to the condition; declining renal function and osteoporosis may be indications for surgery.3,5
Malignancy is the most common cause of low intact PTH and true hypercalcemia, especially when the calcium level is >14 mg/dL.1 A PTHrP >1.0 pmol/L is highly specific for malignancy because this level does not occur in healthy people.1 In a prospective case series of patients with hypercalcemia and malignancy, 54% had elevated PTHrP levels.7 The authors found that an elevated PTHrP in patients younger than 65 years of age doubles the risk of death from malignancy compared to patients the same age with normal PTHrP (hazard ratio=1.9; 95% CI, 1.1-3.4).
TABLE
Causes of hypercalcemia
| Primary hyperparathyroidism |
Malignancy
|
| Chronic renal failure |
| Endocrine disorders (hyperthyroidism, pheochromocytoma, Addison’s disease) |
| Familial hypocalciuric hypercalcemia |
| Immobilization |
| Laboratory artifact resulting from altered albumin concentration or pH |
| Medications (vitamin A toxicity [dietary fads, isotretinoin overdose], estrogens, antiestrogens, thiazides, lithium) |
| Milk alkali syndrome |
| Vitamin D toxicity (granulomatous disease [sarcoidosis, tuberculosis], vitamin D supplementation) |
| Based on Hutton E,1 and Carroll MF et al.2 |
Identify less common causes
Serum calcitriol in association with a low intact PTH level and elevated calcium lower than 14 mg/dL helps differentiate the less common causes of hypercalcemia. Calcitriol is high in granulomatous diseases such as sarcoidosis, tuberculosis, and histoplasmosis, and normal in hyperthyroidism and Addison’s disease.1
Immobilization as a cause of hypercalcemia can be distinguished from PHPT by history and normal PTH levels and from malignancy by a normal alkaline phosphatase level.1
Recommendations
In addition to the recommendations discussed previously, Williams Textbook of Endocrinology advises repeating the initial calcium level twice and measuring serum BUN, creatinine, electrolytes, albumin, globulin, and phosphate.8 The authors recommend a generalized work-up for malignancy, including mammography, chest radiography with or without CT, abdominal CT, serum and urine immunoelectrophoresis, and temporary discontinuation of lithium for patients taking the drug. They also recommend using PTHrP only when PTH is suppressed but an underlying malignancy can’t be found.