Primary Hyperparathyroidism

David L. Steward

History

A 64-year-old woman has a history of osteoporosis and elevated serum calcium found on a routine renal panel. She denies a history of kidney stones or fragility fracture or a family history of hypercalcemia. She does report fatigue, which she had attributed to aging. She has no significant psychiatric history and denies gastrointestinal distress or bone pain. She is on a bisphosphonate for osteoporosis and a multivitamin. Her physical examination is unremarkable.

Differential Diagnosis—Key Points

Asymptomatic hypercalcemia associated with osteoporosis is most likely primary hyper-parathyroidism. Confirmation with a repeat renal panel and simultaneous parathyroid hormone (PTH) level are indicated. More severe hypercalcemia can be seen with malignancy, either through tumor production of PTH-related peptide (PTHrP), which can be measured, and is seen in small cell lung cancer or through extensive bone metastases, such as with multiple myeloma. Hypercalcemia may also be seen with excess calcium or vitamin D ingestion and is termed milk–alkali syndrome. It may also be seen in granulomatous disease such as tuberculosis or sarcoidosis resulting from extrarenal vitamin D production in macrophages. Intact PTH levels will be low in these cases, essentially ruling out primary hyperparathyroidism. Familial hypocalciuric hypercalcemia can mimic primary hyperparathyroidism and is excluded with a 24-hour urinary calcium level below the reference range or a fractional excretion of calcium below 1%. Lithium may cause or mimic primary hyperparathyroidism via alteration in the calcium-sensing receptor. Thiazide diuretics may exacerbate or unmask primary hyperthyroidism and occasionally cause hypercalcemia.

Primary hyperparathyroidism is most often sporadic, with about 90% of patients having a solitary parathyroid adenoma and 10% having multigland disease, primarily four-gland hyper-plasia or sometimes multiple adenomas. Familial primary hyperparathyroidism is seen with multiple endocrine neoplasia (MEN) type I and MEN-IIa. MEN-I is associated with a menin gene mutation resulting in parathyroid hyperplasia that is difficult to treat surgically. MEN-IIa is associated with a ret proto-oncogene mutation, and when accompanied by primary hyper-parathyroidism this mutation is often associated with multiple parathyroid adenomas. Biochemical screening for medullary thyroid carcinoma and pheochromocytoma is indicated in MEN-IIa (see medullary thyroid carcinoma case).

A repeat measurement of calcium level with a simultaneous intact PTH level can confirm primary hyperparathyroidism if both are elevated. Obtaining ionized calcium may be more accurate than serum calcium but is more sensitive to pH change and may be less reliable in the outpatient setting. A renal panel routinely provides serum calcium, phosphorous, creatinine, and albumin levels, which aid greatly because the serum calcium can be corrected for albumin [corrected Ca = measured Ca + (4.0 − albumin) × (0.8)]. Further, serum phosphorous should be reduced in primary hyperparathyroidism. Creatinine or creatinine clearance can be an indication of renal function.