Definition and incidence

Primary hyperparathyroidism is characterized and diagnosed by the presence of elevated serum parathyroid hormone (PTH) levels despite high serum calcium levels. The incidence of primary hyperparathyroidism in the United States is approximately 0.1% to 0.5%, with a higher occurrence in females and elderly adults. Stimulation of the parathyroid gland during pregnancy or lactation, prior neck irradiation, and a family history of parathyroid disease are predisposing etiologic factors.

Pathophysiology

Primary hyperparathyroidism may result from a parathyroid adenoma, gland hyperplasia, or parathyroid cancer. In approximately 80% of cases, primary hyperparathyroidism is caused by hypersecretion of a single parathyroid adenoma. Hyperplasia of one or more parathyroid glands accounts for about 15% of the cases. Carcinoma of the parathyroid gland is found in fewer than 1% of patients and is associated with particularly high serum calcium levels. Hereditary hyperparathyroidism may exist as part of a multiple endocrine neoplasia (MEN type 1, MEN type 2A).

Clinical manifestations

Sustained overactivity of the parathyroid glands is characterized by high serum calcium levels. Most patients remain asymptomatic until the total serum calcium level rises above 11.5 to 12 mg/dL. Severe hypercalcemia (>14 to 16 mg/dL) may be life threatening and demands immediate attention.

With the development of sensitive laboratory assays for calcium, more than half of patients today with hyperparathyroidism are asymptomatic at diagnosis. Sustained and high levels of PTH over time lead to exaggerated osteoclast activity in bone, resulting in diffuse osteopenia, subperiosteal erosions, and elevated extracellular calcium levels. As osteoblasts attempt to reconstruct the ravaged bone, they secrete large amounts of the enzyme alkaline phosphatase. A heightened serum alkaline phosphatase level, therefore, is a significant diagnostic feature of hyperparathyroidism. Despite an increased mobilization of phosphorus from bone, the serum phosphate concentration usually remains normal or low as a result of increased urinary excretion. The effect of hyperparathyroidism on bone becomes clinically apparent when osteoclastic absorption of bone overwhelms osteoblastic deposition. With severe and protracted disease, the weakened bones become filled with decalcified cavities, making them painful and susceptible to fracture. Because of early diagnosis, the destructive bone disease associated with hyperparathyroidism, osteitis fibrosa cystica, is rare today.

Many of the nonskeletal manifestations of primary hyperparathyroidism are related to the accompanying hypercalcemia. Sustained hypercalcemia may produce calcifications and other deleterious effects in the pancreas (pancreatitis), kidneys (nephrolithiasis, nephrocalcinosis, polyuria), blood vessels (hypertension), heart (shortened ventricular refractory period, bradyarrhythmias, bundle branch block, heart block), and acid-producing areas of the stomach (peptic ulcer). The mnemonic “stones, bones, and groans” summarizes the renal, skeletal, and gastrointestinal features of advanced hyperparathyroidism. Profound muscle weakness, confusion, nausea, vomiting, and lethargy are additional features of the disorder.

Secondary hyperparathyroidism develops in patients with chronically low levels of serum calcium, such as those with chronic renal failure and gastrointestinal malabsorption. A compensatory parathyroid response develops in response to the hypocalcemia. Their clinical course is marked by the same PTH-mediated skeletal assault seen in the primary form of the disorder, but because it is an adaptive response, secondary hyperparathyroidism is seldom associated with hypercalcemia.