Hyperparathyroidism (HPT) is a clinical syndrome causing specific symptoms and signs that result from excessive parathyroid hormone (PTH) secretion, PTH-induced bone resorption, and hypercalcemia. The three types of HPT are primary, secondary, and tertiary.

The prevalence of primary HPT in the United States is 0.1% to 0.3% of the general population. The female-to-male ratio is 2:1 to 3:1. The incidence increases with age, and the incidence in postmenopausal women is five times higher than that in the general population.

Primary HPT is characterized by abnormal regulation of PTH secretion by calcium, resulting in excessive PTH secretion and hypercalcemia. Although the cause of primary HPT is not known, increased PTH secretion is due in part to elevation of the calcium-suppressible PTH secretion set point and a change in the slope of the calcium-PTH curve that causes relatively nonsuppressible PTH secretion. Expression of the calcium sensor-receptor (CaSR) is reduced in parathyroid adenomas and hyperplasia and may be partly responsible for this relative PTH nonsuppressibility.

Most patients with primary HPT have a single parathyroid adenoma (85%), whereas four-gland hyperplasia (10%) and multiple adenomas (5%) are less common, and parathyroid carcinomas are rare (<5%). More than 95% of those with parathyroid adenomas have a single adenoma and fewer than 5% have two or more adenomas. Normal parathyroid glands weigh less than 50 mg each. The average weight of parathyroid adenomas is 500 mg to 5 g; however, some may weigh more than 25 g. The largest reported tumor weighed 120 g, and the largest number of glands reported in one patient was eight.

Persistent hypercalcemia with increased or high-normal serum PTH levels confirms the diagnosis of primary HPT. Associated low or low-normal serum phosphate makes this diagnosis more likely. Primary HPT should be suspected whenever a patient has documented hypercalcemia, which is the most common cause of hypercalcemia. Because symptoms of primary HPT are nonspecific or absent (see question 12), one must base the diagnosis primarily on laboratory studies. Furthermore, most patients with mild primary HPT have no specific symptoms or signs. Most cases are suspected after an elevated serum calcium value is found on routine laboratory screening.

The laboratory reference range for intact PTH (10-65 pg/mL) and calcium (8.5-10.5 mg/dL) may be different in the elderly and young individuals. However, the PTH reference range is not usually adjusted for age. PTH levels normally increase with age. Why PTH increases with age is unclear, but the change may be related to age-related declines in renal function and vitamin D levels. Thus, PTH levels in the upper normal range are more likely to represent HPT in patients who are younger than in those older than 50 years. Although serum calcium levels decline with age, the decline is usually related to decreasing albumin and does not generally affect serum PTH levels.

Obtain at least three fasting serum calcium levels, ideally with no venous occlusion, and two PTH measurements at least several weeks apart. Ensure that the patient has normal renal function. Discontinue any thiazide diuretics for at least 1 week before measurement. Discontinue lithium if safe to do so. Measure serum total calcium and calculate the correction for albumin and total protein levels; order an ionized calcium measurement if there is any doubt (see Chapter 13). If calcium is elevated and the PTH value is high or high-normal, primary HPT is usually present. If calcium is normal and PTH is high, measure the serum 25-hydroxyvitamin D (25-OHD) level, because vitamin D deficiency is a common cause of secondary HPT. To exclude vitamin D deficiency, the 25-OHD level should be higher than 30 ng/mL. The immunoradiometric assay (IRMA) for intact PTH is standard and sufficient for diagnosis. However, if there is concern about the IRMA results, immunochemiluminometric assay (ICMA), which also measures intact PTH (1-84), can be used.

Increased serum chloride (Cl), decreased phosphate (PO₄), a Cl/PO₄ ratio greater than 33, elevated urinary pH (> 6.0), and increased alkaline phosphatase levels support the diagnosis of primary HPT but are not specific. If the PTH level is normal or low and the patient has suspected cancer, serum PTH-related peptide (PTHrP) should be measured. Ectopic PTH is rare and should be considered only if the patient has cancer or results of surgical neck exploration for HPT are negative.

If there is a family history of hypercalcemia and/or the serum calcium and PTH are mildly elevated chronically, consider familial hypocalciuric hypercalcemia (FHH). Calculate the fractional excretion of calcium (FECa) (see Chapter 13). The FECa is less than 1% in FHH and more than 2% in primary HPT. If the FECa is low, test family members to confirm the diagnosis. If they test positive, FHH is probably present. Avoid neck exploration, which will have no effect on reversing hypercalcemia in this genetic condition.

Renal failure increases serum PO₄ and decreases serum 1,25(OH)₂D (calcitriol). Because PO₄ directly stimulates and calcitriol directly inhibits PTH secretion, serum PTH levels increase in renal failure (secondary HPT). High PO₄ and low calcitriol levels also directly decrease serum calcium. The resulting absolute or relative hypocalcemia further increases PTH secretion. Symptoms and signs of renal insufficiency, such as lethargy, depression, anorexia, nausea, constipation, and weakness, may be identical to those of primary HPT. Thus, unless it is overt, the diagnosis of primary HPT may be more difficult in renal failure. Before parathyroidectomy for presumed primary HPT, tissue localization with ultrasound and with a technetium 99m sestamibi scan may be appropriate.

In renal failure, PTH rises above normal because of the stimulatory effects of high PO₄ and low calcitriol levels. In addition, a molecular fragment of PTH (PTH 7-84), which has antagonistic actions to those of intact PTH, accumulates in renal failure and cross-reacts with intact PTH in the intact two-site assays. For this reason, measured levels of intact PTH in patients with renal failure may be more than 1.5 times those of normal subjects to maintain physiologic PTH concentrations.

More than 85% of patients with primary HPT are asymptomatic. However, vascular, musculoskeletal, gastrointestinal, and neurologic symptoms may occur in primary HPT. The classic phrase for many of these features is “stones, bones, abdominal groans, and psychic moans.” Because of earlier diagnosis today, the incidence of nephrolithiasis has decreased to less than 10% in patients with primary HPT. Proximal muscle weakness is also characteristic. Other characteristic symptoms and signs and their probable cause(s) are outlined in Table 14-1.