Primary hyperparathyroidism (PHPT) results from the overproduction of parathyroid hormone (PTH) by one or more autonomously hyperfunctioning parathyroid glands that usually causes hypercalcemia. PHPT is usually caused by a single parathyroid adenoma (85%); the remaining cases (15%) are caused by multigland disease (MGD) in which more than one parathyroid gland is hyperfunctional.

PHPT is the most common cause of hypercalcemia in the outpatient setting. Approximately 100,000 new cases per year of PHPT occur in the United States. Since the advent of routine laboratory testing, the prevalence of the disease has increased from 0.1% to 0.4%.1 PHPT may present at any age, with the majority occurring in patients older than age 45 years. Furthermore, women are affected twice as often as men; this is believed to be secondary to estrogen deficiency after menopause that unmasks underlying hyperparathyroidism.1

Definite risk factors for PHPT can be identified in only a few patients. More specifically, PHPT may be associated with genetic abnormalities such as multiple endocrine neoplasia (MEN) syndromes or familial isolated hyperparathyroidism (FIHPT) and a history of radiation exposure. Some patients have a history of therapeutic neck radiation 30 to 40 years before developing PHPT. In one study of 2555 patients followed for 50 years, even low doses of radiation exposure during the teenage years was associated with a slight risk of developing PHPT 2.

Several genetic anomalies, including tumor suppressor genes and proto-oncogenes, have been identified in the development of PHPT. A DNA mutation in a parathyroid cell may confer a proliferative advantage over normal neighboring cells, thus allowing for clonal growth. Large populations of these abnormal cells containing the same mutation within hyperfunctioning parathyroid tissue suggest that such glands are a result of clonal expansion.3

MEN1 is a tumor suppressor gene that may play a role in the development of PHPT. The MEN1 gene, located on chromosome 11, encodes for the transcription factor menin. This gene has been found to be mutated in up to 16% of patients with sporadic PHPT.4PRAD1 proto-oncogene abnormalities have also been found in approximately 20% to 40% of patients with parathyroid adenomas. PRAD1, which is located on chromosome 11, encodes for cyclin D1, which is an important regulator of the cell cycle. Inversion of the PRAD1 gene allows for cyclin D1 overexpression, leading to adenoma formation.5 In families with hyperparathyroidism–jaw tumor syndrome (HPT-JT), inactivation of the HRPT2 gene that encodes the protein parafibromin has been established as a possible mechanism in the development of parathyroid tumors. HRPT2 mutations that inactivate parafibromin and its tumor suppressor function are found in patients with HPT-JT and parathyroid carcinoma and in a few cases of parathyroid adenomas with cystic features. There is evidence to suggest that whereas parafibromin expression remains intact in benign parathyroid adenomas, its loss of expression is indicative of HRPT2 mutations, which are highly associated with HPT-JT and parathyroid carcinoma.6

The clinical presentation of PHPT has evolved throughout the years. The classic descriptions of osteitis fibrosa cystica, nephrocalcinosis, peptic ulcer disease, and severe proximal myopathy are now infrequently encountered in the United States. Currently, the most common signs and symptoms identified are bone pain, nephrolithiasis, fatigue, weakness, mood swings, irritability, anxiety, depression, poor concentration, and memory loss. Other findings associated with this condition include polydipsia, polyuria, constipation, nocturia, and heartburn. Nonetheless, up to 80% of patients currently present with nonspecific symptoms and are often considered asymptomatic.7

After PHPT is suspected or hypercalcemia is encountered, biochemical confirmation of the disease is necessary. Total serum calcium or ionized calcium levels are reliable laboratory measurements for hypercalcemia. Intact PTH levels are also measured, and if they are elevated, the diagnosis of PHPT is confirmed (Figure 8-1). However, up to 10% of patients with PHPT may actually have a “normal” or inappropriately elevated PTH level, possibly because of a different PTH “set point” within individuals that may vary with age or overall calcium levels.8 Other causes of altered calcium levels also need to be excluded, including use of thiazide diuretics, lithium, or biphosphonates; vitamin D excess; malignancy; sarcoidosis; and prolonged immobilization. Other biochemical studies that assist in making the diagnosis of PHPT include the chloride:phosphate ratio. Patients with PHPT have chloride levels in the high-normal range and phosphate levels in the low-normal range. A chloride:phosphate ratio greater than 33 is indicative of PHPT.9

Patients with PHPT may also present with normocalcemic hyperparathyroidism. In these patients, normal calcium levels are associated with elevated PTH levels. This condition is generally recognized in patients after they are evaluated for osteoporosis. In some patients, this may be the earliest presentation of symptomatic PHPT. Nevertheless, other causes of secondary PTH elevation, such as vitamin D deficiency, need to be excluded.10

Benign familial hypocalciuric hypercalcemia (BFHH) is a rare condition that must be considered in the differential diagnosis. Biochemically, BFHH may mimic PHPT, with patients presenting with elevated calcium and PTH levels. An autosomal dominant disease, BFHH is caused by a systemic underexpression of the calcium-sensing receptor gene. This condition is characterized by a long-standing history of hypercalcemia since birth along with decreased urine calcium excretion. Patients with BFHH may have a family history of hypercalcemia in relatives before age 10 years, a condition that is rarely seen in individuals with PHPT, FIHPT, or MEN syndrome. Furthermore, the urine calcium levels in these patients are usually less than 50 mg/24 hours. Similarly, the urinary calcium:creatinine clearance ratio is less than 0.01; in patients with PHPT, it is greater than 0.02.

Dual-energy x-ray absoptiometry (DEXA) measurement of bone mineral density (BMD) is widely used for the study of osteopenia and osteoporosis. Patients with decreased BMD should be monitored for hypercalcemia secondary to PHPT. Conversely, the majority of patients with PHPT should undergo BMD testing. If osteoporosis is documented (t-score < −2.5), parathyroidectomy should be considered. In patients with PHPT, bone density losses are greater in areas of cortical bone such as the radius, but they may occur at all bony sites. The benefit of parathyroidectomy, however, is more pronounced at the hip and spine because of the morbidity and mortality associated with bone fracture at these sites.

After PHPT is biochemically confirmed and the patient is a surgical candidate, the abnormal parathyroid gland(s) should be localized. Because the parathyroid glands can have varied anatomic locations, preoperative parathyroid localization can be invaluable. Ultrasonography and technetium pertechnetate (99mTc) sestamibi scans are most commonly used for parathyroid localization. Either imaging study alone can localize abnormal glands, with an accuracy nearing 80%. Ultrasonography has the advantages of being noninvasive and less costly than sestamibi scans and provides detailed information regarding the anatomic relationships of the diseased parathyroid gland(s) that may be useful to the operating surgeon (Figure 8-2). Several studies have demonstrated that surgeon-performed ultrasonography has similar or better sensitivity to sestamibi scans and radiologist-performed ultrasonography.11,12

Sestamibi has been used for the past 20 years, and several variations have been developed (Figure 8-3). There is general agreement that sestamibi, especially when combined with single-photon emission computed tomography (SPECT), is the single best imaging study for parathyroid localization. Several studies report the sensitivity and specificity of sestamibi imaging to be around 91% to 99%, respectively. A limitation of sestamibi scans is related to the additional presence of thyroid nodules or lymph nodes that may cause false-positive findings and mimic the hyperactivity of parathyroid adenomas.13