Primary hyperparathyroidism (1°HPT) is characterized by autonomous hypersecretion of one or more parathyroid glands. The incidence of 1°HPT in the United States is approximately 100,000 patients per year, and its prevalence is estimated to be between 0.2% and 1% (3). It predominantly affects those between the ages of 55 and 70 with a female-to-male ratio of 2:1. Recent reports from large series indicate that the etiology is a single parathyroid adenoma in 89% of cases, and hyperplasia or multiple adenomas in the remainder (4). The incidence of double adenomas ranges from 4% to 16% (5, 6, 7).

Secondary hyperparathyroidism (2°HPT) is characterized by elevation of PTH level as a result of chronic hypocalcemia, most commonly from chronic renal failure, but it can also be caused by chronic vitamin D deficiency. In chronic renal failure, renal tubular excretion of phosphate is impaired, leading to hyperphosphatemia and binding with free calcium. In addition, renal hydroxylation of vitamin D is impaired leading to hypovitaminosis D. Vitamin D deficiency leads to decreased calcium absorption from both the gut and reabsorption of calcium in the renal tubules. The end effect is lower extracellular calcium, which in turn, stimulates the parathyroid glands to secrete PTH, resulting in hyperplasia of the parathyroid glands and elevation of PTH level. Other possible causes of elevated PTH associated with normal or low calcium are low calcium intake, inefficient calcium absorption from gastrointestinal disorders, and deficiency in intake of vitamin D; all these conditions result in low calcium and a compensatory rise in PTH level. In tertiary hyperparathyroidism, the chronically hyperplastic glands autonomously secrete PTH, which usually occurs after successful renal transplantation but can also occur after long-standing hypocalcemia of any other cause is corrected.

Malignancy of the parathyroid gland is a very rare cause of hyperparathyroidism, representing less than 0.2% of patients with 1°HPT (7). It can rarely occur in association with hyperthyroid-jaw bone syndrome. Patients with this syndrome are carriers of the HRPT2 gene (8). This condition typically manifests with extremely high plasma calcium levels, usually greater than 13 mg/dL. Rarely a mass may be palpable (9).

FHH is an autosomal dominant genetic disorder characterized by mutations in the intracellular part of the CaSR (10, 11). The result is a defect in the CaSR of the parathyroid cell resulting in a lack of PTH suppression in the setting of hypercalcemia. Genetic linkage studies have shown that chromosome 3q is the major, but not the sole, locus for FHH-causing gene (11, 12). There are at least two other genetic loci, one linked to chromosome 19p and another family described in which linkage to 3q and 19q loci has been excluded but the FHH-causing gene has not yet been identified (13, 14). While this condition is usually diagnosed at a younger age, it may manifest for the first time in older patients who have not sought medical attention throughout life. It typically has a benign course without the hypercalcemia-induced morbidities and is therefore generally not a surgical disease (15, 16).

The diagnosis of 1°HPT is made based on plasma calcium and PTH levels. Plasma calcium and PTH levels should be drawn on the same day. Normal range for plasma calcium in most laboratories is 8.5 to 10.2 mg/dL (or 2.2 to 2.5 mmol/L). Since most of the body’s plasma calcium is bound to albumin, a decrease in plasma albumin will lower the plasma calcium level even though the free calcium remains the same. Therefore if the albumin level is low, the plasma calcium should be corrected such that 0.8 mg/dL should be added to the total calcium for every drop in albumin of 1.0 g/dL. Alternatively, one can measure ionized calcium, which represents free calcium. Normal range for ionized calcium in most labs is 1.14 to 1.28 mmol/L. PTH is an 84 amino acid peptide chain with a C-terminal and an N-terminal. Laboratories in the past measured PTH levels by measuring the N-terminal or C-terminal. Today, the most accurate assessment of PTH level is measurement of the entire chain, known as intact PTH. Normal range for PTH in most laboratories is 15 to 72 pg/mL. The classic laboratory findings of 1°HPT are elevated plasma calcium level and high intact PTH level. Some patients may present with elevated plasma calcium levels and PTH levels only in the midrange to upper limits of normal. In the absence of 1°HPT, elevated plasma calcium should suppress the PTH level. Therefore, unsuppressed PTH in the setting of elevated plasma calcium is “inappropriate” and indicates 1°HPT. In addition to plasma calcium and intact PTH levels, it is also helpful to look at 24-hour urine calcium and serum phosphate levels. Typically in 1°HPT, the serum phosphate is low, and the 24-hour urine calcium is normal or elevated. Some patients may present with only periodic elevations of plasma calcium. In patients with mildly elevated or normal calcium, if the PTH levels are persistently elevated, the serum phosphate is low and 24-hour urine calcium is high (greater than 350 mg), the diagnosis of 1°HPT is likely. In a patient with normal or occasional mildly elevated calcium levels, intermittent mild elevation of PTH, normal phosphate and low to normal 24-hour urine calcium, the diagnosis of 1°HPT is somewhat questionable. If the diagnosis is uncertain, it would be prudent to repeat calcium and intact PTH levels and follow the laboratory values. Other than 1°HPT, the differential diagnosis of hypercalcemia includes thiazide diuretics, immobilization, and hypercalcemia of malignancy and granulomatous diseases. Contrary to 1°HTP, the PTH level is generally low in these conditions.

Elevated plasma calcium and PTH with a low 24-hour urine calcium is suggestive of FHH. The diagnosis of FHH should be considered if there is a family history of hypercalcemia, PTH is not markedly elevated, or the 24-hour urinary calcium is low. In that setting 24-hour urine for calcium, plasma calcium, serum creatinine and 24-hour urine creatinine levels should be obtained to calculate calcium-creatinine clearance ratio. These tests should all be performed at the same time. FHH manifests with hypercalcemia and mildly elevated or normal PTH levels (17, 18). In FHH, the 24-hour urine calcium is below normal range. The calcium-creatinine clearance ratio, calculated using
the following formula, is helpful in differentiating FHH from 1°HPT.

A ratio that is greater than 0.01 is consistent with 1°HPT, though does not absolutely exclude FHH, and less than 0.01 is suggestive of FHH.

Some patients may also present with plasma calcium values in the mid to upper normal range but exhibit elevated ionized calcium. In recent years, a new entity known as normocalcemic hyperparathyroidism has been recognized where calcium level, including ionized calcium, is normal and PTH is elevated (19, 20). It has been proposed that there is a generalized targeted tissue resistance to PTH in patients with this entity. A study by Maruani et al. (21) showed PTH-dependent functions of the kidney to be attenuated in the normocalcemic hyperparathyroid patients despite an identical primary hypersecretion of PTH. They concluded that: (a) PTH induces milder biologic bone effects than in hypercalcemic patients; (b) Calcium absorption in the renal tubular system is lower in patients with normocalcemic 1°HPT compared to that of patients with hypercalcemic form of the disease. (c) The ability of PTH to decrease tubular phosphate reabsorption and stimulate synthesis of 1,25-dihydroxyvitamin D is also blunted in the patients who remain normocalcemic, compared with those who are hypercalcemic. Normocalcemic 1°HPT can be difficult to diagnose, and 2°PTH from other conditions such as chronic vitamin D deficiency, renal insufficiency, and renal calcium leak need to be excluded first. In 2°HPT, the typical laboratory finding is elevated PTH but unlike 1°HPT, the plasma calcium level is low or normal. Those with 2°HPT from chronic renal failure also exhibit elevated blood urea nitrogen, serum creatinine, and phosphate.

Vitamin D levels should also be measured. In 1°HPT, the 25-hydroxy form will typically be low, and 1,25-hydroxy form is often elevated. Vitamin D levels are generally not used to make a diagnosis of 1°HPT but may be helpful in differentiating 2°HPT due to chronic vitamin D deficiency from “normocalcemic” 1°HPT. Since both conditions will present with normal calcium and elevated PTH, if the 25-hydroxyvitamin D level is low, one can correct the vitamin D deficiency and follow the calcium level. If the calcium level becomes elevated or the PTH level does not correct back down to normal range with vitamin D replacement, the diagnosis is likely to be 1°HPT.

While imaging studies are used primarily to localize parathyroid adenomas for surgical planning, they may also be helpful in confirming the diagnosis of 1°HPT. If the lab values are intermittently or only mildly elevated, the diagnosis of 1°HPT can be confirmed if the imaging study unequivocally detects a parathyroid adenoma. The two most commonly used imaging studies are parathyroid ultrasound and technetium-99m-sestamibi parathyroid (MIBI) scan. The sensitivity of each test varies considerably, depending on the equipment and more importantly how experienced is the individual performing or interpreting the study. In the hands of a highly experienced ultrasonographer, which can be radiologist, surgeon, or endocrinologist, the sensitivity is 80% to 85%. On ultrasound, parathyroid adenomas appear hypoechoic and hypervascular (Fig. 134.3). Generally ultrasound should be able to detect adenomas located dorsal to the esophagus. The limitation of ultrasound is detecting adenomas located retroesophageally or in the mediastinum. The principle of sestamibi parathyroid scanning is that 99Tc MIBI tracer is taken up by both the thyroid and parathyroid adenoma but washes out of the thyroid faster than the parathyroid. Therefore early images at 20 minutes after injection are obtained, followed by delayed images typically at 2 hours (Fig. 134.4A). It is quite specific; however, its sensitivity
can be low in detecting small glands. One of its limitations is that concurrent thyroid disease can result in a falsepositive study. Another limitation is that the images are two-dimensional (2D) planer views and therefore do not provide information on the depth of the adenoma. This information is important for glands that are located inferior to the thyroid. On a 2D planer anterior-posterior view, without the information on the depth of the gland, a retroesophageal or paraesophageal gland can look virtually identical to an anteriorly located inferior gland. Oblique views or single photon emission computerized tomography (SPECT) obtained in conjunction with the 2D planer sestamibi scans can be helpful in providing information on the anterior-posterior location of the adenoma (Fig. 134.4B). Knowing this information obviates unnecessary extensive or missed exploration. If localization with sestamibi scan and ultrasound performed in experienced hands fail, thin-cut CT with intravenous contrast may be helpful. It is especially useful in detecting ectopic glands such as paraesophageal, retroesophageal, or mediastinal glands (Fig. 134.5).