PHPT is caused by overproduction or inappropriate production of PTH by the parathyroid gland. The most common cause is a single adenoma. The incidence of parathyroid carcinoma is listed in reviews as 2%-3%, although the actual percentage is probably less. About 15% (possibly more) of cases are due to parathyroid hyperplasia, which involves more than one parathyroid gland. The most frequent clinical manifestation is renal stones (see the box). The reported incidence of clinical manifestations varies widely, most likely depending on whether the patient group analyzed was gathered because of the symptoms, whether the group was detected because of routine serum calcium screening, or whether the group was mixed in relation to the method of detection.

Symptoms or Clinical Syndromes Associated with Primary Hyperparathyroidism, with Estimated Incidence*

Urologic: nephrolithiasis, 30%-40% (21%-81%); renal failure
Skeletal: 15%-30% (6%-55%); osteoporosis, fracture, osteitis fibrosa cystica
Gastrointestinal: peptic ulcer, 15% (9%-16%); pancreatitis, 3% (2%-4%)
Neurologic: weakness, 25% (7%-42%); mental changes 25% (20%-33%)
Hypertension: 30%-40% (18%-53%)
Multiple endocrine neoplasia syndrome: 2% (1%-7%)
Asymptomatic hypercalcemia: 45% (2%-47%)
*Numbers in parentheses refer to literature range.

About 5% (literature range, 2%-10%) of patients with renal stones have PHPT.

Laboratory tests. Among nonbiochemical tests, the hemoglobin level is decreased in less than 10% of cases (2%-21%) without renal failure or bleeding peptic ulcer. A large number of biochemical tests have been advocated for diagnosis of PHPT. The classic findings on biochemical testing are elevated serum calcium, PTH, and alkaline phosphatase levels and a decreased serum phosphate level.

Serum calcium (total serum calcium). Most investigators consider an elevated serum calcium level the most common and reliable standard biochemical test abnormality in PHPT. Even when the serum calcium level falls within the population reference range, it can usually be shown to be inappropriately elevated compared with other biochemical indices. However, PHPT may exist with serum calcium values remaining within the reference range; reported incidence is about 10% of PHPT patients (literature range, 0%-50%). Normocalcemic PHPT has been defined by some as PHPT with at least one normal serum calcium determination and by others as PHPT in which no calcium value exceeds the upper reference limit. Some of the confusion and many of the problems originate from the various factors that can alter serum calcium values in normal persons, as listed here.

1. Reference range limits used. Reference range values may be derived from the literature or from the reagent manufacturer or may be established by the laboratory on the local population. These values may differ significantly. For example, the values supplied by the manufacturer of our calcium method are 8.7-10.8 mg/100 ml (2.17-2.69 mmol/L), whereas our values derived from local blood donors (corrected for effects of posture) are 8.7-10.2 mg/100 ml (2.17-2.54 mmol/L).
2. The patient’s normal serum calcium value before developing PHPT compared with population reference values. If the predisease value was in the lower part of the population reference range, the value could substantially increase and still be in the upper part of the range.
3. Diet. A high-calcium diet can increase serum calcium levels up to 0.5 mg/100 ml. A high-phosphate diet lowers serum calcium levels, reportedly even to the extent of producing a normal calcium value in PHPT.
4. Posture. Changing from an upright to a recumbent posture decreases the serum calcium concentration by an average of 4% (literature range, 2%-7%). A decrease of 4% at the 10.5 mg/100 ml level is a decrease of 0.4 mg/100 ml. Therefore, reference ranges derived from outpatients are higher than those established in blood donors or others who are recumbent. This means that high-normal results for outpatients would appear elevated by inpatient standards.
5. Tourniquet stasis. Prolonged stasis is reported to produce a small increase in serum calcium and total protein values.
6. Changes in serum albumin concentration (discussed under ionized calcium).
7. Laboratory error or, in borderline cases, usual laboratory test degree of variation.

Malignancy-associated hypercalcemia (MAH)

Malignancy may produce hypercalcemia in three ways. The first is primary bone tumor; the only common primary bone tumor associated with hypercalcemia is myeloma, which begins in the bone marrow rather than in bone itself. Hypercalcemia is found in about 30% of myeloma patients (literature range, 20%-50%). The alkaline phosphatase level is usually normal (reported increase, 0%-48%) unless a pathologic fracture develops. About 5% of acute lymphocytic leukemia patients develop hypercalcemia. The second cause of hypercalcemia in malignancy is tumor production of a hormone resembling PTH called parathyroid hormone-related protein. This is known as the “ectopic PTH syndrome,” sometimes called “pseudohyperparathyroidism” (about 50% of solid-tumor MAH). The most frequent source of solid-tumor MAH is lung carcinoma (25% of MAH cases) followed by breast (20%), squamous nonpulmonary (19%) and renal cell carcinoma (8%).

The third cause of MAH is metastatic carcinoma to bone (about 20% of solid tumor MAH). The breast is the most frequent primary site, followed by lung and kidney. Although prostate carcinoma is frequent in males, prostatic bone lesions are usually osteoblastic rather than osteolytic and serum calcium is usually not elevated.

In addition, in some studies about 5% of patients with hypercalcemia and cancer also had PHPT.

Selected nonneoplastic causes of hypercalcemia Among the conditions traditionally associated with hypercalcemia is sarcoidosis. There seems to be a much lower incidence of hypercalcemia in these patients today than in the past. Estimated frequency of hypercalcemia in sarcoidosis is about 5%-10% (literature range, 1%-62%). Serum phosphate levels are usually normal. Many of these patients have increased urine calcium excretion; the exact percentage is difficult to determine from the literature. Bone lesions are reported in 5%- 16% of cases. Tertiary hyperparathyroidism is another cause of hypercalcemia. In chronic renal failure, secondary hyperparathyroidism develops, consisting of decreased serum calcium, elevated PTH, elevated serum phosphate, and elevated alkaline phosphatase levels and development of rental osteodystrophy. If renal failure persists for a long time, secondary hyperparathyroidism may become tertiary hyperparathyroidism, which displays elevated serum calcium, elevated PTH, decreased serum phosphate, and elevated alkaline phosphatase levels and bone lesions (i.e., most of the biochemical changes usually associated with PHPT, but with diffuse hyperplasia of the parathyroid glands rather than a single adenoma). Hyperthyroidism produces hypercalcemia in about 15% of thyrotoxic patients and alkaline phosphatase (ALP) elevation in about 40%. Lithium therapy frequently increases serum total calcium levels. Although most calcium values remain within population reference range, about 12% of patients on long-term lithium therapy become hypercalcemic and about 16% are reported to develop elevated PTH assay results. Thus, discovery of hypercalcemia becomes a problem of differential diagnosis, with the major categories being artifact, neoplasia, PHPT, and “other conditions.” The incidence of asymptomatic hypercalcemia in unselected populations subjected to biochemical test screening ranges from 0.1%-6%. Many of the diagnostic procedures for PHPT have been developed to separate PHPT from other possible causes of hypercalcemia.