Primary hyperparathyroidism (PHPT), a mineral metabolism disorder secondary to excessive secretion of parathyroid hormone (PTH) from one or more of the parathyroid glands, is the most common cause of hypercalcemia.

The diagnosis of PHPT is usually made after investigation of hypercalcemia, which is frequently asymptomatic, leading to the discovery of elevated or inappropriately normal PTH levels given the patient’s hypercalcemia. It is important to note that familial hypocalciuric hypercalcemia (FHH), lithium, and thiazide diuretics can present with inappropriately normal or mildly elevated PTH levels in the presence of hypercalcemia.

Measurement of 24-hour urinary calcium excretion can help to distinguish PHPT from FHH, because elevated urinary calcium concentration (>200-300 mg/dL) is useful in excluding FHH. Most patients with FHH excrete <100 mg/dL of calcium in their urine every day, whereas most patients with PHPT have normal or elevated values. Fractional excretion of calcium may also be used, because values <0.01 mg/dL in the absence of vitamin D deficiency are highly suggestive of FHH; in most patients with PHPT, the ratio is >0.02.

Asymptomatic PHPT is defined as the presence of PHPT without specific symptoms or signs associated with PTH excess or hypercalcemia. Although many patients with asymptomatic PHPT remain stable and never develop symptoms, up to one-third will present overt features of the disease after 10 to 20 years.

Normocalcemic PHPT is a variant of PHPT, defined by the presence of normal total and ionized serum calcium levels and elevated serum PTH levels in the absence of any known cause for secondary PTH elevation.1

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Etiology

Although PHPT can occur at any age, it is more common after age 60 years, with a higher prevalence in women and blacks. Most cases of PHPT are sporadic and studies have reported an association between head and neck irradiation, environmental radiation exposure (such as in the cities of Hiroshima and Chernobyl), and lithium with PHPT; however, there are several genetic syndromes that are associated with PHPT, including multiple endocrine neoplasia type 1, type 2A, or type 4; familial isolated hyperparathyroidism; or hyperparathyroidism-jaw tumor syndrome.

In most cases (80%-85% of patients), PHPT results from a single adenoma, but multi-gland disease with involvement of all 4 parathyroid glands (5% -15% of patients) is more common in familial syndromes. Parathyroid carcinoma is a rare cause of PHPT.

Clinical Presentation

The signs and symptoms of PHPT can be the result of hypercalcemia itself, including polyuria, polydipsia, constipation, anorexia, vomiting, and arrhythmias, or secondary to target organ involvement, including nephrolithiasis, reduced renal function, fragility fractures (preferential involvement of the distal one-third radius in PHPT as the catabolic effects of excessive PTH would be seen first at a cortical site), skeletal deformities, and bone pain.

Furthermore, fatigue, anxiety, poor concentration, cognitive decline, and reduced quality of life have all been reported. Neuromuscular, cardiovascular, rheumatologic, and gastrointestinal systems may also be involved.