Definition and Epidemiology

The four parathyroid glands, located in the neck next to the thyroid, sense serum levels of ionized calcium by the calcium-sensing receptor and regulate calcium through parathyroid hormone (PTH) release. PTH is an 84–amino acid peptide that raises serum calcium concentration in three ways: (1) by acting directly on bone to release calcium into the extracellular fluid; (2) by acting directly on the kidney to decrease renal loss of calcium; and (3) by acting indirectly on the intestinal tract, through the activation of vitamin D, to increase dietary calcium absorption. Parathyroid disorders cause dysfunction through their effects on bone, kidney, serum calcium, and phosphorus.

The two major categories of parathyroid dysfunction are hyperparathyroidism (the oversecretion of PTH) and hypoparathyroidism (the undersecretion of PTH). PTH levels must always be interpreted in the context of the corrected serum calcium level or serum ionized calcium level (see Chapter 208). Considered in this manner, primary hyperparathyroidism can be defined as the inappropriate secretion of PTH in the setting of hypercalcemia. Secondary hyperparathyroidism is an appropriately increased secretion of PTH in the setting of low or normal serum calcium concentration and can be caused by vitamin D deficiency or renal failure. Tertiary hyperparathyroidism is prolonged secondary hyperparathyroidism in which hypercalcemia develops; it is an initially appropriate secretion that later becomes inappropriate. Hypoparathyroidism is the inappropriately low secretion of PTH in the setting of hypocalcemia.

Automated chemistry measurements have allowed the routine detection of asymptomatic hypercalcemia, increasing the recognition of early primary hyperparathyroidism. The estimated incidence of primary hyperparathyroidism ranges from 1 in 500 to 1 in 1000, with the peak incidence in the sixth decade of life. The incidence in women is higher than that in men, approximately 3:1.¹ For unclear reasons, there was a declining incidence after the 1970s, although some consideration has been given to prior exposure to head and neck irradiation in the 1930s and 1940s as well as nuclear testing in the 1950s and 1960s as potential causes of the increased and subsequently decreased incidence.² Recent work has suggested another peak in incidence in 1998, coincident with the introduction of national osteoporosis screening guidelines.²

Secondary hyperparathyroidism is found commonly in patients with chronic kidney disease (CKD), often when the glomerular filtration rate (GFR) falls below 50 mL/min. Vitamin D deficiency and insufficiency, defined as serum 25-hydroxyvitamin D levels of less than 20 ng/mL and 30 ng/mL, respectively, are other important causes of secondary hyperparathyroidism, particularly in older adults and institutionalized patients, and have been estimated to occur in 40% to 100% of U.S. and European community-dwelling elders.³ Secondary hyperparathyroidism may also occur in patients being treated with glucocorticoids or proton pump inhibitors, which cause decreased intestinal calcium absorption.

Hypoparathyroidism is primarily a consequence of thyroid and parathyroid surgery. The incidence of acute postsurgical hypoparathyroidism ranges from 0.6% to 17%, depending on the skill of the surgeon and the type of operation. A study has suggested that the rate of long-term hypoparathyroidism after thyroidectomy is actually low.⁴

Specialist referral is indicated for all suspected cases of parathyroid disorders.

Pathophysiology

In 80% of cases of primary hyperparathyroidism, excess PTH is produced by a single parathyroid adenoma. In 15% to 20% of cases, it is produced by hyperplasia of all four glands, which may be associated with multiple endocrine neoplasia (MEN) type I or type II. Primary hyperparathyroidism is produced by a parathyroid carcinoma in less than 0.5% of cases.¹

Excess PTH stimulates osteoclast-mediated bone degradation, releasing calcium and phosphorus into the extracellular space. As a result, prolonged exposure to excess PTH will erode bone, particularly cortical (dense) bone. Trabecular bone is relatively spared because of a concomitant increase in osteoblast-mediated bone formation. Skeletal sites with primarily cortical bone, such as the wrist and proximal radius, are particularly at increased risk for fracture.

PTH acts on the kidney to increase calcium reabsorption and to increase phosphorus losses. The rising serum calcium concentration gradually exceeds the kidney’s ability to reabsorb the filtered calcium, thus increasing urinary calcium. Nephrocalcinosis, nephrolithiasis, and renal dysfunction may result. PTH receptors also exist on a variety of tissues, including brain, skin, and heart. The effects of PTH on these tissues are not yet well characterized.

Secondary hyperparathyroidism represents a compensation for decreased serum levels of ionized calcium. The kidney is important in calcium and phosphorus homeostasis, and renal insufficiency disturbs calcium metabolism in four ways. First, decreased phosphorus clearance, hyperphosphatemia, and increases in fibroblast growth factor 23 decrease serum ionized calcium and calcitriol production. Second, decreased renal activation of vitamin D decreases intestinal calcium absorption. Third, uremia produces PTH resistance, thus necessitating higher levels of PTH. Finally, uremia decreases the inhibitory effect of calcium on PTH release. As with primary hyperparathyroidism, excess PTH will erode bone. These derangements in mineral metabolism may also lead to extraskeletal and vascular calcification.⁵ Prolonged stimulation of the parathyroid glands by hypocalcemia results in hyperplasia of the glands. On occasion, this leads to autonomous parathyroid function and hypercalcemia (tertiary hyperparathyroidism).

Vitamin D deficiency results in decreased intestinal calcium absorption. This, coupled with the daily loss of calcium in the urine and the feces, leads to a net loss of calcium. To prevent overt hypocalcemia, the parathyroid glands secrete more PTH, releasing calcium from the bone and thus preserving normal serum calcium levels. Long-standing vitamin D deficiency may lead to overt hypocalcemia if calcium stores in the bone are depleted.

Hypoparathyroidism results from the destruction of the parathyroid glands, whether the result of surgery, irradiation, infiltration (hemochromatosis, amyloidosis, hemosiderosis), malignant disease, or autoimmune disease. As may be expected, decreased PTH affects the renal conservation of calcium, the intestinal absorption of calcium, and the degradative release of calcium from bone. Hypocalcemia results from these effects. Of note, hypomagnesemia or hypermagnesemia may decrease PTH secretion or diminish PTH action on the bone and should be considered a potential cause of hypoparathyroidism.

Clinical Presentation

Asymptomatic elevation of serum calcium is the most common presentation of primary hyperparathyroidism. The hypercalcemia may be masked by hypoalbuminemia or minimized by concomitant vitamin D deficiency and the PTH levels may fall, inappropriately nonsuppressed, within the normal range. This hypercalcemia is usually accompanied by a fasting hypophosphatemia. A preclinical state, called normocalcemic primary hyperparathyroidism, has recently been identified but is currently not well characterized.⁶

Some patients may report nonspecific neurocognitive symptoms, which vary with the magnitude of hypercalcemia: weakness, easy fatigability, depression, intellectual weariness, cognitive impairment, loss of initiative, anxiety, irritability, and insomnia, some of which they or their physician may attribute to normal aging. Cardiovascular manifestations may include hypertension, coronary artery disease, left ventricular hypertrophy, and cardiac or valvular calcifications, which are associated with higher levels of serum calcium.⁶ Kidney stones are also a common presenting symptom of primary hyperparathyroidism, although some “asymptomatic” patients may have a history of unexplained hematuria, nocturia, and polyuria.

Often, primary hyperparathyroidism may be identified during the evaluation of osteoporosis, which typically affects predominantly cortical bone sites (radius, femoral neck) more than predominantly trabecular bone sites (lumbar spine). A severe form of parathyroid bone disease, osteitis fibrosa cystica (OFC), is associated with multiple lytic bone lesions and subperiosteal bone resorption. OFC may be found in conjunction with an acute hyperparathyroid crisis in which the hypercalcemia develops quickly, causing obtundation, volume depletion, and cardiac arrhythmias.

Hyperparathyroidism may occur as part of a familial disorder such as MEN. MEN type I includes hyperparathyroidism, pituitary tumors, and pancreatic tumors (insulinoma, gastrinoma). MEN type IIA includes hyperparathyroidism, pheochromocytoma, and medullary thyroid carcinoma. In these disorders, the hyperparathyroidism is caused by parathyroid hyperplasia.

Secondary hyperparathyroidism is typically found with CKD stages 3 to 5 and vitamin D deficiency. Patients may be initially seen with bone pain or a pathologic fracture. Risk factors for vitamin D deficiency include minimum sun exposure, inadequate vitamin D dietary intake, obesity, malabsorption, prior gastric surgery, and medications that may increase the metabolism of vitamin D (e.g., rifampin, ketoconazole, and anticonvulsants). Other factors, such as aging, sunscreen use, and heavily pigmented skin, decrease sunlight-mediated vitamin D synthesis in the skin.³ Secondary hyperparathyroidism in CKD produces a host of metabolic derangements, including hypocalcemia, hyperphosphatemia, and low 1,25-dihydroxyvitamin D levels. This hyperparathyroidism may be associated with increased vascular disease and vascular or soft tissue calcification.

Hypoparathyroidism manifests as hypocalcemia accompanied by hyperphosphatemia. The presentation can range from symptoms of perioral and digital paresthesias to life-threatening cardiac arrhythmias, seizures, and laryngospasm. The severity of presentation depends on the rapidity of the development of hypocalcemia. It may also depend on the presence of acidemia, which increases ionized calcium, or alkalemia, which decreases ionized calcium. Chronic hypocalcemia can produce premature cataract formation or basal ganglia calcifications, at times with a reversible Parkinson syndrome.

Physical Examination

Physical clues to primary hyperparathyroidism include band keratopathy, a white cloudiness at the nasal and temporal borders of the cornea. It may be mistaken for arcus senilis and is not specific for hypercalcemia caused by hyperparathyroidism. On occasion, there may be bone tenderness, particularly of the sternum and tibia. Rarely, there may be a palpable neck mass that is indicative of parathyroid carcinoma or medullary thyroid carcinoma (in MEN type II).

The physical clues to hypoparathyroidism include the signs indicative of hypocalcemia. The Chvostek sign may be present in cases of hypocalcemia. This test is performed by tapping (the point of a triangular reflex hammer or a fingertip may be used) over the facial nerve (cranial nerve VII). Contraction of the facial muscles (seen at the corner of the lip and cheek) is a positive test result. The Trousseau sign may also be present in hypocalcemia. This test is performed by placing a blood pressure cuff around the biceps and inflating the cuff approximately 10 to 20 mm Hg above the systolic blood pressure. The cuff is left inflated, maintaining a constant pressure, for 3 minutes or until a positive result is elicited. The test result is positive if carpal spasm occurs (flexion at the wrist and extension of the fingers). The presence of Chvostek and Trousseau signs can be affected by abnormalities in acid-base balance, potassium level, and magnesium level. Bone tenderness over the sternum or tibia may be present in vitamin D deficiency.³

Pseudohypoparathyroidism type Ia, a resistance to PTH and notable for hypocalcemia with elevated PTH, may be associated with obesity, short stature, round facies, brachydactyly of hands or feet, shortened fourth and fifth metacarpals, mild mental retardation, and subcutaneous ossifications.⁷