Hyperparathyroidism

Primary hyperparathyroidism is a generalized disorder resulting from excessive secretion of parathyroid hormone by one or more parathyroid glands. It probably is the most common cause of hypercalcemia Hypercalcemia Hypercalcemia is a total serum calcium concentration > 10.4 mg/dL (> 2.60 mmol/L) or ionized serum calcium > 5.2 mg/dL (> 1.30 mmol/L). Principal causes include hyperparathyroidism... read more , particularly among patients who are not hospitalized. Incidence increases with age and is higher in postmenopausal women. It also occurs in high frequency ≥ 3 decades after neck irradiation.

Primary hyperparathyroidism causes hypercalcemia Hypercalcemia Hypercalcemia is a total serum calcium concentration > 10.4 mg/dL (> 2.60 mmol/L) or ionized serum calcium > 5.2 mg/dL (> 1.30 mmol/L). Principal causes include hyperparathyroidism... read more , hypophosphatemia Hypophosphatemia Hypophosphatemia is a serum phosphate concentration < 2.5 mg/dL (0.81 mmol/L). Causes include alcohol use disorder, burns, starvation, and diuretic use. Clinical features include muscle weakness... read more , and excessive bone resorption (leading to osteoporosis Osteoporosis Osteoporosis is a progressive metabolic bone disease that decreases bone mineral density (bone mass per unit volume), with deterioration of bone structure. Skeletal weakness leads to fractures... read more ). Patients most frequently present with asymptomatic hypercalcemia. Nephrolithiasis Urinary Calculi Urinary calculi are solid particles in the urinary system. They may cause pain, nausea, vomiting, hematuria, and, possibly, chills and fever due to secondary infection. Diagnosis is based on... read more is also common, particularly when hypercalciuria occurs due to long-standing hypercalcemia.

Histologic examination of parathyroid tissue removed from patients thought to have primary hyperparathyroidism preoperatively shows a parathyroid adenoma in about 85% of patients, hyperplasia of ≥ 2 glands in about 15% of cases and parathyroid cancer Parathyroid cancer Most parathyroid tumors are benign. Parathyroid tumors secrete parathyroid hormone (PTH). Elevated parathyroid hormone levels ( hyperparathyroidism) causes hypercalcemia. Parathyroid adenomas... read more in < 1%.

Secondary hyperparathyroidism occurs most commonly in advanced chronic kidney disease Chronic Kidney Disease Chronic kidney disease (CKD) is long-standing, progressive deterioration of renal function. Symptoms develop slowly and in advanced stages include anorexia, nausea, vomiting, stomatitis, dysgeusia... read more when decreased formation of active vitamin D in the kidneys and other factors lead to hypocalcemia Hypocalcemia Hypocalcemia is a total serum calcium concentration < 8.8 mg/dL (< 2.20 mmol/L) in the presence of normal plasma protein concentrations or a serum ionized calcium concentration < 4... read more and chronic stimulation of PTH secretion. Hyperphosphatemia that develops in response to chronic kidney disease also contributes.

Other less common causes of secondary hyperparathyroidism include

Once the hyperparathyroidism is established, hypercalcemia or normocalcemia may occur. The sensitivity of the parathyroid glands to calcium may be diminished because of pronounced glandular hyperplasia and elevation of the calcium set point (ie, the amount of calcium necessary to reduce secretion of PTH).

Tertiary hyperparathyroidism results when PTH secretion becomes autonomous of serum calcium concentration. Tertiary hyperparathyroidism generally occurs in patients with long-standing secondary hyperparathyroidism, as in patients with end-stage renal disease Chronic Kidney Disease Chronic kidney disease (CKD) is long-standing, progressive deterioration of renal function. Symptoms develop slowly and in advanced stages include anorexia, nausea, vomiting, stomatitis, dysgeusia... read more of several years’ duration.

Hypercalcemia frequently causes hypercalciuria with resultant nephrolithiasis Urinary Calculi Urinary calculi are solid particles in the urinary system. They may cause pain, nausea, vomiting, hematuria, and, possibly, chills and fever due to secondary infection. Diagnosis is based on... read more , and patients with hypercalcemia can present with pain due to passage of a kidney stone. Chronic hypercalcemia may also cause proximal weakness and muscle atrophy.

Excess parathyroid hormone stimulates osteoclastic activity, which over time can cause osteitis fibrosa cystica. In osteitis fibrosa cystica, increased osteoclastic activity causes rarefaction of bone with fibrous degeneration and cyst and fibrous nodule formation.

Conservative management with methods to ensure that serum calcium concentrations remain low may be used for patients with who are either asymptomatic primary hyperparathyroidism with no indications for surgery. It may also be used for patients at high risk for surgery due to unrelated medical problems, but this is usually limited to patients with a shorter life expectancy because maintaining low serum calcium levels long-term may result in bone disease.

Patients should do the following:

Serum calcium and renal function are monitored every 6 months. Bone density is monitored every 12 months. However, recurrent hypercalcemia, subclinical bone disease, and hypertension are concerns. Patients with hypercalcemia alone can be managed with cinacalcet. Osteoporosis is treated with bisphosphonates.

In patients with symptomatic or progressive hyperparathyroidism, surgery is indicated. The indications for surgery in patients with asymptomatic, primary hyperparathyroidism are controversial. Surgical parathyroidectomy increases bone density and may have modest effects on symptoms that impact quality of life, but most patients do not have progressive deterioration in biochemical abnormalities or bone density. Many experts recommend surgery in the following circumstances (1 Treatment reference Hyperparathyroidism occurs when one or more of the parathyroid glands become overactive, causing elevated serum levels of parathyroid hormone and leading to hypercalcemia. Patients may be asymptomatic... read more ):

Surgery consists of removal of adenomatous gland(s). Parathyroid hormone concentration can be measured before and after removal of the presumed abnormal gland using rapid assays. A fall of ≥ 50% 10 minutes after removal of the adenoma indicates successful treatment. In patients with disease of > 1 gland, several glands are removed, and often a small portion of a normal-appearing parathyroid gland is reimplanted in a more accessible location in the body such as the belly of the sternocleidomastoid muscle or subcutaneously in the forearm to prevent hypoparathyroidism. Rarely, this residual gland is the source of recurrent secondary hyperparathyroidism, which can be managed with additional surgical removal.

Parathyroid tissue is also occasionally preserved using cryopreservation to allow for later autologous transplantation in case persistent hypoparathyroidism develops.

Serum calcium must be monitored several times a day in the immediate postoperative period. When surgery is done for mild hyperparathyroidism, the serum calcium concentration drops to just below normal within 24 to 48 hours. In patients with more severe or prolonged hyperparathyroidism, particularly secondary hyperparathyroidism with severe osteitis fibrosa cystica, prolonged, symptomatic hypocalcemia may occur postoperatively.

When symptomatic hypocalcemia is expected, loading with 10 to 20 g elemental calcium in the days before surgery may prevent a precipitous postoperative decline in calcium. Even with preoperative calcium administration, large doses of calcium and vitamin D may be required in the postoperative period while bone calcium is repleted.

In patients with severe hypercalcemia with primary hyperparathyroidism who are unable to undergo parathyroidectomy, medical treatment is indicated. Cinacalcet, a calcimimetic agent that increases the sensitivity of the calcium-sensing receptor to extracellular calcium, may lower parathyroid hormone and calcium levels.

Although primary hyperparathyroidism can occur, hyperparathyroidism in patients with renal failure is usually secondary. Secondary hyperparathyroidism in patients with renal failure can result in a number of symptoms, including

Secondary hyperparathyroidism can develop in patients with moderate chronic kidney disease (estimated glomerular filtration rate < 60 mL/minute), but it is usually more advanced in patients who require long-term dialysis. The interplay between phosphate retention, hypocalcemia, decreased active vitamin D concentration, and increased fibroblast growth factor-23 stimulates parathyroid secretion in patients with renal failure.

Hyperphosphatemia Hyperphosphatemia Hyperphosphatemia is a serum phosphate concentration > 4.5 mg/dL (> 1.46 mmol/L). Causes include chronic kidney disease, hypoparathyroidism, and metabolic or respiratory acidosis. Clinical... read more should be prevented or treated if present. Treatment combines dietary phosphate restriction and phosphate-binding agents, such as calcium carbonate, calcium acetate, lanthanum, or sevelamer. Despite the use of phosphate binders, dietary restriction of phosphate is also needed. Aluminum-containing compounds have been used to limit phosphate concentration in the past, but they should be avoided, especially in patients receiving long-term dialysis, to prevent aluminum accumulation in bone resulting in severe osteomalacia.

Vitamin D administration is potentially hazardous in patients with chronic kidney disease because it can increase phosphate as well as calcium concentrations and lead to accelerated vascular calcification; vitamin D administration requires frequent monitoring of calcium and phosphate levels. Treatment is generally limited to patients with renal failure patients and secondary hyperparathyroidism. Although oral calcitriol is often given along with oral calcium to suppress secondary hyperparathyroidism, the results are variable in patients with end-stage renal disease. The parenteral form of calcitriol, or vitamin D analogs such as paricalcitol, may better prevent secondary hyperparathyroidism in such patients, because the higher attained serum concentration of 1,25(OH)2D directly suppresses PTH release.

The oral calcimimetic, cinacalcet, modulates the set point of the calcium-sensing receptor on parathyroid cells and decreases PTH concentration in dialysis patients without increasing serum calcium. Symptomatic hypocalcemia can develop with cinacalcet. It should not be started in patients with hypocalcemia at baseline, and calcium should be monitored frequently when titrating cinacalcet dose. Adherence can be limited by gastrointestinal intolerance.

Another calcimimetic, etelcalcetide, is a parenteral alternative.

Simple osteomalacia may respond to calcitriol 0.25 to 0.5 mcg orally once a day. In patients with osteomalacia caused by having taken large amounts of aluminum-containing phosphate binders, removal of aluminum with deferoxamine is necessary before calcitriol administration can reduce bone lesions.

Progressive, severe elevation of parathyroid hormone level that cannot be lowered by medical means without causing significant hyperphosphatemia or hypercalcemia requires surgery to prevent or reverse symptoms. A subtotal parathyroidectomy is done with reimplantation of a portion of the most normal appearing gland in the belly of the sternocleidomastoid muscle or subcutaneously in the forearm.

Postoperatively, calcium can fall precipitously in patients with severe or long standing osteitis fibrosa cystica and is managed with oral and parenteral calcium and cholecalciferol. If the reimplanted parathyroid tissue does not produce parathyroid hormone and the PTH level remains very low or undetectable, the patient will be at risk of developing osteomalacia as well as symptomatic hypocalcemia. Prolonged administration of as much as 2 mcg of calcitriol given orally once a day and ≥ 2 g of elemental calcium supplement per day is generally needed to support the calcium level. If after subtotal parathyroidectomy, patients with end-stage renal disease remain symptomatic due to hypocalcemia, adjustment can be made to the dialysate concentration of calcium.

Tertiary hyperparathyroidism occurs when long-term stimulatory effects causing secondary hyperparathyroidism result in adenomatous transformation of parathyroid tissue. Patients with hypercalcemia as well as severe elevation of PTH while not taking cholecalciferol or calcium-containing phosphate binders suggests the presence of tertiary hyperparathyroidism.

Adenomatous cells do not respond to medical treatment and require surgical intervention.