(See also 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, vitamin... read more .)
The most common cause of hyperparathyroidism is
Parathyroid adenomas are most often isolated solitary adenomas. However, parathyroid adenoma Parathyroid adenoma Most parathyroid tumors are benign. Parathyroid tumors secrete parathyroid hormone (PTH). Elevated parathyroid hormone levels (hyperparathyroidism) causes hypercalcemia. Parathyroid adenomas... read more may be hereditary in patients with other endocrine tumors, particularly certain multiple endocrine neoplasia syndromes Overview of Multiple Endocrine Neoplasias (MEN) The multiple endocrine neoplasia (MEN) syndromes comprise 3 genetically distinct familial diseases involving adenomatous hyperplasia and malignant tumors in several endocrine glands. MEN 1 involves... read more .
Another cause is hyperplasia of the parathyroid glands.
Parathyroid hormone (PTH) increases serum calcium by
Hyperparathyroidism is characterized as:
Primary: Excessive secretion of PTH due to a disorder of the parathyroid glands
Secondary: Hypocalcemia due to non-parathyroid disorders leads to chronic PTH hypersecretion
Tertiary: Autonomous secretion of PTH unrelated to serum calcium concentration in patients with long-standing secondary 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, vitamin... 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, vitamin... 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 ). Although asymptomatic hypercalcemia is the most frequent presentation, 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 shows a parathyroid adenoma in about 85% of patients with primary hyperparathyroidism, although it is sometimes difficult to distinguish an adenoma from a normal gland. About 15% of cases are due to hyperplasia of ≥ 2 glands. 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 occurs in < 1% of cases.
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 4.7 mg/dL ( 1.17... 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
Decreased calcium intake
Poor calcium absorption in the intestine due to vitamin D deficiency Vitamin D Deficiency and Dependency Inadequate exposure to sunlight predisposes to vitamin D deficiency. Deficiency impairs bone mineralization, causing rickets in children and osteomalacia in adults and possibly contributing... read more
Excessive renal calcium loss due to loop diuretic use
Inhibition of bone resorption due to bisphosphonate use
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.
Hyperparathyroidism is often asymptomatic. In asymptomatic patients, the disorder is typically identified by finding an elevated calcium level. Symptoms, when they occur, are due to 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, vitamin... read more and include chronic fatigue, constipation, anorexia, nausea and vomiting, poor concentration, confusion, and depression.
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 atrophy of muscles.
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.
In hyperparathyroidism, the serum calcium is rarely > 12 mg/dL (> 3 mmol/L), but the ionized serum calcium is almost always elevated. Low serum phosphate concentration suggests hyperparathyroidism, especially when coupled with elevated renal excretion of phosphate. When hyperparathyroidism results in increased bone turnover, serum alkaline phosphatase is frequently increased. Increased intact PTH, particularly inappropriate elevation (ie, a high concentration in the absence of hypocalcemia) or an inappropriate high-normal concentration (ie, despite hypercalcemia), is diagnostic.
Urinary calcium excretion is usually normal or high in hyperparathyroidism. Low urinary calcium suggests another diagnosis such as familial hypocalciuric hypercalcemia Familial hypocalciuric 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, vitamin... read more . Chronic kidney disease suggests the presence of secondary hyperparathyroidism, but primary hyperparathyroidism can also be present. In patients with chronic kidney disease, high serum calcium and normal serum phosphate suggest primary hyperparathyroidism, whereas elevated phosphate suggests secondary hyperparathyroidism.
The diagnosis of primary hyperparathyroidism should be made based on blood and urine tests and clinical findings.
Imaging the parathyroid(s) should not be done to determine whether surgery is needed but rather to localize an abnormal gland in preparation for surgery. High-resolution CT with or without CT-guided biopsy and immunoassay of thyroid venous drainage, MRI, high-resolution ultrasonography, digital subtraction angiography, and thallium-201–technetium-99 scanning all have been used and are highly accurate, but they have not improved the usually high cure rate of parathyroidectomy done by experienced surgeons. Technetium-99 sestamibi, a radionuclide agent for parathyroid imaging, is more sensitive and specific than older agents and may be useful for identifying solitary adenomas.
For residual or recurrent hyperparathyroidism after initial parathyroid surgery, imaging is necessary and may reveal abnormally functioning parathyroid glands in unusual locations throughout the neck and mediastinum. Technetium-99 sestamibi is probably the most sensitive imaging test. Use of several imaging studies (MRI, CT, or high-resolution ultrasonography in addition to technetium-99 sestamibi) before repeat parathyroidectomy is sometimes necessary.
Treatment for hyperparathyroidism depends on severity.
Patients with asymptomatic primary hyperparathyroidism with no indications for surgery may be treated conservatively with methods to ensure that serum calcium concentrations remain low. Patients should remain active (ie, avoid immobilization that could exacerbate hypercalcemia), follow a low-calcium diet, drink plenty of fluids to minimize the chance of nephrolithiasis, and avoid drugs that can raise serum calcium, such as thiazide diuretics.
Serum calcium and renal function are monitored every 6 months. Bone density is monitored every 12 months. However, subclinical bone disease, hypertension, and longevity are concerns. 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:
Serum calcium 1 mg/dL (0.25 mmol/L) greater than the upper limits of normal
Calciuria > 400 mg/day (> 10 mmol/day)
Creatinine clearance < 60 mL/minute (< 1 mL/second)
Peak bone density at the hip, lumbar spine, or radius 2.5 standard deviations below controls (T score = −2.5)
Age < 50 years
The possibility of poor adherence with follow-up
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 features... 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 renal failure patients with 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.
Primary hyperparathyroidism causes hypercalcemia which is often asymptomatic.
Diagnosis is made by finding elevated PTH levels in a patient with hypercalcemia.
Primary hyperparathyroidism is most often due to solitary adenomas but these can be multiple in hereditary multiple endocrine neoplasia syndromes.
Treatment can be conservative in asymptomatic patients but usually requires surgical parathyroidectomy in patients with symptoms, severe hypercalcemia, or severe osteoporosis.
Secondary hyperparathyroidism is most often due to advanced renal disease and related to decreased vitamin D and calcium levels as well as persistent hyperphosphatemia.
Medical treatment is with continuous reduction in phosphate intake, phosphate binders, vitamin D, and calcimimetics.
Surgery is reserved for patients with severe and uncontrolled hyperparathyroidism