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 or have symptoms of varying severity, including chronic fatigue, body aches, difficulty sleeping, bone pain, memory loss, poor concentration, depression, and headaches. Diagnosis is with serum levels of calcium and parathyroid hormone. Surgery is done to remove the overactive gland(s).
Etiology of Hyperparathyroidism
The most common cause of primary hyperparathyroidism is:
Parathyroid adenoma
Parathyroid adenomas are most often isolated solitary adenomas. However, parathyroid adenoma may be hereditary in patients with other endocrine tumors, particularly certain multiple endocrine neoplasia syndromes.
Another cause is hyperplasia of the parathyroid glands.
In secondary hyperparathyroidism, disorders that cause hypocalcemia stimulate the parathyroid glands to increase secretion of parathyroid hormone (PTH). Patients with chronic secondary hyperparathyroidism can develop tertiary hyperparathyroidism, characterized by autonomous secretion of PTH unrelated to serum calcium level.
Pathophysiology of Hyperparathyroidism
Parathyroid hormone (PTH) increases serum calcium by:
Enhancing distal tubular calcium reabsorption
Rapidly mobilizing calcium and phosphate from bone (bone resorption)
Increasing intestinal absorption of calcium by stimulating conversion of vitamin D to its most active form, calcitriol
Hyperparathyroidism is characterized as:
Primary: Excessive secretion of PTH due to a disorder of the parathyroid glands
Secondary: Hypocalcemia due to non-parathyroid disorders leading to chronic PTH hypersecretion
Tertiary: Autonomous secretion of PTH unrelated to serum calcium concentration in patients with long-standing secondary hyperparathyroidism
Primary 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, particularly among patients who are not hospitalized. Incidence increases with age and is higher in postmenopausal females. It also occurs in high frequency ≥ 3 decades after neck irradiation.
Primary hyperparathyroidism causes hypercalcemia, hypophosphatemia, and excessive bone resorption (leading to osteoporosis). Patients most frequently present with asymptomatic hypercalcemia. Nephrolithiasis is also common, particularly when hypercalciuria occurs due to long-standing hypercalcemia.
Preoperative evaluation by experienced surgeons include parathyroid imaging to identify patients with multiglandular disease (15%). Further testing with 24-hour urine calcium is used in selected patients to differentiate between primary hyperparathyroidism and familial hypercalcemia hypocalciuria (FHH). FHH can present with hypercalcemia and normal or mildly elevated parathyroid hormone but is differentiated from primary hyperparathyroidism by the presence of low urinary calcium.
Secondary hyperparathyroidism
Secondary hyperparathyroidism occurs most commonly in advanced chronic kidney disease when decreased formation of active vitamin D in the kidneys and other factors lead to hypocalcemia and chronic stimulation of PTH secretion. Hyperphosphatemia that develops in response to chronic kidney disease also contributes.
Secondary hyperparathyroidism can develop in patients with moderate chronic kidney disease (estimated glomerular filtration rate < 60 mL/minute), but it is usually those with more advanced renal disease 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.
Other less common causes of secondary hyperparathyroidism include:
Decreased calcium intake
Poor calcium absorption in the intestine due to vitamin D deficiency
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 calcium concentration necessary to reduce secretion of PTH).
Tertiary hyperparathyroidism
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 of several years’ duration.
Symptoms and Signs of Hyperparathyroidism
Hyperparathyroidism is often asymptomatic. In patients who are asymptomatic, the disorder is typically identified by an incidentally discovered elevated calcium level.
Symptoms, when they occur, are due to hypercalcemia and include chronic fatigue, constipation, anorexia, nausea and vomiting, poor concentration, confusion, and depression.
Hyperparathyroidism in renal failure
Secondary hyperparathyroidism in patients with renal failure can result in a number of symptoms, including:
Osteitis fibrosa cystica with arthritis, bone pain, and pathologic fractures
Spontaneous tendon rupture
Proximal muscle weakness
Extraskeletal calcifications, including soft tissue and vascular calcification
Pruritis
Complications
Hypercalcemia frequently causes hypercalciuria with resultant nephrolithiasis, 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.
Light micrograph of a section of bone affected by osteitis fibrosa cystica showing bone destruction by osteoclast cells.
CNRI/SCIENCE PHOTO LIBRARY
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 formation of cysts and fibrous nodules.
Diagnosis of Hyperparathyroidism
Serum calcium, phosphate, and PTH measurement
The diagnosis of primary hyperparathyroidism should be made based on blood and urine tests and clinical findings.
A diagnosis of hyperparathyroidism is usually first suspected when elevated serum calcium is found on routine blood tests. If calcium remains high on repeat testing, intact PTH should be checked and interpreted based on the calcium level. Patients with primary hyperparathyroidism have an abnormally high PTH concentration in the absence of hypocalcemia. A minority of patients have a high-normal PTH concentration, which should be interpreted as inappropriate when the calcium concentration is elevated (and suppression of PTH would normally be expected) (1).
In hyperparathyroidism, the serum calcium level is rarely > 12 mg/dL (> 3 mmol/L), but 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.
Urinary calcium excretion is usually normal or high in hyperparathyroidism. Low urinary calcium suggests another diagnosis such as familial hypocalciuric hypercalcemia. 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 serum phosphate and low serum calcium suggests secondary hyperparathyroidism. In patients with long-standing advanced kidney disease, tertiary hyperparathyroidism can develop. Parathyroid hormone secretion becomes autonomous, serum calcium and phosphate levels are increased, and the parathyroid hormone level is markedly elevated.
Imaging studies of the parathyroid(s) may be done preoperatively to localize an abnormal gland; imaging is not done to establish the diagnosis or determine whether surgery is needed. However, parathyroidectomy done by experienced surgeons has a high cure rate, and the cure rate has not been improved with use of preoperative imaging.
Many imaging techniques have been used effectively, including the following:
High-resolution CT with or without CT-guided biopsy and PTH immunoassay from thyroid venous drainage
Contrast-enhanced 4-dimensional (4D) CT
MRI
High-resolution ultrasound
Digital subtraction angiography
Technetium-99 sestamibi scanning
Sestamibi-single photon emission computed tomography (SPECT or MIBI-SPECT)
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 for these glands. Use of several imaging studies (MRI, CT, or high-resolution ultrasound in addition to technetium-99 sestamibi) before repeat parathyroidectomy is sometimes necessary. Because false-positive and false-negative results occur with each imaging technique, intraoperative venous sampling for high parathyroid hormone level is frequently needed.
Diagnosis reference
1. Bilezikian JP, Khan AA, Silverberg SJ, et al. Evaluation and management of primary hyperparathyroidism: Summary statement and guidelines from the Fifth International Workshop. J Bone Miner Res. 2022;37(11):2293-2314. doi: 10.1002/jbmr.4677
Treatment of Hyperparathyroidism
Sometimes medical management of hypercalcemia
Often surgical parathyroidectomy
Treatment for hyperparathyroidism depends on severity.
Medical management
Conservative management with methods to ensure that serum calcium concentrations remain low or in the normal range may be used for patients who have asymptomatic primary hyperparathyroidism who are at high risk for surgery due to unrelated medical problems. This approach 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 to help control hypercalcemia:
Remain active (ie, avoid immobilization that could exacerbate hypercalcemia)
Follow a low-calcium diet
Drink plenty of fluids to minimize the chance of nephrolithiasis
Avoid medications that can raise serum calcium (eg, thiazide diuretics)
Patients with mild hypercalcemia alone can be managed with cinacalcet.Patients with mild hypercalcemia alone can be managed with cinacalcet.
Patients managed medically should have serum calcium and renal function monitored every 6 months. Bone density is monitored every 12 months. Recurrent hypercalcemia, subclinical bone disease, and difficult to control hypertension may develop and increase the risk of medical management such that surgery becomes the safer option. Osteoporosis is treated with bisphosphonates.
Surgery
In patients with symptomatic or progressive hyperparathyroidism, surgery is indicated. The indications for surgery in patients with asymptomatic primary hyperparathyroidism are based on the likelihood of eventual morbidity. Surgical parathyroidectomy increases bone density and may have modest effects on symptoms that impact quality of life, but most patients do not develop progressive biochemical abnormalities or deterioration in bone density. Many experts recommend surgery in the following circumstances (1):
Serum calcium 1 mg/dL (0.25 mmol/L) greater than the upper limits of normal
Hypercalciuria (> 250 mg/day [> 6.25 mmol/day] in females or > 300 mg/day [>7.5 mmol/day] in males) or the presence of nephrolithiasis
Creatinine clearance < 60 mL/minute (< 1 mL/second)
Vertebral bone fracture or bone density at the hip, lumbar spine, or radius that is 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 the adenomatous gland(s). Intraoperative parathyroid hormone concentration can be measured in peripheral blood 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 removal of additional parathyroid tissue.
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 48 to 72 hours postoperatively. Depending upon how stable calcium remains, it can be monitored weekly or monthly over the next 2 to 3 months. 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.
Pearls & Pitfalls
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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 in the parathyroid glands to extracellular calcium, may lower 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 in the parathyroid glands to extracellular calcium, may lowerparathyroid hormone and calcium levels.
Treatment of hyperparathyroidism in renal failure
Although primary hyperparathyroidism can occur, hyperparathyroidism in patients with renal failure is usually secondary.
Hyperphosphatemia should be prevented or treated if present in patients with chronic renal disease as well as patients with end-stage renal disease on dialysis. 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. Tenapanor is used for treating hyperphosphatemia in patients requiring dialysis for end-stage kidney disease (should be prevented or treated if present in patients with chronic renal disease as well as patients with end-stage renal disease on dialysis. 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. Tenapanor is used for treating hyperphosphatemia in patients requiring dialysis for end-stage kidney disease (2). This medication inhibits phosphate absorption and is used in patients who do not respond adequately to phosphate-binding agents. Use of aluminum-containing compounds to limit phosphate concentration 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 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 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 administration requires frequent monitoring of calcium and phosphate levels. Treatment is generally limited to patients with renal failure 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 ofcalcitriol, 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 and is used mainly in patients with end-stage renal disease on dialysis who have IV access during hemodialysis sessions. 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 and is used mainly in patients with end-stage renal disease on dialysis who have IV access during hemodialysis sessions.
The oral calcimimetic, cinacalcet, modulates the set point of the calcium-sensing receptor on parathyroid cells and decreases PTH concentration in patients receiving dialysis without increasing serum calcium. The oral calcimimetic, cinacalcet, modulates the set point of the calcium-sensing receptor on parathyroid cells and decreases PTH concentration in patients receiving dialysis without increasing serum calcium.Cinacalcet is frequently given to patients on dialysis to help control PTH. Although typically given daily, it has also been successfully administered 3 time weekly with hemodialysis. 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.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 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 beforecalcitriol administration can reduce bone lesions.
Parathyroidectomy is not recommended for patients with secondary hyperparathyroidism and chronic kidney disease that does not require dialysis, but parathyroidectomy is needed at times in patients with end-stage renal disease and severe hyperparathyroidism.
Treatment of severe hyperparathyroidism
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. If the forearm is used for reimplantation, blood must be drawn from the opposite arm when monitoring systemic PTH levels.
Postoperatively, calcium can fall precipitously in patients with severe or long standing osteitis fibrosa cystica. Low calcium levels are managed with both oral and parenteral calcium and cholecalciferol in patients with normal underlying kidney function or calcitriol in those with advanced (stage 4) chronic kidney disease or end-stage renal disease. If the reimplanted parathyroid tissue does not produce Postoperatively, calcium can fall precipitously in patients with severe or long standing osteitis fibrosa cystica. Low calcium levels are managed with both oral and parenteral calcium and cholecalciferol in patients with normal underlying kidney function or calcitriol in those with advanced (stage 4) chronic kidney disease or end-stage renal disease. If the reimplanted parathyroid tissue does not produceparathyroid hormone and the PTH level remains very low or undetectable, the patient is at risk of developing osteomalacia as well as symptomatic hypocalcemia. In this case, 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 patients with end-stage renal disease remain symptomatic due to hypocalcemia after subtotal parathyroidectomy, adjustment can be made to the concentration of calcium in the dialysate.and the PTH level remains very low or undetectable, the patient is at risk of developing osteomalacia as well as symptomatic hypocalcemia. In this case, 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 patients with end-stage renal disease remain symptomatic due to hypocalcemia after subtotal parathyroidectomy, adjustment can be made to the concentration of calcium in the dialysate.
Treatment of tertiary hyperparathyroidism
Tertiary hyperparathyroidism occurs when long-term stimulatory effects causing secondary hyperparathyroidism result in adenomatous transformation of parathyroid tissue. Hypercalcemia and severe elevation of PTH that occurs in patients who are 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.
Treatment references
1. Bilezikian JP, Khan AA, Silverberg SJ, et al. Evaluation and management of primary hyperparathyroidism: Summary statement and guidelines from the Fifth International Workshop. J Bone Miner Res. 2022;37(11):2293-2314 doi: 10.1002/jbmr.4677
2. King AJ, Siegel M, He Y, et al. Inhibition of sodium/hydrogen exchanger 3 in the gastrointestinal tract by tenapanor reduces paracellular phosphate permeability. Sci Transl Med. 2018;10(456):eaam6474. doi:10.1126/scitranslmed.aam6474
Key Points
Primary hyperparathyroidism causes hypercalcemia, which is often asymptomatic.
Diagnosis of primary hyperparathyroidism 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.
Treatment of primary hyperparathyroidism 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 is related to decreased vitamin D and calcium levels as well as persistent hyperphosphatemia.
Medical treatment of secondary hyperparathyroidism is with continuous reduction in phosphate intake, phosphate binders, vitamin D, and calcimimetics.Medical treatment of secondary hyperparathyroidism is with continuous reduction in phosphate intake, phosphate binders, vitamin D, and calcimimetics.
Surgery is reserved for patients with severe and uncontrolled secondary hyperparathyroidism.
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