(See also Hypercalcemia.)
Etiology of Hyperparathyroidism
The most common cause of 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.
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 leads 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 women. 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.
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 in < 1%.
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.
Other less common causes of secondary hyperparathyroidism include
Decreased calcium intake
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
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 asymptomatic patients, the disorder is typically identified by an incidental 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.
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.
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.
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 with the calcium level. Patients with primary hyperparathyroidism have a 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 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.
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 phosphate suggests secondary hyperparathyroidism.
Imaging studies of the parathyroid(s) may be done preoperatively to localize an abnormal gland; it 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 this 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 four-dimensional (4D) CT
MRI
High-resolution ultrasonography
Digital subtraction angiography
Thallium-201–technetium-99 scanning
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 for these glands. Use of several imaging studies (MRI, CT, or high-resolution ultrasonography in addition to technetium-99 sestamibi) before repeat parathyroidectomy is sometimes necessary.
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 Aug. 19, 2022. 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 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:
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 drugs that can raise serum calcium (eg, thiazide diuretics)
Surgery
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):
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 women or > 300 mg/day [>7.5 mmol/day] in men) 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 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.
Pearls & Pitfalls
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parathyroid hormone and calcium levels.
Hyperparathyroidism in renal failure
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
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
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.
vitamin D
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.
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
Treatment of tertiary hyperparathyroidism
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.
Treatment 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 Aug. 19, 2022. doi: 10.1002/jbmr.4677
Key Points
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.
Surgery is reserved for patients with severe and uncontrolled hyperparathyroidism.
