*Primary Hyperparathyroidism

Chapter: Primary Hyperparathyroidism
McMaster Section Editor(s): Victor M. Montori, Juan P. Brito
Section Editor(s) in Interna Szczeklika: Barbara Jarząb, Ewa Płaczkiewicz-Jankowska
McMaster Author(s): J.E.M. Young,* René Rodríguez-Gutiérrez*
Author(s) in Interna Szczeklika: Franciszek Kokot, Edward Franek, Ewa Płaczkiewicz-Jankowska
* Both authors contributed equally to the chapter.
Additional Information

Definition, Etiology, PathogenesisTop

Primary hyperparathyroidism (PHPT) results from an excessive parathyroid hormone (PTH) secretion caused by a defect in the parathyroid cells that makes them resistant or hyposensitive to the suppressive effects of hypercalcemia. It is the most common cause of hypercalcemia and should be considered in the differential diagnosis of any person with an elevated serum calcium level.

Causes of PHPT include sporadic causes: single adenomas (80%-85% of patients; double adenomas can be found in 5%), glandular hyperplasia (10%-15%; all 4 glands affected), and only rarely parathyroid carcinoma (<1%). In ~5% of patients, PHPT can be part of hereditary syndromes, such as multiple endocrine neoplasia (type 1 or type 2A), hyperparathyroidism-jaw tumor syndrome (HPT-JT), or very rarely familial isolated hyperparathyroidism, which results from an inactivating mutation of the gene encoding the calcium-sensing receptor.

Increased PTH levels cause increased osteolysis (bone resorption), increased gastrointestinal absorption of calcium (due to the increased production of calcitriol), decreased urinary calcium excretion, and increased urinary phosphate excretion; all of these cause elevations in total and ionized calcium levels.

Clinical Features and Natural HistoryTop

Women are affected 2 to 3 times more frequently than men, with the peak incidence occurring in the sixth decade of life. Clinical features of hyperparathyroidism are directly related to the degree of hypercalcemia and PTH elevation, and less so to the duration of the disease, as PHPT may remain asymptomatic for many years or even decades. As a result, the vast majority of cases of PHPT are diagnosed because of mild hypercalcemia detected by routine biochemical screening (asymptomatic PHPT), but the presentation may be atypical and ranges from normocalcemic hyperparathyroidism (normal calcium with high PTH levels) to severe hypercalcemia (parathyroid crisis). The classic presentation, with bone disease, nephrolithiasis, and neuromuscular and neuropsychiatric symptoms, is now rarely seen (sometimes remembered as “bones, stones, abdominal moans, and psychotic groans,” or a similar name).

1. Asymptomatic PHPT: High calcium and PTH levels (usually mild) without any symptoms. On further evaluation, a bone or renal disease may be found, but patients have no clinically apparent or referred symptoms.

2. Classic PHPT:

1) Bone symptoms are caused by generalized or localized bone resorption, local lesions of osteitis fibrosa cystica (back pain; arthralgia; pain in long bones; pathologic fractures of ribs, vertebrae, or other bones; spinal deformity; gait disturbances [waddling]; epulis; brown tumors [osteoclasts with fibrous tissue]), or complications of chronic hypercalcemia.

2) Renal symptoms: Nephrolithiasis occurs in 5% to 15% of patients (most stones are composed of calcium oxalate). Nephrocalcinosis and renal failure are less common.

3) Gastrointestinal symptoms: Constipation, indigestion, nausea/vomiting, and acute pancreatitis.

4) Neuromuscular symptoms: Weakness and fatigue are common among patients with PHPT (atrophy of type II muscle fibers).

5) Neuropsychiatric disturbances: Depression, lethargy, confusion, cognitive dysfunction, memory loss, anxiety and/or psychosis/paranoia.

Other associated signs and symptoms of PHPT are proximal muscle weakness, keratitis, band keratopathy (a band across the central cornea), and hypertension.


Diagnostic Criteria

The diagnosis of PHPT is made exclusively on the basis of biochemical testing and should include:

1) Hypercalcemia (with a rare exception of normocalcemic PHPT with normal calcium levels): Measurement of total serum calcium levels (if a single elevation is found, measurement should be repeated). Correct calcium levels depend on albumin concentration; add 0.8 mg/dL (0.2 mmol/L) to the total serum calcium level reported for every 1.0 g/dL (10 g/L) of albumin below 4.0 g/dL and subtract 0.8 mg/dL for every 1.0 g/dL of albumin above 4.0 g/dL. Ionized calcium levels may yield a potentially more accurate result providing that the test is done in a laboratory known to measure the levels reliably; it is suggested mainly in cases of known or suspected hypoalbuminemia or hyperalbuminemia.

2) Elevated PTH: Intact (second-generation) or third-generation PTH assays (in 90% of patients, PTH levels are ≥65 pg/mL) (7.15 pmol/L). According to the diagnostic algorithm of hypercalcemia, once an elevated serum calcium level is confirmed, the next obligatory step in all patients should be measurement of serum PTH concentration.

3) Exclusion of other causes: Secondary hyperparathyroidism, lithium and thiazide use, and/or familial hypocalciuric hypercalcemia (FHH).

Diagnostic Tests

1. Blood tests: Serum creatinine concentration should be measured in all cases, as hypercalcemia can diminish renal function, and hypocalcemia due to kidney diseases (usually resulting in low vitamin D levels) is the main cause of secondary hyperparathyroidism. Ionized calcium (measured in a reliable laboratory) may be used when protein abnormalities are suspected. Alkaline phosphatase concentration is usually high, serum phosphate is usually normal-low (≤3.5 mg/dL) (1.13 mmol/L) or low (≤2.5 mg/dL) (0.81 mmol/L), and mild hyperchloremic metabolic acidosis may be observed.

1) Urine tests: Low urine specific gravity; increased urinary excretion of calcium (>250 mg/d) (6 mmol/d) and phosphate; minor proteinuria (in the presence of interstitial nephritis); microscopic hematuria (in the presence of nephrolithiasis).

2) ECG: Features of hypercalcemia may be present.

3) Bone mineral density (dual-energy X-ray absorptiometry [DXA]): Features of osteopenia (T-score ≤-1.0 to -2.4 standard deviation) or osteoporosis (T-score ≤-2.5 standard deviation).

4) Vertebral fracture assessment (VFA) can be assessed with plain radiographs or with VFA by DXA (used only when patients do not have osteoporosis in DXA).

2. Imaging studies: Localization studies (eg, ultrasonography, technetium-99m sestamibi, CT, MRI) should not be used to establish the diagnosis. Rather, they should be considered only when the decision to perform a minimally invasive surgery has been made (use in open/bilateral surgery is controversial).

1) Neck ultrasonography detects enlarged parathyroid glands with a sensitivity of 70% to 90% (in experienced hands) and has the advantages of being noninvasive and inexpensive. It cannot always distinguish abnormal parathyroids from abnormal thyroid tissue or abnormal lymph nodes.

2) Radionuclide scans using 99mTc-labeled sestamibi detect 70% to 80% of adenomas and should be performed only in patients with confirmed hyperparathyroidism.

3) Spiral CT is done either with timed flow (four-dimensional or 4D CT) or in conjunction with both contrast and noncontrast imaging. This last technique appears to be far superior to any of the other methods used to detect abnormal parathyroids, since it can identify additional adenomas, can often detect multiglandular disease when all 4 parathyroid glands are only minimally enlarged, accurately demonstrates the anatomy of the neck and the upper mediastinum, and is useful in evaluating abnormalities of the thyroid and the adjacent anatomy.

4) MRI has a sensitivity of 85% to 95%, is noninvasive, and is not associated with exposure to ionizing radiation. It is usually used for reoperative surgery.

5) Bone radiographs are rarely indicated. When performed in advanced PHPT, they may reveal generalized osteoporosis, subperiosteal resorption (most prominent in phalanges), bone cysts in very advanced disease (located in the jaw, ribs, and long bones), osteolysis (calcaneus, pubic bone, distal clavicle, alveolar lamina dura, cranial vault bones [“salt and pepper” appearance on radiographs]), thinning of the cortex of long bones, and pathologic fractures. Plain abdominal radiographs, if done for other reasons, may show urolithiasis, nephrocalcinosis, or calcifications in the pancreas. Other radiographs may reveal calcifications in muscles or in other soft tissues.

6) Venography with PTH sampling from the veins in the neck and the mediastinum is used only when all other methods of localizing have failed, following a previous negative exploration.

7) Positron emission tomography (PET) using either 18F-fluorodeoxyglucose (FDG) or 11C-labelled methionine is performed rarely, in complicated cases.

3. Ophthalmology examination may sometimes reveal calcium deposits in the cornea (band keratopathy).

Diagnostic Difficulties

1. Patients with elevated serum PTH and normal calcium levels usually have vitamin D deficiency rather PHPT. Vitamin D deficiency is exceedingly common, and in most patients in this situation the PTH concentration will decrease to a normal range over time with correction of the low vitamin D level. Only a small number of these individuals subsequently develop hypercalcemia with a persistent elevation of PTH levels.

2. Patients with normal or slightly elevated serum PTH levels and hypercalcemia usually do have PHPT, with elevated serum calcium levels partially inhibiting PTH secretion. In most of these patients, serial ionized calcium and PTH concentrations show a gradual increase over time.

3. “Undetectable” PTH and hypophosphatemic hypercalcemia are observed in hyperparathyroidism caused by secretion of a PTH-related peptide (PTHrP) (secreted by malignant cells); the molecule is biologically active but cannot be detected by the antibodies used in PTH assays.

Differential Diagnosis

Distinguishing between:

1) PHPT and FHH: Measure 24-hour urine calcium excretion. In PHPT, calcium urinary excretion is usually >200 mg/d (5 mmol/d) or 4 mg/kg/d (0.1 mmol/kg/d). In FHH, calcium excretion is usually <50 mg/d (1.25 mmol/d) and the calcium/creatinine (Ca/Cr) clearance ratio is usually <0.01.

Ca/Cr clearance ratio = (24-hour urine Ca × serum Cr) / (serum Ca × 24-hour urine Cr) [with all units either in mg or molar amount or concentration]

2) PHPT and thiazide/lithium adverse effects: In the case of drug use, there are usually mildly elevated/normal calcium and PTH (with lithium use) concentrations; otherwise, the two scenarios are indistinguishable. These should be excluded on the basis of clinical history.

3) PHPT and secondary hyperparathyroidism: Measure creatinine and serum 25-hydroxyvitamin D (25(OH)D) concentrations; it is recommended to measure 25(OH)D levels in all suspected cases of PHPT. If the concentration of 25(OH)D is ≤20 ng/mL (50 nmol/L), repletion with vitamin D3 or D2 is warranted before making any management decisions.

Differential diagnosis should also include other diseases associated with hypercalcemia, osteopenia, osteoporosis or osteomalacia, primary and metastatic bone tumors, multiple myeloma, and Paget disease. Differential diagnosis may prove difficult in familial hypocalciuric hypercalcemia (calciuria <5 mmol/d [200 mg/d]); in parathyroid adenoma in patients with hypercalcemia caused by malignancy (elevated serum PTH and PTHrP levels); and in paraneoplastic endocrinopathy (secretion of PTH and other osteolytic factors by cancers of nonparathyroid origin).


Surgical Treatment

Surgery for PHPT is rarely required urgently. Even patients with markedly elevated calcium levels seldom have significant symptoms. Those rare patients who present to the emergency department obtunded usually respond promptly to basic medical treatment (see Hypercalcemia). The urgency of surgery depends on the severity of symptoms and serum calcium levels. The procedure involves a total removal of adenoma or carcinoma, and in the case of parathyroid hyperplasia, removal of all parathyroid glands with preservation of 50% of one gland (subtotal parathyroidectomy), or removal of all parathyroid glands (total parathyroidectomy) with transplantation of a small portion of one of the removed glands into an adjacent muscle in the neck (usually the sternocleidomastoid muscle or a muscle of the upper extremity). A portion of the remaining glands are frozen and stored so that they may be transplanted in case of postoperative hypoparathyroidism. The effectiveness of parathyroidectomy may be evaluated by intraoperative measurements of PTH levels in blood samples collected 5 to 10 minutes following the removal of the gland (after a successful surgery, levels are <50% of baseline).

Minimally invasive surgical removal of solitary adenomas has been increasingly popular. For more surgical details, see Appendix 1.

Recommended criteria for surgery (according to the Fourth International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism):

1) Classic or symptomatic PHPT: Surgery is warranted in all patients.

2) Asymptomatic PHPT: One or more of the following criteria:

a) Age <50 years.

b) Serum calcium ≥1.0 mg/dL above the upper limit of normal.

c) DXA T-score ≤-2.5 standard deviation in the lumbar spine, total hip, femoral neck, or distal 1/3 radius, or vertebral fracture confirmed by radiography, CT, MRI, or VFA.

d) Creatinine clearance ≤60 mg/dL/min, 24-hour urinary calcium >400 mg/d, or presence of nephrolithiasis.

In specialized centers, the success rates of surgical treatment are >90%. After parathyroidectomy, significant hypocalcemia and hypophosphatemia may occur (hungry bone syndrome).

In patients with primary hyperparathyroidism and a genetic syndrome (MEN 1, MEN 2, or HPT-JT), the results of genetic testing are important in the choice of adequate treatment and, in confirmed cases, subtotal or total parathyroidectomy with transplant is almost always required.


1. Treatment of hypercalcemia.

2. Calcimimetics in patients with contraindications to surgery (these agents inhibit PTH secretion, but hypercalcemia recurs upon discontinuation of the drug): cinacalcet 30 mg bid; the dose may be titrated up every 2 to 4 weeks to 90 mg bid (maximum dose, 90 mg qid).

3. Bisphosphonates inhibit bone resorption by osteoclasts; they may also be used to control hungry bone syndrome (see above) prior to parathyroidectomy.

4. Correction of hypocalcemia and hypophosphatemia following parathyro­idectomy.


In patients with asymptomatic PHPT and no indications for surgery, monitor serum calcium and creatinine levels every 12 months and perform DXA of 3 skeletal locations every 1 to 2 years. The calcium-phosphate metabolism parameters and serum PTH levels should be measured after the confirmation of a normal 25(OH)D concentration (20-50 ng/mL [50-125 nmol/L]).


In patients with mild to moderate bone and renal abnormalities and in those with general symptoms in whom surgical treatment has been successful, the prognosis is good with usual marked improvement. Untreated classical PHPT is associated with increased mortality due to cardiovascular disease (from 20% to 100% risk increase). In asymptomatic PHPT patients, data are limited but appear to be the same when compared to healthy individuals. In parathyroid carcinoma, a complete cure is achieved in 30% to 50% of patients, 30% of individuals can have a prolonged course with recurrence that is still treatable with surgery or radiation, and the remaining group has rapidly progressive disease.


Appendix 1

Since surgery is the only curative treatment for PHPT, it should be considered in all patients with this diagnosis. The operation requires removal of all abnormal parathyroid tissue; in most cases, this requires removal of a solitary adenoma, but if more than one gland is abnormal then 2 or 3 glands need to be removed while the remaining fragment is marked with metal clips for subsequent identification if the patients requires reoperation. The small portion preserved is usually from the most normal looking (smallest of the 4) glands; because reoperation for recurrent or persistent hyperparathyroidism is easier if the abnormal gland is the inferior one, a portion of the inferior parathyroid gland is usually chosen for preservation.

The operating surgeon must be certain of the diagnosis and be aware that occasionally there are more than 4 parathyroid glands. Obviously, this can be confirmed by preoperative imaging, of which CT scanning of the neck and mediastinum is the most useful. If there is any concern on the surgeon’s part that the small preserved fragment may not survive, small fragments of parathyroid tissue can be transplanted in the adjacent sternocleidomastoid muscle (which is easily accessible at the time of operation, and equally accessible if the patient requires removal of the transplant at some time in the future).

Some centers rely on intraoperative measurement of PTH levels done prior to the removal of abnormal parathyroid tissue and after the removal of suspected abnormality. In most centers, these assays take longer to obtain than the operation itself requires and the use of preoperative CT scanning rarely makes this technique necessary even in the case of reoperative surgery. The increased use of imaging preoperatively over the past several decades has made the use of minimally invasive parathyroidectomy (with identification of adenoma and usually one normal parathyroid gland) the standard operation in most centers. This technique can be expected to have a success rate of 95%.

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