Primary hyperparathyroidism is the most common cause of hypercalcemia in the outpatient setting. Phenotypically, it has evolved from a disease of overt symptomatology to one of vague complaints and biochemical diagnosis. Preoperative localization and intraoperative parathyroid hormone have revolutionized the surgical management of these patients. Minimally invasive operations are now common worldwide with low morbidity and high patient satisfaction.
Primary hyperparathyroidism (PHPT) has been recognized as a disease process since the 1920s when it was discovered in both Europe and the United States. In 1925, the first parathyroid surgery was performed by Felix Mandl in Vienna, Austria, who showed that by removing the affected gland, the patient had resolution of severe symptoms associated with the disease. The first successful parathyroid surgery in the United States was performed by Dr Isaac Olch in 1928 at Barnes Hospital in St Louis. Since that time, the recognition, diagnosis, and treatment of PHPT have evolved because of improved laboratory testing, accurate preoperative localization, and less invasive surgical procedures.
The prevalence of PHPT is in the range of 0.1% to 0.4%, and the incidence increases with age reaching a peak between age 50 and 60 years. After the introduction of automated serum calcium measurements in the 1970s, the prevalence increased significantly and has since leveled out. PHPT has a higher frequency in women and in patients who have a history of neck irradiation. Over the last few decades, patients are presenting less frequently with overt or classical symptoms of the disease and more often with vague symptoms, which has prompted the National Institutes of Health (NIH) to publish guidelines for the management of asymptomatic PHPT. Once a diagnosis is made and the patient is deemed an appropriate surgical candidate, preoperative localization of the involved gland or glands aids in the choice of operation. With the advent of intraoperative PTH (IOPTH) in addition to prelocalization, minimally invasive techniques for parathyroidectomy have become more popular.
Pathology and etiology
PHPT is the third most common endocrine disorder and the most common cause of hypercalcemia in the outpatient setting. It is defined as hypercalcemia secondary to overproduction of PTH by one or more parathyroid glands. Normally, increased calcium levels suppress the production of PTH because of a negative feedback mechanism. Parathyroid glands detect small changes in serum calcium through the calcium sensing receptor, which results in significant changes in PTH secretion. The goal of this pathway is to normalize serum calcium. In PHPT, however, the feedback mechanism does not work appropriately so that unregulated PTH production results from elevated serum calcium. The effects of this altered feedback loop include increased or inappropriate PTH production, increased renal absorption of calcium, increased synthesis of 1,25(OH) 2 D 3 , phosphaturia, and increased resorption of bone.
In patients who present with hypercalcemia and elevated PTH, it is essential to exclude other causes of elevated calcium including chronic renal disease, thiazide diuretic use, lithium use, and familial hypocalciuric hypercalcemia (FHH). Once these factors have been ruled out, the next step is to determine the etiology of the patient’s PHPT. Most cases are sporadic; however, approximately 5% of cases are familial. Patients can present with single or double adenomas, multigland disease (MGD), or rarely parathyroid cancer. Several studies have shown that most patients have a single adenoma (80%–85%). MGD occurs less frequently (10%–15%) and double adenomas are even more rare (4%–5%). Parathyroid cancer is diagnosed in less than 1% of patients with HPT.
Familial syndromes with a PHPT component include multiple endocrine neoplasia (MEN) I, MEN IIA, hyperparathyroidism–jaw tumor syndrome, and neonatal severe PHPT. Prevalence of PHPT and its clinical features differ among the various inherited syndromes.
MEN I is an autosomal-dominant disorder caused by an inactivating mutation of the menin gene on chromosome 11q13 with a high penetrance for PHPT, which is usually the initial presentation of the disease ( Box 1 ). Approximately 90% to 95% of patients with MEN I develop PHPT, which often presents at a younger age in this population and may be the only manifestation of the syndrome. PHPT presents as MGD most of the time, necessitating a subtotal or total parathyroidectomy with autotransplantation. Patients can also have pituitary tumors and pancreatic tumors.
MEN I
Hyperparathyroidism
Pituitary tumor
Pancreatic gastrinoma
MEN IIA
Medullary thyroid carcinoma
Pheochromocytoma
Hyperparathyroidism
Lichen planus amyloidosis
Hirschsprung disease
MEN IIB
Medullary thyroid carcinoma
Pheochromocytoma
Marfanoid body habitus
Mucosal neuromas
Ganglioneuromatosis of the gastrointestinal tract
MEN IIA is an autosomal-dominant disorder caused by activating mutations involving the RET proto-oncogene. Only 20% to 30% of patients with this disorder have PHPT, which tends to be mild in its course. Patients display single gland disease or MGD, which usually does not require an aggressive surgical approach. MEN IIA patients usually present with medullary thyroid cancer and pheochromocytoma, which can be life threatening. It is imperative to rule out a pheochromocytoma before parathyroidectomy or any invasive procedure.
Hyperparathyroidism–jaw tumor syndrome is another autosomal-dominant disorder caused by an inactivating mutation of HRPT2. PHPT is the most common feature of the syndrome and these patients have an increased risk of parathyroid cancer. PHPT presents at an early age as single gland or multigland involvement. Surgical options for these patients vary. If parathyroid cancer is present an en bloc resection is required. If cancer is not suspected, all four parathyroid glands should be identified to ensure there is no abnormal-appearing parathyroid tissue. These patients also develop fibro-osseus tumors of the mandible or maxilla and they may have renal pathology.
Neonatal severe PHPT is caused by homozygous inactivating mutations of the calcium sensing receptor and can be fatal if not treated immediately with a total parathyroidectomy.
Parathyroid cancer is an extremely rare cause of PHPT accounting for less than 1% of all cases. It is difficult to diagnose preoperatively because there are no definitive cytologic criteria. These patients present with severe symptomatic hypercalcemia and require hospitalization to correct the high levels of serum calcium; they also have markedly elevated intact PTH levels. Rarely, a palpable neck mass may be found on physical examination, but more often the disease is identified intraoperatively. Characteristics of a cancerous parathyroid gland include adherence to and invasion into surrounding tissues including the thyroid and involvement of blood vessels and the recurrent laryngeal nerve (RLN). The gland is usually white-gray in color and very firm. En bloc resection of the parathyroid, ipsilateral thyroid lobe, and any adherent or suspicious-appearing soft tissue in the central neck including lymph nodes is the best surgical option for these patients. Postoperatively, a metastatic work-up including CT of the chest and abdomen should be completed. The 5-year survival rate for this cancer is 86%.
Presentation and diagnosis
Over the last 30 years, a shift has occurred in the presentation of PHPT. Historically, patients presented with clinical findings related to long-standing disease, such as nephrolithiasis, brown tumors, osteitis fibrosa cystic, and muscle atrophy. With the advent of routine serum calcium measurements, patients present with hypercalcemia much earlier and subsequently have fewer, if any, overt symptoms. Up to 80% of patients have been described as asymptomatic; however, many studies have shown these patients actually have vague symptoms that are more difficult to qualify. In one study, there was some benefit to doing neuropsychological testing and evaluation of health-related quality of life to determine the need for surgery in patients with biochemically diagnosed PHPT. Some of these nonspecific symptoms include fatigue, weakness, bony pain, depression, memory loss, decreased concentration, and sleep issues. Many patients who do not complain of symptoms before surgery report significant improvement postoperatively, implying that these subtle symptoms are meaningful in terms of patient well-being.
Interestingly, nephrolithiasis is the most common clinical manifestation of PHPT, occurring in 20% of patients presenting with the disease. These patients are often followed for years before they are diagnosed with PHPT because hypercalcemia is not considered as a cause of kidney stones. They are often not diagnosed with PHPT until they have another manifestation of the disease.
Subtle changes on bone densitometry are noted in patients with PHPT. Bone integrity is altered by high bone turnover because of increased PTH resulting in osteopenia, osteoporosis, and increases risk of fracture. Primarily cortical and cancellous bone loss is seen. Postoperatively, bone loss is often stalled or improved with increased bone density over time.
Various cardiovascular conditions are associated with PHPT including hypertension, valvular calcifications, left ventricular hypertrophy, and cardiovascular mortality. Surgery does not affect hypertension in these patients so that most remain on their antihypertensive medication postoperatively. The risk of cardiovascular mortality decreases in patients with severe PHPT who have parathyroidectomy. Unfortunately, studies on cardiovascular mortality in patients with mild PHPT are limited and inconclusive.
The diagnosis of PHPT is usually made biochemically with elevated serum calcium and elevated PTH. Some patients present with normocalcemia, which is within the continuum of the disease. Patients can also have PTH values within the reference range, which reflects an inappropriate response to hypercalcemia. Vitamin D levels should be checked initially in all patients with a diagnosis of PHPT because the presence of vitamin D deficiency can affect the interpretation of the PTH assay resulting in elevated PTH levels. Patients who have vitamin D deficiency should be repleted before diagnosing PHPT.
Other laboratory tests that are useful in making the diagnosis include phosphorous, creatinine clearance, and 24-hour urine calcium level. Although a 24-hour urine calcium level is no longer required per the NIH Guidelines for all patients, it is important to have when there is a concern for FHH ( Box 2 ). Prior family history is very helpful when FHH is suspected. In this case, urine calcium levels less than 100 make the diagnosis and prevent unnecessary surgery.
- •
Serum Ca >1 mg/dL above upper limit of normal
- •
Creatinine clearance <30% of age-matched normal subjects
- •
Diminished bone density (T score <−2.5) or fragility fracture
- •
Age <50 years
- •
Difficult periodic follow-up
Bone densitometry is recommended to measure the effect of hypercalcemia on the bones. A bone density T-score of −2.5 or less at any site in perimenopausal and postmenopausal women and men greater than 50 years old or a Z-score of −2.5 or less in premenopausal women and men less than 50 years old are diagnostic for bone loss resulting in osteopenia or in more advanced cases osteoporosis.
Indications for surgery include patients with a biochemical diagnosis of PHPT and overt clinical signs or symptoms, such as kidney stones, decreased bone density, prior fracture, or brown tumors. For patients who have a biochemical diagnosis but are asymptomatic, the NIH has developed a set of guidelines, which were modified in 2008 (see Box 2 ). A 24-hour urine calcium level is no longer indicated per the new guidelines. As previously discussed, patients who have vague symptoms and a biochemical diagnosis should also be strongly considered for surgery. Several studies report overall improvement especially in neurocognitive symptoms and better quality of life for these patients after parathyroidectomy.
Imaging
Preoperative localization of abnormal parathyroid glands has become very important in the era of minimally invasive parathyroid (MIP) surgery. The two most common imaging modalities are ultrasonography and 99m Tc-sestamibi scintigraphy. When these two modalities are used together, the accuracy of localizing the suspect gland increases. CT and MRI are less used but are useful in patients with failed parathyroidectomy or persistent HPT to identify ectopic glands ( Table 1 ).
| % Ultrasound | % Sestamibi | % CT | % MRI | % Positron Emission Tomography |
|---|---|---|---|---|
| 60–92 | 78–100 | 36–100 | 51–100 | 70–74 |
High-resolution ultrasound is a useful modality to locate enlarged parathyroid glands in the neck. Normal parathyroids, which average 5 × 3 × 1 mm in size are usually not visualized on ultrasound. One of the benefits of cervical ultrasound is the ability to study the thyroid gland concurrently for any abnormalities. Because MIP surgery limits the surgeon’s ability to palpate or visualize the thyroid intraoperatively, sonography is an invaluable preoperative tool. Eighteen percent of patients with PHPT have synchronous thyroid disease with an overall malignancy rate of 2%. Ultrasound is also beneficial because it is inexpensive, it does not use ionizing radiation, and it has a sensitivity in the range of 72% to 85%. One downside of ultrasonography is the difficulty in finding glands located in the mediastinum, the retroesophageal space, and other ectopic locations. It is also less helpful in patients who have a multinodular goiter or minimally enlarged parathyroid glands.
On ultrasound, a parathyroid adenoma is hypoechoic, homogenous, and solid with a bean-shaped or oval appearance ( Fig. 1 ). There is usually a small branch from the inferior thyroid artery, which enters the gland at one of its poles. It is difficult to distinguish both thyroid nodules and cervical lymph nodes from parathyroid glands, which decreases the accuracy of this modality when used without other imaging.
99m Tc-sestamibi is taken up by both parathyroid and thyroid tissue making it a logical choice for preoperative localization in patients with HPT. Adenomatous and hyperplastic parathyorids have more avid and more prolonged uptake than the thyroid tissue. After injection of the radiotracer, one set of images is taken within 15 minutes and then a delayed set is taken at 2 hours. Asymmetry of uptake can be noted on early images, but usually, the delayed images are necessary to locate the focus of radiotracer, which characterizes hyperfunctioning parathyroid ( Figs. 2 and 3 ).
Single-photon emission CT (SPECT) can help differentiate parathyroid tissue from thyroid tissue increasing the sensitivity of scintigraphy. For solitary adenomas, there is a sensitivity of 87% when using SPECT. Its sensitivity decreases with double adenomas (30%) and MGD (44%). A hybrid of SPECT and CT used for the early images has also been shown to enhance the accuracy of localization when combined with various delayed imaging methods, particularly dual-phase imaging, which is better than single-phase imaging.
The combination of ultrasound and 99m TC-sestamibi scintigraphy to localize parathyroid adenomas preoperatively increases the sensitivity to 95% because each modality contributes different data to help determine the gland location. Ultrasonography is more specific for anatomic location of the gland in relation to the thyroid, whereas scintigraphy is better at finding ectopic glands especially in the mediastinum. For double adenomas and MGD, the sensitivity continues to be lower even when these modalities are combined.
For patients with persistent disease, CT with thin cuts from the skull base through the chest can identify contrast-enhanced parathyroid tissue with a sensitivity ranging from 46% to 87%. CT is particularly useful in patients who have altered anatomy or a failed parathyroidectomy ( Fig. 4 ). MRIs, which are rarely done, can also identify abnormal parathyroid tissue and are used in patients with recurrent or persistent disease.
Presentation and diagnosis
Over the last 30 years, a shift has occurred in the presentation of PHPT. Historically, patients presented with clinical findings related to long-standing disease, such as nephrolithiasis, brown tumors, osteitis fibrosa cystic, and muscle atrophy. With the advent of routine serum calcium measurements, patients present with hypercalcemia much earlier and subsequently have fewer, if any, overt symptoms. Up to 80% of patients have been described as asymptomatic; however, many studies have shown these patients actually have vague symptoms that are more difficult to qualify. In one study, there was some benefit to doing neuropsychological testing and evaluation of health-related quality of life to determine the need for surgery in patients with biochemically diagnosed PHPT. Some of these nonspecific symptoms include fatigue, weakness, bony pain, depression, memory loss, decreased concentration, and sleep issues. Many patients who do not complain of symptoms before surgery report significant improvement postoperatively, implying that these subtle symptoms are meaningful in terms of patient well-being.
Interestingly, nephrolithiasis is the most common clinical manifestation of PHPT, occurring in 20% of patients presenting with the disease. These patients are often followed for years before they are diagnosed with PHPT because hypercalcemia is not considered as a cause of kidney stones. They are often not diagnosed with PHPT until they have another manifestation of the disease.
Subtle changes on bone densitometry are noted in patients with PHPT. Bone integrity is altered by high bone turnover because of increased PTH resulting in osteopenia, osteoporosis, and increases risk of fracture. Primarily cortical and cancellous bone loss is seen. Postoperatively, bone loss is often stalled or improved with increased bone density over time.
Various cardiovascular conditions are associated with PHPT including hypertension, valvular calcifications, left ventricular hypertrophy, and cardiovascular mortality. Surgery does not affect hypertension in these patients so that most remain on their antihypertensive medication postoperatively. The risk of cardiovascular mortality decreases in patients with severe PHPT who have parathyroidectomy. Unfortunately, studies on cardiovascular mortality in patients with mild PHPT are limited and inconclusive.
The diagnosis of PHPT is usually made biochemically with elevated serum calcium and elevated PTH. Some patients present with normocalcemia, which is within the continuum of the disease. Patients can also have PTH values within the reference range, which reflects an inappropriate response to hypercalcemia. Vitamin D levels should be checked initially in all patients with a diagnosis of PHPT because the presence of vitamin D deficiency can affect the interpretation of the PTH assay resulting in elevated PTH levels. Patients who have vitamin D deficiency should be repleted before diagnosing PHPT.
Other laboratory tests that are useful in making the diagnosis include phosphorous, creatinine clearance, and 24-hour urine calcium level. Although a 24-hour urine calcium level is no longer required per the NIH Guidelines for all patients, it is important to have when there is a concern for FHH ( Box 2 ). Prior family history is very helpful when FHH is suspected. In this case, urine calcium levels less than 100 make the diagnosis and prevent unnecessary surgery.
- •
Serum Ca >1 mg/dL above upper limit of normal
- •
Creatinine clearance <30% of age-matched normal subjects
- •
Diminished bone density (T score <−2.5) or fragility fracture
- •
Age <50 years
- •
Difficult periodic follow-up
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