| Hyperparathyroidism Hypercalcemia has an incidence of approximately 0.5% in the general population. Although the differential diagnosis of hypercalcemia is extensive , hyperparathyroidism is the most common cause of hypercalcemia in nonhospitalized patients (Table 431). Primary hyperparathyroidism, due to a parathyroid adenoma, is the most common of the parathyroid disorders. Secondary and tertiary hyperparathyroid disease is mostly seen in patients with renal disease. | Table 431. Causes of Hypercalcemia.
| | | Hyperparathyroidism | | Malignant neoplasms | | Breast, lung, kidney, prostate, and thyroid malignant growths, as well as multiple myeloma, leukemia, and PTH-secreting cancers | | Endocrine disorders | | Hyperthyroidism, adrenal insufficiency, pheochromocytoma, and VIPoma | | Granulomatous diseases | | Sarcoidosis, tuberculosis, histoplasmosis, coccidiomycosis, and leprosy | | Drugs and vitamins | | Thiazide diuretics, lithium, aluminum, and vitamins A and D | | Immobilization | | Milk alkali syndrome | | Renal disease | | Benign familial hypocalciuric hypercalcemia | |
| Primary Hyperparathyroidism Essentials of Diagnosis - Elevated serum calcium.
- Elevated serum parathyroid hormone.
- Familial hypocalciuric hypercalcemia may be incorrectly diagnosed as primary hyperparathyroidism.
General Considerations Primary hyperparathyroidism is most common in postmenopausal women, with a peak incidence in the third to fifth decades. Primary hyperparathyroidism is characterized by the production and secretion of excess parathyroid hormone (PTH) and has been associated with low-dose radiation therapy . Primary hyperparathyroidism can be attributed to a single parathyroid adenoma (83%), double adenomas (23%), multigland hyperplasia (12%), or, rarely, carcinoma of the parathyroid gland (1%). The overproduction of PTH results in the mobilization of calcium from bone and inhibition of the renal absorption of phosphate. Clinical Findings Historically, renal disease and skeletal manifestations have been the presenting problems of patients with primary hyperparathyroidism. Currently, most patients are diagnosed with the disease through routine laboratory tests. Many patients are asymptomatic or have nonspecific symptoms that resolve after successful surgical treatment. Symptoms and Signs The signs and symptoms of primary hyperparathyroidism include the following categories: neurologic, renal, gastrointestinal , and cardiovascular. They can be loosely described as "stones, bones, abdominal groans, psychic moans, and fatigue overtones." Neurologic Symptoms The neurologic signs and symptoms include muscular weakness, fatigue, depression, anorexia , confusion, headache , and memory loss. Renal Symptoms Polyuria, polydipsia, renal colic, and nephrocalcinosis are the most common renal symptoms. Gastrointestinal Symptoms Patients may present with constipation, nausea, vomiting, pancreatitis , peptic ulcer disease, or abdominal pain. Cardiovascular Symptoms Hypertension and cardiac arrhythmias are the most common cardiovascular symptoms. Other Symptoms Other common presenting signs and symptoms include arthralgia, myalgia, and pruritus. Laboratory Findings Calcium Hypercalcemia is the most important biochemical finding when evaluating patients for primary hyperparathyroidism. It is important to recognize that hypoalbuminemia can give the appearance of a normal total calcium level, despite an elevated level of ionized serum calcium. Parathyroid Hormone An elevated serum PTH level in the setting of an elevated serum calcium level is virtually diagnostic for primary hyperparathyroidism. PTH is low for essentially all other causes of hypercalcemia. Phosphate PTH tends to increase the renal excretion of phosphate, causing the serum level of phosphate to be decreased in hyperparathyroidism. Urine Calcium Patients with primary hyperparathyroidism should have a high or normal 24-hour urinary calcium level. If the patient is noted to have a low 24- hour urinary calcium level, the cause of the patient's hypercalcemia can be secondary to familial hypocalciuric hypercalcemia syndrome rather than primary hyperparathyroidism. Imaging Studies Preoperative localization imaging studies are indicated for patients who are candidates for minimally invasive parathyroidectomy, failed prior surgery, or recurrent primary hyperparathyroidism. Ultrasound High-resolution ultrasound has been used for the preoperative localization of parathyroid adenoma. The sensitivity of ultrasound in preoperatively detecting parathyroid adenoma has been reported to be in the range of 6090%. This modality is highly dependent on the experience of the individual performing the imaging study and may help to explain the large variability in the sensitivities reported . Sestamibi Scans One of the main advances in both the imaging of the parathyroid glands and the preoperative localization of parathyroid adenoma has come with the use of technetium-99m sestamibi scans. The sensitivity of sestamibi scans is in the range of 7080% for the localization of parathyroid adenoma. Recently, the use of delayed technetium-99m sestamibi single-photon emission computed tomography (SPECT) has allowed for the localization of an adenoma in two-dimensional space. Sestamibi SPECT scans have been reported to have a sensitivity of 87%, an accuracy of 94%, and a positive predictive value of 86%. The sensitivity of sestamibi SPECT scans is similar in patients undergoing operative exploration and subsequent surgery. Methylene Blue The preoperative injection of methylene blue (ie, methylthionine chloride) has been reported by some clinicians to facilitate the intraoperative identification of parathyroid adenoma. The sensitivity of this technique has been reported to be similar to sestamibi scans. When these two modalities have been used together, they have been reported to increase diagnostic sensitivity to 96%. Neurotoxicity has been reported with higher doses of methylene blue in patients on selective reuptake inhibitors . Similar side effects have been avoided with lower doses and without degradation in efficacy. Treatment Surgery is the only effective treatment for primary hyperparathyroidism. Nephrolithiasis, bone disease, and neuromuscular symptoms all respond very well to the surgical removal of diseased parathyroid tissue. Historically, only patients with symptomatic hyperparathyroidism or extremely high calcium levels were considered to be good surgical candidates. At present, it is generally accepted that all patients with either symptomatic or asymptomatic hyperparathyroidism will benefit from surgery. Early surgical intervention can not only alleviate symptoms, but it can also prevent the potential future complications of hyperparathyroidism and in most cases reverse some of the associated bone loss. Principles of Operative Intervention Bilateral neck exploration has previously been considered the gold standard surgical approach for primary hyperparathyroidism. The operation is accomplished through a transverse incision in the lower neck. This incision is carried down through the platysma muscle. Subplatysmal flaps are elevated. The strap muscles are divided in the midline and retracted laterally. One thyroid lobe is exposed and retracted medially, and the parathyroid glands are identified. If a bilateral neck exploration fails to reveal four parathyroid glands that are located relatively symmetrically , the thymic pedicle should be explored. In addition, the thyroid lobe on the side of the missing gland should be mobilized and palpated, which then allows for exploration of the retrolaryngeal area, the tracheoesophageal groove, and the great vessels of the neck (Table 432). | Table 432. Aberrant Locations of Parathyroid Adenoma.
| | | Anterior mediastinum | | Posterior mediastinum | | Retroesophageal area | | Retrolaryngeal area | | Tracheoesophageal groove | | Intrathyroidal area | | Carotid bifurcation | |
| Once the parathyroid glands have been identified, an intraoperative decision has to be made regarding the extent of resection. Although a single adenoma is most likely, both double adenomas and multigland hyperplasia must be considered. If a single abnormal-appearing parathyroid gland is identified, it is removed and parathyroid tissue is confirmed by frozen section. In the event that a four-gland hyperplasia is identified, there are two acceptable surgical options. The first option is a total parathyroidectomy with autotransplantation of parathyroid tissue into either the sternocleidomastoid muscle or the brachioradialis muscle of the nondominant arm. This technique offers the advantage of easy access to the implanted tissue if the patient requires a reoperative procedure for recurrent or persistent hyperparathyroidism. The main disadvantage of total parathyroidectomy is the potential for permanent hypoparathyroidism if the transplanted gland tissue does not function. The second approach is a subtotal parathyroidectomy with removal of three and one half of the parathyroid glands, leaving a portion of a parathyroid gland in situ. The advantage of this approach is that the parathyroid tissue remains attached to its native blood supply. Intraoperative Parathyroid Hormone Monitoring The intraoperative use of a rapid PTH assay has become an important adjunct in helping the surgeon determine the adequacy of the parathyroid gland resection. The normal half-life of PTH is approximately 35 minutes, making it easy to evaluate a decrease in serum PTH following the resection of adenomatous or hyperplastic parathyroid tissue. A decrease in the PTH level by 50% or more at 10 minutes after adenoma excision compared with the preexcision baseline PTHreliably predicts surgical success. Compared with frozen sections, intraoperative PTH has been shown to be indispensable in guiding the operative strategy during focused exploration parathyroid surgery. Autotransplantation of Parathyroid Tissue If parathyroid tissue is removed with the intent of autotransplantation, it should be promptly placed in iced saline. When the surgeon is ready to perform the autotransplantation, the specimen is removed from the saline and sectioned into 12 mm pieces. Individual muscle beds are created for each slice of parathyroid tissue in either the sternocleidomastoid or the brachioradialis muscle of the arm. Once the parathyroid tissue has been transplanted into the muscle, the site of implantation is marked with a surgical clip. In most cases, within 23 months from the time of autotransplantation, the graft is neovascularized and functioning. Parathyroid tissue can also be sent for cryopreservation for up to 18 months. If the initial autotransplantation of the graft fails and is nonfunctional after 2 months, the sample, which has been cryopreserved, can be autotransplanted with a 50% chance of eventual function. Complications of Parathyroidectomy Postoperative hypocalcemia can occur following parathyroidectomy. The chronic stimulation of the bone with PTH results in the skeletal depletion of calcium. The normalization of PTH causes the bone reuptake of calcium, with a resultant fall in serum calcium; this condition is clinically referred to as the "hungry bone syndrome." The preoperative elevation of serum alkaline phosphatase predicts this problem. Permanent hypoparathyroidism may complicate parathyroidectomy in < 2% of cases of adenoma and in 1030% of cases of hyperplasia. Conversely, persistent hyperparathyroidism complicates 5% of the operative procedures of primary hyperparathyroidism; it may reoccur in up to 16% of patients with nonfamilial hyperplastic parathyroid disease and in 2636% of patients with familial hyperplastic disease. Permanent recurrent laryngeal nerve injury occurs in < 1% of patients undergoing parathyroidectomy. Neck hematoma and infection are unusual complications after parathyroidectomy. Secondary Hyperparathyroidism Hyperparathyroidism can develop as a consequence of chronic renal failure, which results in increased serum phosphate levels and a decrease in 1-hydroxylase (ie,  -1-hydroxylase) activity in the kidney. These factors act in synergy to cause hypocalcemia, which causes the parathyroid glands to be chronically stimulated. Treatment of this disorder is focused on treating the underlying renal failure. Tertiary Hyperparathyroidism Some patients with secondary hyperparathyroidism develop tertiary hyperparathyroidism. In this condition, the parathyroid glands autonomously secrete PTH, despite correction of the underlying cause of the hyperparathyroidism (eg, after kidney transplantation ). Hyperparathyroidism in Pregnancy Hyperparathyroidism in pregnancy is a rare disorder that can have detrimental consequences for the fetus. Surgical exploration should be accomplished during the second trimester of pregnancy to minimize the potential complications of neonatal tetany, stillbirth, and spontaneous abortion. Total parathyroidectomy with autotransplantation is the treatment of choice for this disorder. During pregnancy, the PTH of the mother does not cross the placenta, which results in chronic suppression of the fetal parathyroid glands. After birth, the neonate's serum calcium level quickly drops without the maternal calcium via the placenta. It takes approximately 710 days for the newborn 's parathyroid glands to respond to the hypocalcemia by secreting adequate PTH. Thus, profound hypocalcemia can occur in the early perinatal period. | 