Chapter 43. Parathyroid Disorders

The parathyroid gland is a key regulator of calcium homeostasis. While hyperparathyroidism is now most often diagnosed in asymptomatic patients, untreated it can have devastating effects on multiple organ systems. Primary hyperparathyroidism, the most common cause of hypercalcemia in nonhospitalized patients, is treated surgically in most cases.

During the fifth week of gestation, the parathyroid glands form from the third and fourth branchial pouches. The glands derived from the third pouches descend caudally in the neck along with the thymus gland (formed from the third branchial arch), while the glands from the fourth pouches remain stationary. Knowledge of this embryologic migration, which results in the glands arising from the fourth pouches to be superiorly located and those from the third pouches to be inferior, is critical when searching for ectopically located glands.

The superior parathyroid glands are typically closely associated with the posterolateral aspect of the superior poles of the thyroid gland. The inferior glands, which are more variable in positioning, are most commonly found near the inferior poles of the thyroid gland. These are sometimes embedded within the superior aspect of the thymus gland or within the thyrothymic ligament.

Deviation from the standard migratory pattern during embryogenesis can lead to aberrantly located glands in approximately 15 to 20% of patients, although this has been reported to be higher in individuals with renal hyperparathyroidism. Aberrant glands can occur in any location along their migration course and have been identified from the carotid bifurcation to the level of the aortic arch.

While the majority of people have four parathyroid glands, approximately 2 to 5% have five or more glands. A similar percentage has fewer than four glands.

The blood supply to parathyroid glands is fairly constant. Both the superior and inferior glands are fed from branches of the inferior thyroid artery. Occasionally, superior glands are supplied by an anastomotic branch from the inferior to the superior thyroid artery or are fed by both arteries. These arteries enter the glands at their hila, an anatomic characteristic which distinguishes them from surrounding fat. The arterial branches supplying the glands can be variably positioned relative to the recurrent laryngeal nerve.

Normal parathyroid glands, often bean shaped, appear a distinct yellowish brown, often described as caramel in color. Manipulation of the glands and their blood supply during surgery will change the color to a darker mocha brown. Healthy glands weigh 30 to 40 mg on average.

Physiology

Parathyroid hormone (PTH) impacts calcium homeostasis by targeting the kidneys, skeletal system, and gastrointestinal tract. The parathyroid chief cells are responsible for the production and storage of PTH. Hormone release by parathyroid glands is directly controlled by feedback inhibition of the glands by serum calcium.

PTH acts to raise calcium levels by several mechanisms. It influences the kidneys to increase calcium reabsorption, promotes resorption and calcium release by the bones and enhances absorption of calcium in the intestines by increasing renal activation of vitamin D.

Hyperparathyroidism is the most common disorder of parathyroid function. Hyperparathyroidism is categorized as primary, secondary or tertiary depending on the etiology. Primary and tertiary hyperparathyroidism are treated surgically while secondary hyperparathyroidism is usually managed medically.

Primary Hyperparathyroidism

Essentials of Diagnosis

• Elevated serum calcium level
• Elevated serum PTH level
• Must differentiate between primary, secondary and tertiary hyperparathyroidism.

Primary hyperparathyroidism is due to a primary defect in the parathyroid glands, such that elevated serum calcium fails to inhibit additional PTH release. Approximately 0.3 to 1% of the general population develops primary hyperparathyroidism. Rare prior to puberty, its incidence peaks in women in their fourth to seventh decades.

Pathogenesis

In a majority of primary hyperparathyroidism patients, dysfunctional calcium sensing receptors on the surface of chief cells is the cause. Single adenomas are present in 80 to 85% of cases, double adenomas in 2 to 3%, and multigland hyperplasia in 12 to 15%. Parathyroid carcinoma is a rare cause of primary hyperparathyroidism.

Clinical Findings

The introduction over 30 years ago of accurate and mechanized laboratory tests for serum calcium levels has allowed for earlier and more frequent detection of primary hyperparathyroidism. Historically, patients presented with the classic constellation of “groans, bones, stones, and psychiatric overtones”. Currently, the vast majority of patients are diagnosed on routine lab testing and are asymptomatic. Long-standing, untreated primary hyperparathyroidism can lead to early death, often from cardiac dysfunction.

In addition to generalized fatigue and weakness, multiple systems can be impacted:

• Gastrointestinal: Abdominal pain, constipation, nausea, vomiting, peptic ulcer, and pancreatitis.
• Rheumatologic: Bone pain, osteoporosis, arthralgia, myalgia, and gout.
• Renal: Nephrolithiasis, polyuria, polydipsia, and renal failure.
• Psychiatric: Depression, dementia, and confusion.
• Cardiovascular: Hypertension and cardiac arrhythmias.

Diagnosis

Laboratory

While there are numerous physiological derangements that can occur in primary hyperparathyroidism, elevated calcium and PTH levels are fundamental to the diagnosis. Several additional laboratory tests can contribute to making an accurate diagnosis.

• Hypercalcemia: An elevated calcium level is a hallmark of the diagnosis. While an elevated serum calcium level is almost always present and adequate for diagnosis, in some situations, only the physiologically active ionized calcium is elevated. In the blood, approximately 50% of calcium is bound to protein, typically albumin, 5% is complexed with phosphate or citrate and the remainder is ionized. In the setting of hypoalbuminemia, serum calcium levels can be normal while the ionized fraction is elevated.
• Hyperparathyroidism: The introduction of new assays has allowed accurate assessments of intact PTH levels. In primary hyperparathyroidism, PTH levels can range from the high end of normal to markedly elevated level. In the setting of hypercalcemia, a PTH level at the high end of normal should be considered inappropriate and needs further diagnostic workup.
• Hypophosphatemia: Increased PTH levels promote renal excretion of phosphate. Approximately 50% of patients with primary hyperparathyroidism have below normal serum phosphate levels.
• Normal to elevated urine calcium: A 24 h total urine calcium level and calcium clearance can help in differentiating familial hypocalciuric hypercalcemia (FHH) from primary hyperparathyroidism, in which normal to elevated urine calcium levels are present. Inappropriately low urine calcium excretion suggests FHH.

Radiologic

The development of effective imaging modalities for identifying hyperfunctioning parathyroid glands has promoted the performance of directed, or minimally invasive, parathyroidectomies.

• Radionuclide Scanning: The localization ability of Technetium 99m sestamibi scintigraphy is based on its preferential uptake by parathyroid cells, due to their high mitochondrial activity. (Figure 43–1) Delayed images taken 2 to 3 h after injection are sensitive in up to 90% of single adenoma cases, with over 90% specificity. Sestamibi imaging is also effective in cases of double adenoma. However, it has significantly reduced accuracy in cases of four-gland hyperplasia. Its physiologic basis aids in identification of ectopic glands. More recently, some have used this technique in combination with single-photon emission computed tomography and report improved three-dimensional localization.
• Ultrasound: High-resolution ultrasonography (US) can be used for localization of parathyroid adenomas. (Figure 43–2) US is a noninvasive, easily performed and inexpensive modality to evaluate primary hyperparathyroidism patients. In skilled hands, its sensitivity and specificity are high. Its usefulness is limited in cases of deeply placed ectopic glands.
• Magnetic resonance imaging: Magnetic resonance imaging is usually used as an adjuvant modality in cases of ectopic glands or re-exploration for persistent hyperparathyroidism.

Treatment

Surgical intervention is the treatment of choice for primary hyperparathyroidism. Prior to routine screening of serum calcium levels, patients often presented with significant complications of their disease. However, currently most patients are asymptomatic when identified. There are some who argue that primary hyperparathyroidism does not progress in many asymptomatic patients and they can be observed for progression of their disease. Most experts, however, support parathyroidectomy for all patients irrespective of their symptoms. Parathyroidectomy is effective at alleviating symptoms and in preventing additional sequelae.

For patients who are not operative candidates supportive medical therapy can be utilized. Recently, selective angiography with embolization of parathyroid adenomas has been used successfully in some instances.

Surgery

The gold standard for management of primary hyperparathyroidism has been bilateral neck exploration with four-gland examination. This approach is effective for cases of single adenomas, double adenomas, and four-gland hyperplasia. A horizontal cervical incision is made through the skin and platysma muscle. Subplatysmal flaps are then elevated and strap muscles are divided in the midline and retracted. The thyroid gland is retracted medially to allow for serial identification and examination of all four parathyroid glands. Additional dissection may be required if a gland is ectopically located. Depending on the appearance of the glands, several excisional options exist. If one or two glands appear abnormal, as with a single or double adenoma, they can be removed. If there is suspicion of four-gland hyperplasia, either a total or subtotal parathyroidectomy can be performed.

Total parathyroidectomy requires excision of all four parathyroid glands. After removal, in order to prevent lifelong hypoparathyroidism, a portion of a gland is reimplanted. The tissue to be reimplanted is cut into 1 to 2 mm pieces and then placed in a pocket created in the sternocleidomastoid muscle or in a presternal subcutaneous pocket. A clip or suture is placed to mark the reimplantation site in the muscle for easy identification if revision surgery is required.

Alternatively, a subtotal parathyroidectomy can be performed, in which 3½ glands are removed. The remaining half of the most normal-appearing gland is left in place with an intact blood supply. Preference is given to leaving an inferior gland, since re-exploration (if necessary) will incur lower risk to the recurrent laryngeal nerve.

Directed parathyroidectomy, including minimally invasive approaches, is now widely practiced (Figure 43–3). These focused techniques became feasible with the introduction of imaging studies that provided accurate preoperative localization of hyperfunctional or enlarged parathyroid glands. Rather than explore and examine all parathyroid glands, localization permits dissection and excision of the pathologic gland only. These procedures, which require minimal dissection and time, can be performed under local anesthesia if dictated by patient preference.

Several other innovations have enhanced the performance of directed parathyroidectomy. Assays that rapidly measure PTH levels, which have a half-life of 2 to 5 min, allow for intraoperative assessment of the efficacy of surgery. Numerous protocols for the use of intraoperative PTH have been described. Typically, a 50% reduction in PTH level 5 to 10 min after removal of the gland, with a fall into the normal range, is considered a positive outcome. Some surgeons utilize a preoperative injection of methylene blue or sestamibi to aid in focusing their dissection. Abnormal parathyroid glands will stain strongly with methylene blue, although it should be used cautiously because of the possibility of neurologic reactions, particularly in patients taking SSRI's. For radioguided procedures, a radioprobe is used to detect the gland with above average uptake of the radio-tagged sestamibi and then to direct dissection for its removal. Based on surgeon preferences, these different modalities can be used in various combinations to perform the most efficient and successful surgery.

In the past, patients were hospitalized after surgery to monitor their calcium levels until they stabilized. Currently, most patients undergoing parathyroidectomy, particularly targeted procedures, are discharged the same day. These patients are routinely started on oral calcium supplementation to mitigate transient postoperative hypocalcemia.

Regardless of the technique utilized, the success rate for primary surgery exceeds 90%. Recurrent or persistent hyperparathyroidism occurs in the remainder, with unsuccessful surgeries often due to unrecognized double adenomas or four gland hyperplasia or ectopically located glands. Revision surgery achieves cure in about 85 to 90% of cases.

Pathology

Adenomas are typically composed of large numbers of relatively uniform, polygonal chief cells. The presence of normal appearing parathyroid tissue, which often can be detected as a thin, compressed rim at the periphery of the gland, confirms an adenoma. A large number of oxyphil cells are often present and adenomas can occasionally consist of these cells only.

Hyperplasia affects all four glands, causing all to be grossly enlarged. As opposed to adenomatous lesions, in hyperplasia all tissues are involved and no normal gland is found.

Complications

The risk of complications from parathyroidectomy is low. The potential complications include the following:

• Temporary hypocalcemia and hypoparathyroidism: In many patients the hyperfunctional tissue has suppressed the activity of the normal glands. Consequently, patients may become temporarily hypoparathyroid and hypocalcemic until their normal glands regain their function. Typically, calcium levels will reach a nadir at 48 to 72 h after surgery. If a total parathyroidectomy with autotransplantation is performed, patients may remain hypoparathyroid until the implanted glandular tissue revascularizes and starts to function. This may take 3 to 6 months.
• Hungry bone syndrome: Certain patients with long-standing hyperparathyroidism can become severely hypocalcemic as the bone repletes its calcium deposits after surgery. Patients can develop parathesias, tetany, and seizures if not aggressively supplemented with calcium. In addition to hypocalcemia, these patients also can have hypophosphatemia and hypomagnesemia, which require supplementation. Older patients, patients with elevated preoperative alkaline phosphatase levels, and those with large adenomas are at increased risk of developing this complication.
• Permanent hypoparathyroidism: In rare instances, in patients who underwent total parathyroidectomy and autotransplantation, the implanted tissue never becomes functional and patients develop permanent hypoparathyroidism.
• Recurrent laryngeal nerve injury: The rate of temporary or permanent dysfunction after parathyroidectomy is approximately 1%.
• Postoperative hematoma or infection: These are rarely occurring complications.

Secondary Hyperparathyroidism

In secondary hyperparathyroidism PTH levels are elevated in response to chronic hypocalcemia. While any disorder that results in hypocalcemia can lead to secondary hyperparathyroidism, chronic renal failure and vitamin D deficiency are the most common causes. Stimulation of the parathyroid glands by chronic hypocalcemia results in hyperplasia of all glands. In contrast to primary hyperparathyroidism, treatment is medical. The critical elements are correction of the hypocalcemia, repletion with vitamin D analogues and addressing the underlying cause (Figures 43–4 and 43–5).

Tertiary Hyperparathyroidism

The parathyroid glands are chronically stimulated in secondary hyperparathyroidism. Tertiary hyperparathyroidism occurs when the cause of the stimulation is corrected, and the glands remain autonomously hyperfunctional. This disorder often requires subtotal or total parathyroidectomy, although selective parathyroidectomy may be appropriate.

Familial Hypocalciuric Hypercalcemia

An autosomal dominant disease, FHH can be a diagnostic challenge. Due to an inactivating mutation in the gene for the calcium sensing receptor, the parathyroid glands and kidneys are less sensitive to calcium, which leads to inappropriate PTH production and renal calcium reabsorption. In these patients, PTH and calcium levels are usually at the high end of normal or only mildly elevated. The course of the disease is most often benign, due to the relatively mild hyperparathyroidism and these patients should just be observed. Diagnostically, a low urinary calcium clearance will differentiate between FHH and primary hyperparathyroidism.

Carcinoma

Parathyroid carcinoma is the cause of less than 1% of primary hyperparathyroidism and is often difficult to diagnose prior to surgery. A high index of suspicion must be maintained in patients with extremely elevated calcium and PTH levels. A palpable mass is reportedly present in up to half of patients with carcinoma.

Histologically, parathyroid carcinoma is difficult to differentiate from adenomatous change. Diagnosis requires either capsular or local invasion, nodal or distant metastases or local recurrence after excision.

If a preoperative diagnosis is made or if intraoperative findings, such as local tissue invasion or adhesiveness, suggest carcinoma, wide local excision of the gland with surrounding tissue is indicated. An ipsilateral hemithyroidectomy should be performed with removal of tissue from the tracheoesophageal groove and central compartment. If any palpable neck adenopathy is present, a modified radical or selective neck dissection should be included in the resection. Recurrence or persistence of disease is common, even after many years, and treated with re-excision of any resectable tumor. Medical interventions have not been successful at controlling parathyroid carcinoma.

Multiple Endocrine Neoplasias

Hereditary multiple endocrine neoplasia (MEN) syndromes often involve the parathyroid glands. These are transmitted in an autosomal dominant pattern with variable expression and should be considered in any patient who presents with multiple endocrine organ neoplasias or has a family history of endocrine organ neoplasias.

Hyperparathyroidism from parathyroid hyperplasia occurs in the following:

• MEN 1 (Werner's syndrome): Includes parathyroid hyperplasia, pituitary adenomas, and pancreatic islet cell tumors.
• MEN 2A (Sipple's syndrome): Includes medullary thyroid carcinoma, pheochromocytomas and parathyroid hyperplasia.

Hypoparathyroidism

Hypoparathyroidism is a rare entity that results in chronic hypocalcemia. Iatrogenic sources, almost always parathyroid or thyroid surgery, are the most frequent cause. Less frequently, congenital abnormalities of the third and fourth pharyngeal pouches, such as DiGeorge syndrome, can be responsible for the hypoparathyroidism. Lifelong supplementation with calcium and vitamin D is necessary.

We would like to acknowledge Karsten Munck, MD and David W. Eisele, MD for their contribution to this chapter in the previous editions of CDT.