Hyperparathyroidism

What is Hyperparathyroidism?

The parathyroid glands are 4 small glands located in the neck, on either side, immediately adjacent to the thyroid. In spite of their diminutive size, these glands are essential to the maintenance of normal calcium homeostasis.   These glands are paired on either side posterior to the thyroid and are commonly designated as superior and inferior parathyroids.   Running along the trachea, immediately behind the parathyroids and thyroid is the recurrent laryngeal nerve, which is responsible for controlling movement of the vocal cords. During thyroid or parathyroid surgery, it is essential to avoid injury to these nerves. Because of the manner in which the parathyroids develop during embryonic life, their location is somewhat variable. This presents a problem for the surgeon attempting to locate a small structure in an area of the body densely packed with vital other structures. In order for the reader to understand the rationale for procedures to be discussed below, a basic understanding of the development of the parathyroid glands is essential.

  Very early during embryonic development there exist structures in the developing pharynx called pharyngeal pouches of which there are five pairs. These pouches ultimately develop into several head and neck organs.   The 3rd and 4th pharyngeal pouches develop into the parathyroid glands. These pouches, however, in the embryo, are much higher than the normal location of the parathyroid glands. Thus, during development, these structures must migrate downward to their normal, fully developed location. The 3rd pharyngeal pouch gives rise to the inferior parathyroids while the 4th gives rise to the superior parathyroids. Thus, the 3rd pharyngeal pouch structures must migrate further than the 4th. Also developing from the 3rd pharyngeal pouch is the thymus gland, which is ultimately located in the superior mediastinum. This gland functions during childhood in the development of the immune system. Because of this co-migration of these two glandular organs, the ultimate location of the inferior parathyroids is variable. Though generally they are found where they are supposed to be, they in fact may be located anywhere from the base of the tongue to within the mediastinum.

A comprehensive discussion of calcium metabolism would be extremely tiresome and complicated for the purposes of this discussion; however, one cannot discuss hyperparathyroidism without a basic understanding of the normal function of the parathyroid glands. Calcium exists in our bodies in two distinct forms, ionized free calcium and calcium salts in bone. Free ionized calcium is important for normal electrical conduction in nerves, the brain and cardiac, skeletal and smooth muscle. The concentration of ionized calcium in the blood is carefully regulated to assure normal function. Parathyroid hormone plays an integral part in the maintenance of normal ionized calcium levels. Low serum calcium levels result in the increased secretion of parathyroid hormone by the parathyroid glands. Parathyroid hormone causes the release of calcium from bone and the reabsorption of calcium in the kidneys to prevent loss in the urine. High calcium levels depress parathyroid hormone levels and cause calcium to be deposited in bone and permit the kidneys to lose calcium in the urine. Many other factors play a role in this delicate balance including Vitamin D, calcitonin, albumin to name a few.

Hyperparathyroidism is a state of over secretion of parathyroid hormone by the parathyroid glands. Because of the complicated feedback mechanisms that exist, serum calcium levels may be normal even in symptomatic patients. Hyperparathyroidism exists in three main forms designated primary, secondary, and tertiary.

Primary hyperparathyroidism is caused by a defect in the parathyroid gland itself causing primary hypersecretion. This may be caused by hyperplasia of all four glands, by a functioning adenoma in a single gland or rarely parathyroid carcinoma.

Secondary hyperparathyroidism is hypersecretion of the parathyroids in response to a defect elsewhere in the body causing chronic calcium depletion. The most common cause is renal failure.

Tertiary hyperparathyroidism occurs in a patient who has had chronic secondary hyperparathyroidism, in which the hypersecreting parathyroids begin to function autonomously without response to the normal control mechanisms, after the cause of secondary hyperparathyroidism has been corrected. The best example is the patient who developed secondary hyperparathyroidism as a result of renal failure who then underwent a kidney transplant.

The remainder of this discussion will focus on primary hyperparathyroidism since this largely is a surgical condition.

Who gets hyperparathyroidism?

Primary hyperparathyroidism is a relatively common problem with about 100,000 new cases detected each year in the United States. Women are affected about 4 times more commonly than men. 80 to 90 percent of cases of primary hyperparathyroidism are due to a functioning parathyroid adenoma usually involving only a single gland. Parathyroid carcinoma accounts for less than 2 percent of cases. Parathyroid hyperplasia accounts for the remainder. Though parathyroid hyperplasia may occur sporadically, it is associated with an inherited spectrum of endocrine tumors known as multiple endocrine neoplasia. These patients may have tumors of the thyroid, adrenal medulla, and pancreatic islet cells in different combinations with parathyroid hyperplasia. In assessing a patient with primary hyperparathyroidism it is important to establish whether there is a family history of this disease so that a search for these other tumors can be undertaken. However, in patients with multiple endocrine neoplasia, hyperparathyroidism is usually the least manifest of the other tumors that may be present.

What are the symptoms of Hyperparathyroidism?

The symptoms of hyperparathyroidism relate to the role calcium plays in electrical conduction in tissues such as the central nervous system, the heart, skeletal and smooth muscle, and to deposition of insoluble calcium salts in tissues such as the kidney. Remember that patients may be symptomatic even in the face of normal serum calcium levels. The classic presentation is a syndrome of bone pain, kidney stones, abdominal pain and constipation or nausea, psychiatric disturbances such as depression and memory loss, and fatigue. Patients may also exhibit peptic ulcer disease, pancreatitis, hypertension, frequent urination and intolerable thirst. Each of these symptoms alone is non-specific, but taken as a constellation of symptoms the diagnosis should be suspected. Additionally, patients may have changes on the electrocardiogram suggestive of elevated serum calcium level.

The diagnosis is confirmed by several relatively common laboratory tests. Though serum calcium may be normal, the combination of other electrolytes frequently is not. Ultimately, diagnosis depends on confirming an abnormal parathyroid hormone level. In reality, this is not quite as easy as it sounds owing to the complicated metabolism of parathyroid hormone and its very low normal concentration in blood. Nevertheless, utilizing a combination of standard parathyroid hormone assays and a high clinical index of suspicion confirmation of the diagnosis should be relatively straightforward.

What is the treatment?

Surgery is required to treat primary hyperparathyroidism and is curative in 95% of cases. Standard surgery entails exploration of the neck through an incision about 1 inch above the collarbone. Surgery is performed under general anesthesia. All four glands are identified and examined prior to removing any. If an adenoma is encountered, the involved gland alone is removed. If all four glands are enlarged, all four are removed but one is cut in half, the remaining half is finely chopped and inserted into a muscle in the neck. Because of the excellent blood supply of muscle, this parathyroid tissue will take root and begin to function normally.

Parathyroid carcinoma is a rare finding and may only be discovered at the time a pathology specimen is examined for a presumed adenoma. However, frequently these patients have very elevated serum calcium levels that may require multiple medications and vigorous intravenous hydration to bring under control. From a surgical standpoint, the operation is unaltered, though if a parathyroid "adenoma" appears suspicious at the time of surgery, in some cases a wider excision may be necessary. Post-operative treatment with chemotherapy and/or radiation therapy may be employed but probably doesn't add anything to surgery alone.

The challenge of parathyroid surgery comes when one performs a neck exploration on a patient with primary hyperparathyroidism and encounters only 3 normal appearing glands. The problem is that of an adenoma occurring in an abnormally located parathyroid gland due to the normal variability in parathyroid anatomy described at the beginning of this paper. With a more thorough understanding of parathyroid embryology than that described here, there is a systematic approach that the surgeon employs in locating the missing parathyroid gland, usually with success. Under no circumstances should normal parathyroid tissue be removed under these circumstances as this only leads to problems with calcium metabolism when the missing parathyroid adenoma is ultimately localized, perhaps at a later operation.

If a thorough systematic search for this concealed adenoma is unsuccessful, the patient is generally closed and parathyroid localizing studies are then employed.
Several modalities are useful for locating parathyroid glands but no single study is sensitive or specific in determining abnormal parathyroid tissue. This is one of the reasons that they are generally not used before primary surgery. In spite of the above scenario, surgery is 90 - 95% successful in localizing and removing abnormal parathyroid tissue. However, when necessary, ultrasound may be helpful particularly in locating parathyroid glands situated within the thyroid though these may appear very similar to a thyroid adenoma or cyst. Results are improved with ultrasound combined with fine needle aspiration biopsy to confirm the presence of parathyroid tissue in a nodule so visualized. CT scanning and MRI may be useful; MRI is probably more sensitive. Newer nuclear medicine techniques are particularly useful in locating abnormally situated parathyroid adenomas. Sestamibi scanning is very sensitive and relatively specific if only one gland is abnormal and this fact is exploited in the technique of Radio Guided Parathyroid Surgery for parathyroid adenoma. If multiple glands are involved as in parathyroid hyperplasia or multiple parathyroid adenomas, these glands will not show up on Sestamibi scanning. Arteriography, with contrast injected into the arteries supplying the area where the parathyroid adenoma is suspected, has been employed and is occasionally helpful. Similarly, a catheter passed into the veins draining the area can be used to sample blood and test for parathyroid hormone concentration. The sample that yields the highest concentration, suggests the location of the tumor. Often, a combination of these tests must be employed to firmly establish the location of a parathyroid adenoma that has escaped detection on initial surgical exploration.

I have intentionally kept this discussion brief and relatively simplistic. All discussions of endocrine physiology are very complex and I do not wish to overwhelm the reader with excessive detail.

As always I encourage an interested party to E-Mail me with any questions that one may have.

Steven P. Shikiar, MD, FACS email