TITLE: PARATHYROID DISEASE
SOURCE: Dept. of Otolaryngology, UTMB, Grand Rounds
DATE: February 12, 1997
RESIDENT PHYSICIAN: John Yoo, M.D.
FACULTY: Luke Tan, M.D.
SERIES EDITOR: Francis B. Quinn, Jr., M.D.

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Physiology

Parathyroid glands help maintain serum calcium and phosphorus homeostasis in conjunction with calcitonin and vitamin D by secreting parathyroid hormone (PTH). PTH is an 84-amino acid chain that is cleaved in the liver to its active form, producing a biologically active N-terminal segment and an inactive C- terminal fragment. Secretion of PTH is stimulated by low levels of ionized calcium and suppressed by high levels of ionized calcium.

PTH protects the body against hypocalcemia through a combination of direct and indirect effects, mediated most likely through an intracellular cAMP mechanism at three sites: kidney, bone, and gut. PTH, with the help of calcitriol and magnesium, stimulates osteolysis and release of calcium and phosphorus from bone into extracellular fluid. PTH increases reabsorption of calcium and magnesium in the kidney. PTH also increases the excretion of phosphorus and bicarbonate in the kidney. The excretion of phosphorus is increased so that it does not bind to ionized calcium and decrease its concentration. The excretion of bicarbonate causes a relative acidosis which results in less protein binding of calcium. PTH indirectly enhances intestinal absorption of calcium by increasing the synthesis of the active form of vitamin D from its inactive form, 25- hydroxyvitamin D in the kidney. All three sites of calcium homeostasis are believed to be dependent on magnesium.

Embryology and Anatomy

There are usually 4 parathyroid glands (two superiorly and two inferiorly) that are oblong in shape, caramel colored that become dark reddish brown on traumatization, 4-6 mm in greatest dimension, and weigh 30-40 mg each. However, some patients may have more than 4 glands, with 6% of the population believed to have 5 glands and 0.5% felt to have 6 glands.

The parathyroid glands are derived from the dorsal endoderm of third and fourth branchial pouches and develop during the fifth week of gestation. The superior glands are from the fourth branchial pouch and descend with the superior pole of the thyroid from the base of the tongue. The inferior parathyroid glands are from the third branchial pouch and descend with the thymus gland, and as a result, has a wider variation in terms of location.

The position of the upper glands is more consistent and usually at the junction of the upper and middle one-third of the thyroid gland at the posterolateral aspect at the cricothyroid junction. Wang found 77% in this location, 22% behind the upper pole of the thyroid, and 1% in the retro-pharyngeal, retro-esophageal areas. Occasionally, an upper parathyroid gland may be intra-thyroidal (1-5%), appearing to be a cold nodule on thyroid scan or eluding discovery during surgical exploration.

Wang's study found that over 98% of normal parathyroid glands are found in the neck and only about 2% migrate into the mediastinum. The lower glands vary in location more so than the upper ones. Forty two percent are found near the inferior pole of the thyroid gland and 39% are found near the thymic tongue. The rest may be found posterior to the esophagus, anterior to the trachea, in the mediastinum, in the tracheoesophageal groove, or at the angle of the jaw.

The position of the parathyroid glands may change as they become diseased. The parathyroid glands are nourished by the superior and inferior parathyroid arteries, both of which usually arise from the inferior thyroid artery, although the superior parathyroid artery may receive some to all supply from the superior thyroid artery. It is important that blood supply in the form of these parathyroid arteries be preserved as the parathyroid glands do not receive nourishment from the adjacent thyroid gland. The inferior thyroid artery must be clamped at the capsule of the thyroid gland in thyroid surgery in order to preserve the blood supply to the parathyroid glands.

Histology

Parathyroid glands are made of predominantly three types of cells. Chief cells are small cells with eosinophilic cytoplasm, clear cells have abundant clear cytoplasm and basal nucleus, and oxyphil cells have abundant brightly eosinophilic cytoplasm with numerous mitochondria. Fat cells make up about 20-30% of the adult gland. It is believed that the chief cells are responsible for production of PTH.

Diagnosis

Hypercalcemia can be due to multiple causes including primary hyperparathyroidism, malignancy, endocrine disorders, granulomatous diseases, lymphomas, drugs, immobilization, acute and chronic renal disease, and benign familial hypocalciuric hypercalcemia. Primary hyperparathyroidism is felt to be the most common cause of hypercalcemia, and will be highlighted in this presentation.

The symptoms of hypercalcemia are denoted by the mnemonic, painful bones, renal stones, abdominal groans, and psychic moans, and indicates the wide systemic effects of hypercalcemia. Neurologic manifestations include irritability, depression, insomnia, lethargy, weakness, headaches, memory loss, confusion, apathy, and coma. Renal findings include polyuria, renal colic, hematuria, azotemia, and hypertension. There may also be musculoskeletal signs and symptoms including bone pain, arthralgias, and proximal weakness. Gastrointestinal manifestations include constipation, anorexia, nausea and vomiting, and heartburn. Hypercalcemia can also affect the cardiovascular system in the way of hypertension and arrythmias. General findings also include weight loss, fatigue, pruritis, and metastatic calcification.

Hyperparathyroidism is being diagnosed more frequently and earlier with the advent of automated serum analyzers for routine chemistry profiles. In fact, over half of the patients with hyperparathyroidism have hypercalcemia as their only manifestation. The classic bony change is osteitis fibrosa cystica as manifested by the radiologic appearance of salt-and-pepper mottling of the skull and subperiosteal resorption of the cortex in the phalanges. Renal manifestations include nephrocalcinosis (in less than 10%) and renal stones, which is the most common metabolic complication of the disease. Patients with hyperparathyroidism have increased likelihood of peptic ulcer disease and pancreatitis. Pseudogout is also more likely with calcium pyrophosphate crystals in joint fluid and chondrocalcinosis.

More acute and severe manifestations of the above findings can present if the calcium rises above 16 mg/dL, especially if it does so rapidly. Also called acute parathyroid poisoning or parathyroid crisis, it requires emergent medical and possible surgical intervention.

In evaluating hyperparathyroidism, the history should include information relating to etiologic associations such as low dose radiation to the head and neck and genetic syndromes such as multiple endocrine neoplasias (MEN). Questions relating to other causes of hypercalcemia should also be made. Physical examination is usually fruitless due to the deep position of the parathyroid glands, with the exception of neck masses in parathyroid carcinoma.

Laboratory tests include serum calcium levels. Calcium exists in ionized and protein-bound fractions roughly in equal portions. Ionized calcium provides more diagnostic information, but if not available, total calcium level adjusted for serum albumin can be used to determine the serum calcium level: Calcium(adjusted)=Calcium(total) - 0.8(albumin-4.0). The normal calcium level should not exceed 10.2-10.5 mg/dL and should be elevated on at least 2, possibly 3 occasions to be considered abnormal. An assay that measures both the N-terminal and C-terminal fragments of PTH has been developed that has a high specificity and can differentiate elevated PTH in hyperparathyroidism and the humoral hypercalcemia of malignancy. Alkaline phosphatase should be measured, and if elevated in the absence of liver disease, suggests bone hunger, and most likely will require calcium and magnesium supplementation in the post-operative period while calcium returns to the skeleton. Serum phosphorus will usually be low, as a result of the action of PTH, unless there is concomitant renal disease. Urinary calcium levels may be helpful in diagnosing benign familial hypocalciuric hypercalcemia.

Parathyroid disorders

The most common cause of hypercalcemia is primary hyperparathyroidism. Primary hyperparathyroidism is caused by the disruption of normal feedback control of calcium and the parathyroid glands. The glands secrete PTH inappropriately and autonomously despite an elevation in ionized serum calcium. Male:female ratio is approximately 1:2-3 and peak incidence occurs in the fifth to eighth decades of life. Primary hyperparathyroidism can be caused by a single adenoma (83%), diffuse parathyroid hyperplasia (14-16%), or parathyroid carcinoma (1-3%).

Adenomas vary in size and shape, dependent in some degree to the location of the adenoma. Those adenomas within the thyroid capsule tend to be flat, adenomas in the superoposterior mediastinum tend to be teardrop-shaped, and they are round near the thymus gland. Adenomas can range from 100 mg to greater than 45 gm. Adenomas are usually smooth, well-encapsulated, and fairly easy to resect. The color of the adenoma is usually beefy red and becomes orange-brown on resection. There are predominantly chief cells. The diagnosis is made at surgery by the presence of a second normal gland by histology.

Primary hyperplasia is less common than adenomas. It causes hypercalcemia by secreting PTH autonomously from all four (or more, if supernumerary) glands in the classic case. The hyperplasia can be due to proliferation of the chief cell or the clear cell. The chief cell hyperplasia is more common than the clear cell form, and it is also associated with the multiple endocrine neoplasia syndromes. Chief cell hyperplasia appears similar to an adenoma microscopically and grossly because both are due to proliferation of the chief cells. The differentiating factor is that there is more than one diseased gland in cases of hyperplasia. As a result, the surgeon must identify one additional normal gland for the diagnosis of adenoma and one additional diseased gland for hyperplasia. Primary hyperplasia can be differentiated intraoperatively from adenoma by the density test. It relies on the fact that normal parathyroid tissue floats in a mannitol solution with a density of 1.049 to 1.069 whereas diseased tissue sinks. Therefore, if both specimens sink, then it is hyperplasia. If the presumed normal tissue floats and the suspected diseased tissue sinks, then the diagnosis is adenoma. Size cannot be used to determine if a gland is normal or abnormal. In about half the cases, one or two of the glands are enlarged, and the rest are just slightly enlarged or even normal in size.

Only about 3% of the cases of hyperparathyroidism are caused by carcinoma. The clinical manifestations of parathyroid carcinoma are similar to those caused by adenomas and hyperplasia, although the clinical manifestations are felt to be more severe in the carcinomas than in the benign parathyroid diseases. The PTH is generally 3-4 times that of normal and serum calcium can be greater than 14mg/dL. The appearance of the surgical bed differs from that found for benign parathyroid disease. The malignant tissue is hard, and there is matting of the surrounding tissue caused by an intense local reaction. Surrounding structures such as the recurrent laryngeal nerve, esophagus, and trachea may be involved with the malignant process. Local recurrence rate is 30%. Regional and distant mets to the lung, liver, and bone occur in 25-30%.

Secondary hyperparathyroidism is caused by an increased production of PTH as a result of decreased levels of calcium due to end-organ resistance to PTH. In most cases, the cause is chronic renal failure, but intestinal malabsorption and lack of vitamin D can also cause secondary hyperparathyroidism. This mechanism will generally result in hyperplasia of every parathyroid gland, and the elevated PTH level will decrease on treatment of the underlying disease process.

Tertiary hyperparathyroidism is caused by autonomous production of PTH by the parathyroid glands from prolonged compensatory stimulation even after the underlying disease process (in secondary hyperparathyroidism) has been corrected, such as in kidney transplantation.

In multiple endocrine neoplasia syndrome (MEN) type I, or Wermer's syndrome, there are parathyroid adenomas (although hyperplasia is less likely), pituitary tumors, and pancreatic tumors. Hyperparathyroidism occurs in greater than 90% of the cases. It is also possible to get carcinoid, ovarian, and thyroid tumors and melanoma. This condition is autosomal dominant with variable expression. Prevalence is 0.02-0.2/1000. Because of the high incidence of persistent hypercalcemia, total parathyroidectomy with autotransplantation into an easily accessible site such as brachioradialis is recommended. Thymectomy is also recommended due to the high incidence of supernumerary glands.

In MEN type II, or Sipple syndrome, there are parathyroid hyperplasia or adenoma, medullary thyroid carcinoma, and pheochromocytoma. Type IIA is limited to these lesions, but type IIB in addition has mucosal neuromas, marfanoid habitus with pectus excavatum, but no hyperparathyroidism. Hyperparathyroidism occurs in 10-40% of the cases.

In pseudohyperparathyroidism or humoral hypercalcemia of malignancy, there is expression of a parathyroid-hormone related protein by the non-parathyroid malignancy. It acts like PTH because of the similar N-terminal segment (active segment) of the protein. Malignancy can also cause hypercalcemia through metastases to bone, most notably prostate, breast, thyroid, lung, and renal carcinoma.

Localization techniques

It is widely agreed that pre-operative localization studies are essential prior to re-operation because of the increased risk of operating in a previously operated field and the likelihood of abnormal gland location. The concept of performing localization studies previous to the first parathyroid surgery, however, is controversial because of the 95% success rate in experienced hands. Proponents for localization prior to every parathyroid surgery argue that since greater than 80% of the cases of hyperparathyroidism are due to adenomas, surgical time and consequently morbidity can be decreased if the adenoma is localized prior to surgery. Contralateral neck dissection would be less likely. There are numerous tests to localize the parathyroid galnds. Among them is the thallium-technetium subtraction scan. Thallium-201 accumulates in thyroid and parathyroid glands. Technetium-99m accumulates in the thyroid gland. The technetium scan is then subtracted from the thallium scan resulting in imaging of the parathyroid glands. Identification of glands is best if the parathyroids are greater than 5-7mm or weigh more than 300-400mg. Problems with the scan may arise if the patient is on thyroid suppresion or have thyroid disease. Sensitivity is 88-95% for adenoma and 56-80% for hyperplasia in patients never operated on. The sensitivity drops to 27-47% in previously operated on patients.

Technetium-99m-sestamibi (methoxy-isobutyl isonitrile) has recently been developed as an alternative to thallium-technetium subtraction scan for localizing the parathyroid glands. Technetium-99m-sestamibi has a different biokinetic handling in parathyroid and thyroid tissues. As a result, this single agent can be used for localization if delayed imaging is performed. The sensitivity of this scan is at least as good as it is for thallium-technetium subtraction scanning, and perhaps better. Technetium-99m-sestamibi may also be a superior substitute to thallium-201 for subtraction scanning with technetium-99m-pertechnetate.

Ultrasonography can evaluate glands greater than 5 mm in size. Adenomas appear homogeneous, solid, and hypoechoic. The thyroid appears hyperechoic. It is not very helpful for the mediastinum because of its problem with bone penetration and cannot locate glands in the retrotracheal or retroesophageal area because of the intervening air-containing structures. It may also confuse the parathyroid glands with lymph nodes. It has a low morbidity and can be combined with ultrasound-guided needle biopsy, but has a heavy reliance on the abilities of the ultrasonographer. Sensitivity in previously unexplored patients is 71-80% and 40% in previously explored patients.

Computerized tomography (CT) can localize glands greater than 1 cm in size and has a sensitivity of 70-80% in un-operated patients. The sensitivity drops to 44-47% in operated patients. It can be used in conjunction with CT-guided needle aspiration. It can be used for searching for mediastinal parathyroid glands. However, it is more expensive than an ultrasound, and cannot differentiate parathyroids intimately associated with the thyroid gland. Intravenous contrast must be used and problems with differentiating lymph nodes from parathyroid glands may limit its usefulness.

Magnetic resonance imaging (MRI) can evaluate glands as small as 5mm, does not require contrast, does not involve radiation, and is good for searching the mediastinum. However, it cannot distinguish thyroid from parathyroid and cannot be combined with a guided needle biopsy. Its sensitivity in non-operated patients is 74-81% and 50-75% in operated patients.

Invasive tests for localization are usually reserved for complicated patients who have had failed explorations. They are time-consuming, expensive, and not without risk. Arteriography uses selective injections of contrast into the superior and inferior thyroid arteries combined with digital subtraction to see glands 4mm in size. Its sensitivity is 91-95%. It has a potential complication of injections into the costocervical trunk and release of contrast into the spinal cord.

Venous catheterization is the only localizing test that gives a functional assessment of the parathyroid glands. Fifteen to 30 samples are taken from the thyroid venous plexus and thymic veins and allows differentiation of adenoma from hyperplasia in 90% of the cases. It also allows evaluation of recurrent or metastatic carcinoma and for evaluating auto-implanted parathyroid tissue in the forearm.

Medical treatment

The manifestations of hyperparathyroidism are usually chronic in nature after a prolonged exposure to increased PTH. Occasionally, however, the patient may experience acute hyperparathyroidism that requires medical management prior to surgical intervention. There is exquisite bone pain and nausea and vomiting, and if serious enough, confusion, delusional behavior, and mental deterioration. Serum calcium rises quickly, sometimes to levels greater than 14mg/dL, with increased BUN and creatinine levels. The initial step is saline-furosemide diuresis is begun with 4-10 L of saline every 24 hours with furosemide 40-80 mg IV given every 4-6 hours. This maneuver expands extracellular fluid volume and will increase glomerular filtration rate and decrease calcium reabsorption, in addition to diluting serum calcium level. Magnesium and potassium levels must be monitored and adjusted if necessary. Mithramycin decreases bone resorption by inhibiting osteoclastic activity. Twenty five micrograms/kg are given IV and repeated in 48 hours if no response. Calcitonin decreases bone resorption and increases urinary excretion of calcium. 2-32 mrc units/kg/day is given IM and lasts for about 2 days. Biphosphates such as disodium etidronate decreases bone resorption. Given 7.5 mg/kg/day for 3-7 days, it is switched to oral phosphates 1-2 gm/day. It is contraindicated with high creatinine and may get CaPO4 precipitation in soft tissues. If above measures are inadequate, then consider dialysis. Estrogens and progestins can be used to treat more chronic states of hypercalcemia. Gallium nitrate can be used to block the effects of elevated PTH in parathyroid carcinoma.

Surgical treatment

Patients with elevated calcium levels 1 mg above the normal limit and those with metabolic complications of hyperparathyroidism should benefit from parathyroid surgery. In addition, most agree that even those patients that are asymptomatic , but have mildly or intermittently elevated serum calcium may also benefit from parathyroid surgery as studies have shown that over time, if the parathyroid pathology is untreated, some form of metabolic complication of hyperparathyroidism will eventually develop. Surgery in the elderly and in poor- risk patients should be at the discretion of the surgeon.

Technique begins with a low cervical incision, retraction of the strap muscles, rotation of the thyroid gland medially, and a search for the inferior thyroid artery and recurrent laryngeal nerve. Dissection is continued superiorly keeping the recurrent laryngeal in full view at all times while looking for the superior parathyroid glands. If not found, then the dissection proceeds inferiorly and sites discussed above must be explored. Also, keep in mind that 1-5% are intrathyroidal. Once diseased parathyroid has been identified and biopsied, a second gland must be located and biopsied. If it is normal, then the diagnosis is adenoma and the surgery is complete. If the second gland is hyperplasia, then there are three options: (1) removal of 3 of the glands, (2) total parathyroidectomy with auto-transplantation into the brachioradialis or sternocleidomastoid, or (3) total parathyroidectomy with cryopreservation of the resected parathyroid tissue for later implantation. It is recommended that total parathyroidectomy with auto-transplantion be performed for those patients with MEN due to high recurrence rate, patients undergoing reoperation for recurrent disease, and patients with renal failure. Proponents of subtotal parathyroidectomy quote a smaller incidence of permanent hypocalcemia post- operatively.

Auto-transplantation is performed by dicing the parathyroid tissue into 1 mm blocks and placing them in their own individual pockets made in the sternocleidomastoid or brachioradialis muscles. Clips can be placed at the implantation sites for later identification. The forearm is more readily accessible for later removal of the parathyroid pieces and is easier for venous sampling to test for viability.

Surgery for parathyroid carcinoma must include removal of the parathyroid gland, ipsilateral thyroid lobe, thymus, skeletonization of the tracheoesophageal groove, excision of the paratracheal lymph nodes. Neck dissection is performed for palpable lymph nodes. XRT has been disappointing in the treatment of parathyroid carcinoma.

In 5% of the cases, parathyroid exploration is unsuccessful. In 2%, this is due to mediastinal location of the parathyroid gland(s). If pre-operative localization was not performed, most recommend a staged procedure for the performance of a sternotomy with the help of cardiothoracic surgery. In instances where a re-operation is necessary, a pre-operative localization test is mandatory.

Complications

About 20-30% of the patients develop temporary hypocalcemia with the nadir being reached at 1-3 days post-op as the calcium returns to bone in patients with hungry bone syndrome. Asymptomatic low levels of calcium act to stimulate the remaining parathyroids, but if the patient develops symptoms of muscular irritability as manifested by Chvostek's or Trousseau's signs, calcium and vitamin D therapy is recommended. Chvostek's sign is twitching of the facial musculature in response to tapping the facial nerve through the skin near the exit at the stylomastoid foramen. Trousseau's sign is carpopedal spasms after applying a blood pressure cuff above the systolic pressure for a few minutes. If the patient manifests symptoms of hypocalcemia despite normal levels of calcium, magnesium supplements may be necessary, as both calcium and magnesium are being returned to the bone at supra-normal rates.

Persistent hypercalcemia may be due to a missed parathyroid gland at an abnormal location, persistent hyperparathyroisim from the residual parathyroids, incorrect pre-op diagnosis (most commonly malignancy), technical problems such as incomplete excision of sufficient amount of hyperplastic glands to effect cure.

Vocal cord paralysis as a result of recurrent laryngeal nerve damage occurs in less than 1% of parathyroid surgery, and can be avoided by careful dissection of the RLN and keeping it in full view during surgery in the area.

Seromas and hematomas can be avoided by using suction drains.

BIBLIOGRAPHY

Harvey, H.: Disorders of the thyroid and parathyroid I. Otolaryngologic Clinics of North America, vol 23, April 1990, pp.175-231, 291-303, 339-357.

Marcus, R.: Hypercalcemia, Endocrine, and Metabolism Clinics of North America, Sept. 1989, W.B.Saunders and Co.

Goretzk, P., et al. Management of primary hyperparathyroidism caused by multiple gland disease. World Journal of Surgery, Vol 15, Nov/Dec 1991, 693- 697.

Basso, L., et al. Parathyroid imaging: use of dual isotope scintigraphy for the localization of adenomas before surgery. Clinical Nuclear Medicine, May 1992, pp.380-383.

Yousem DM. Parathyroid and thyroid imaging. Neuroimaging clinics of North America. 6(2):435-59, 1996.

Petti GH. Parathyroid disease and surgery. In: Head and Neck Surgery- Otolaryngology, edited by Byron J. Bailey. J.B. Lippincott Co., Philadelphia, 1993.

Giron J, et al. Imaging of hyperparathyroidism: US, CT, MRI, and MIBI scintigraphy. European Journal of Radiology. 21(3):167-73, 1996 Feb.

Mitchell BK, Merrell RC, Kinder BK. Localization studies in patients with hyperparathyroidism. Surgical Clinics of North America. 75(3):483-98, 1995 June.

Wang C. Surgical management of parathyroid disorders. In: Otolaryngology- Head and Neck Surgery, edited by Cummings, et al. Mosby Year Book, St. Louis, 1993.

Morioka WT. Trends in primary hyperparathyroidism surgery. Laryngoscope 102, April 1992, pp. 422-425.

O’Doherty MF and Coakley AF. Parathyroid imaging. In: Nuclear Medicine in Clinical Diagnosis and Treatment, edited by Murray IPC and Ell PJ. Churchill Livingstone, Edinburgh, 1994.

Tenta LT, Seligman I, Keyes GR. The logic of parathyroid surgery and the viscerovertebral angle. SIPAC. American Academy of Otolaryngology-Head and neck Surgery, 1987.

Andreoli TE, Carpenter CJ, Plum F, Smith LH. The parathyroid glands, hypercalcemia, and hypocalcemia. In: Cecil's Essentials of Medicine, second edition. W.B. Saunders and Co., Philadelphia, 1990.