----------------------------------------------------------------------------- TITLE: PARATHYROID DISEASE SOURCE: Dept. of Otolaryngology, UTMB, Grand Rounds DATE: May 26, 1993 RESIDENT PHYSICIAN: Denise Guendert, M.D. FACULTY: John Kinsella, M.D. DATABASE ADMINISTRATOR: Melinda McCracken, M.S. ----------------------------------------------------------------------------- "This material was prepared by resident physicians in partial fulfillment of educational requirements established for the Postgraduate Training Program of the UTMB Department of Otolaryngology/Head and Neck Surgery and was not intended for clinical use in its present form. It was prepared for the purpose of stimulating group discussion in a conference setting. No warranties, either express or implied, are made with respect to its accuracy, completeness, or timeliness. The material does not necessarily reflect the current or past opinions of members of the UTMB faculty and should not be used for purposes of diagnosis or treatment without consulting appropriate literature sources and informed professional opinion." I. Anatomy, Embryology, and Histology - Usually 4 glands that are 4-6 mm in greatest diameter, are oblong in shape, caramel colored, and weigh 30-40 mg. - ~5.9% have 5 glands and ~0.4% have 6 glands. Supernumerary glands frequently associated with the thymus. - Parathyroid glands develop during the fifth week of gestation. - Histologically see chief cells which are small cells with eosinophilic cytoplasm, clear cells which are cells with abundant clear cytoplasm and basal nucleus, and oxyphil cells which have abundant brightly eosinophilic cytoplasm with numerous mitochondria. Fat cells make up ~ 20-30% of the adult gland. A. Upper Parathyroid Glands -Formed from the dorsal endoderm of the forth branchial pouch, they then descend with the superior pole of the thyroid from the base of tongue. -Final position fairly consistent at the junction of the upper and middle one-third of the thyroid at the posterolateral aspect at cricothyroid junction. It is usually near the crossing of the middle thyroid artery and recurrent laryngeal nerve behind Berry's ligament. Wang found 77% here, 22% behind upper pole and 1% retroesophageal. -Blood supply is from both the inferior and the superior thyroid artery. -Ectopic glands reported in 15-20%, these may be in posterior mediastinum. -Occasionally the upper glands are embedded in the thyroid (1-10%), and may appear as a cold thyroid nodule. B. Inferior Parathyroid Glands -Arise from the dorsal endoderm of the third branchial pouch and descend caudally with the thymus. -Final location less consistent than upper glands. Usually lie posterolateral to the inferior pole of the thyroid gland at the junction of the inferior thyroid artery and the recurrent laryngeal nerve, anterior to the nerve. -Up to 39% reported to lie lower in the neck within the thymic tongue. 2-10% lie within the mediastinal thymus. ~2% can be found at the carotid bifurcation. May also be found posterior to esophagus or anterior to the trachea. -Blood supply is from the inferior thyroid artery. II. Physiology A. Normal Physiology -Parathyroid glands secrete parathyroid hormone which has the primary responsibility of maintaining serum calcium and phosphorus levels. This is accomplished through stimulation of osteoclastic activity for mobilization of calcium from bone and inhibition of renal excretion of calcium. -The complete regulation of calcium throughout the day is provided by the actions of PTH, calcitonin, & vitamin D(1,25-D). -PTH is synthesized as a large polypeptide with 115 aminoacids (pre-proparathyroid hormone). Before secretion from glands, it is fragmented into 90 aminoacids (proparathyroid hormone) and then 84 aminoacids. After secretion the hormone is further fragmented into two segments one of which is biologically active (N-terminal segment) and one which is inactive (C-terminal segment). -PTH acts on the gut indirectly through vitamin D to increase calcium reabsorption from the intestines. -Vitamin D3 is produced in the epidermis under the influence of ultraviolet B sunlight this is also known as cholecalciferol. This in turn is converted to calcidiol by hydroxylation in the liver. Finally, PTH stimulates the kidney to synthesize 1,25 dihydroxycholicalciferol or calcitriol by hydroxylation. Calcitriol induces the intestinal mucosal cells to synthesize a calcium binding protein which results in increased calcium uptake. -PTH increases renal distal tubular resorption of calcium via the adenylate cyclase system. It also results in excretion of phosphorus in urine by inhibiting proximal tubular absorption. -PTH acts with calcitriol to increase the phagocytic activity of osteoclasts resulting in increased bone turnover and release of calcium and phosphorus. Increased levels of phosphorus then reduce formation of calcitriol. -Calcitonin has no effect on intestinal absorption of calcium but does slow osteoclastic bone resorption and inhibits resorption of calcium from kidney. -Main mode of regulation of PTH secretion is via negative feedback of serum calcium. Also a loop between serum calcium and calcitonin levels (Ca^ and calcitonin^). Calcium also stimulates gastrin which is a secretogogue for calcitonin. -Magnesium is instrumental in release of calcium from bone surfaces and is involved in the conversion of vitamin D3 to calcitriol as well as the synthesis of PTH. III. Parathyroid Disorders A. Hyperparathyroidism 1. Primary Hyperparathyroidism -Disruption of normal feedback control resulting in inappropriately high PTH in regard to serum calcium. -May be caused by a single adenoma (80%), primary hyperplasia (15-20%), or carcinoma (1-3%). There has been an increase in the percentage of hyperplasia in last 25 years. -First recognized as an entity in 1925 by Felix Mandle who removed a large parathyroid tumor from a patient with osteitis fibrosa cystica. -~ 100,000 new cases diagnosed each year in the U.S.. Routine chemistry panels revealing hypercalcemia have resulted in increase in early diagnosis. -Male:female ratio is 1:2-3. Peak incidence is 40-70 years. -Etiologic associations include exposure to head and neck irradiation in childhood, genetic predispositions such as in patients with multiple endocrine neoplasias, and previous treatment with goitrogens such as lithium. Hashimotos thyroiditis is also associated and this is thought to be due to stimulation of glands by increased thyroid stimulating hormone. -Primary hyperparathyroidism is the most common cause of elevated calcium in patients less than 50. a. Adenoma -Diagnosis is confirmed at surgery by presence of a second normal gland histologically. -Size and shape are variable. Those of upper glands tend to lie within the thyroid capsule and are very flat whereas those of lower glands are ovoid or tear-drop shaped. More commonly seen in inferior glands. -These lesions are well encapsulated, smooth and readily resectable. The gland appears beefy red compared to the normal caramel color. -Histologically chief cells predominate and few fat cells present. -Adenomatous glands may range in size from 100mg to 100gm. b. Primary Hyperplasia -More than one gland producing increased amounts of PTH. -Two types. Chief cell hyperplasia is the most common then clear cell. Chief cell hyperplasia is also associated with MEN1 and MEN 2A. -In the classic form of hyperplasia all four glands are enlarged and hypercellular. -In clear cell hyperplasia glands will be chocolate brown, irregular with pseudopod projections. c. Parathyroid Carcinoma -Gland will be hard, grey or white with a thick capsule and fixed to surrounding tissue. Average weight is 10 gms. -Histologically see increased mitotic figures, large pleomorphic chief cells, vascular invasion, and intralymphatic parathyroid cells. -Local invasion especially of recurrent laryngeal nerve, esophagus, and trachea as well as neck node metastases often seen at presentation. -Local recurrence rate is 28-50%. Metastases are present in 20-28% and occur in liver, lungs, kidneys and pancreas. -Think carcinoma when significant elevation of calcium (>14mg/100ml) and PTH levels are three to four times higher than normal. 2. Secondary Hyperparathyroidism -PTH is elevated in response to end organ resistance to PTH and decreased levels of calcium. -Usually the underlying disease is chronic renal failure. Intestinal malabsorption is also possible as is hypovitaminosis D. -Usually all glands will show chief cell hyperplasia. -Elevated PTH usually subsides when underlying causative factor treated. 3. Tertiary Hyperparathyroidism -PTH is irrepressible or production is autonomous from prolonged compensatory stimulation after appropriate treatment of causative factor in secondary hyperparathyroidism. -Patients will have normal or low calcium levels. B. Parathyroid Cyst -Can be functional and result in hyperparathyroidism though usually is non-functional. -Tends to be the only parathyroid lesion that presents with a palpable neck mass. -Usually associated with the inferior parathyroid glands. -Fine needle aspiration often diagnostic as one will obtain clear or slightly cloudy fluid with elevated PTH levels. -FNA can be therapeutic as well since regression may occur after aspiration. -Recurrences should be treated with tetracycline sclerosis or excision. -Cystadenoma is a form of adenoma that has undergone cystic degeneration. C. Hypoparathyroidism -Most commonly secondary to thyroidectomy, otherwise relatively rare and due to autoimmune destruction of parathyroids. -Have hypocalcemia, hyperphosphatemia and decreased levels of PTH. -Patients have neuromuscular irritability secondary to inadequate calcium for membrane stabilization. Will c/o circumoral and distal extremity paresthesias. Up to 50% will have undefined psychiatric disorder, mental retardation, organic brain syndrome or psychosis. May have extrapyramidal signs secondary to basal ganglia calcification. -On exam patients may have Chvosteks &/or Trousseau's sign. QT interval may be prolonged on EKG. -Treatment is with calcium and vitamin D. IV. Diagnosis of Hyperparathyroidism A. Signs and Symptoms -"Painful bones, renal stones, abdominal groans and psychic moans". -Majority of patients picked up on routine laboratory testing and are asymptomatic, must exclude other reasons for elevated calcium of which there are many. -Patients may complain of fatigue, lethargy, proximal muscle weakness, confusion, polydipsia, polyuria, constipation, arthralgias, and may acquire decreased respiratory capacity and loss of consciousness. -Elderly are at greatest risk for central nervous system effects and commonly present with dementia, psychosis and obtundation. -The classic bone change is that of osteitis fibrosa cystica which was first described by Von Recklinghausen in 1891. Less than 10% will have this. Can be seen on x-rays of hands. -Post-menopausal women suffer more significant bone loss and vertebral fractures may occur. -Nephrocalcinosis occurs in less than 10% of patients. -Hyperparathyroid patients are twice as likely to be hypertensive than non-hyperparathyroid patients and this is likely of renal orgin. -Patients are more likely to have peptic ulcer disease and pancreatitis. -Patients amy acquire a pseudogout syndrome with chondrocalcinosis on x-rays and pyrophosphate crystals in joints. -Hypercalcemic crises may occur usually when calcium >16mg/dl, these patients very likely to be in coma. Emergent medical and surgical treatment indicated. B. Laboratory 1. Calcium -Two forms of calcium in serum, ionized and protein bound. Ionized makes up 50% of total. Of the bound calcium, 80% bound to albumin, 20% to globolin. -Ionized calcium provides greatest diagnostic sensitivity, if not available may use total calcium with correction for serum albumin levels as follows: Ca (adj.)= Ca(total)-0.8 X (albumin-4.0). -86% of hypercalcemic patients in the community have hyperparathyroidism (Christensson), whereas most hospitalized patients with hypercalcemia have malignancy. -Normal total calcium levels should be <10.2-10.5mg/100ml and should be elevated on two occasions to be considered abnormal. 2. Parathyroid Hormone -The first radioimmunoassay of PTH was developed in 1963. It was a multivalent antisera with low sensitivity. -Now use a synthetic fragment of PTH for the immunogen and produce fragment PTH assays. There is a C-terminal, midregion, and N-terminal assay. There are also polyvalent antisera. -N-terminal assays provide measure of biologic activity, but midregion assays have best specificity/sensitivity. -Recently have developed a two-site immunoassay that provides better sensitivity and specificity than others. -Up to ~12% of patients with primary hyperparathyroidism have normal PTH levels, but these patients can be discovered by plotting serum calcium against PTH. 3. Other -Unless renal insufficiency present, phosphorus levels will be decreased. -Creatinine and BUN tend to be elevated. -Alkaline phosphatase may be elevated and is an indication of bone involvement. C. Miscellaneous -Normal parathyroid tissue floats in a mannitol solution (density 1.049-1.069) while diseased tissue sinks. If two glands found and one sinks the other floats think adenoma. -Commonly with an adenoma the other glands will be suppressed and have increased fat content that can be assessed by intracytoplasmic fat stains. D. Localization Techniques -Most agree that localization studies are needed prior to reoperation secondary to the increased risk of complications and the increased likelihood of abnormal gland location, but fewer agree with the use of localization at all times since the success rate for primary cases is as high as 95%. -Problems with localization studies: difficulty discriminating hyperplasia from adenoma and the variability of gland location (ie mediastinum). -Most agree that all patients who are poor operative risks should have localization studies in attempt to decrease length of operation, some say this is reason for studies in all patients. 1. Thallium-Technetium Subtraction Scan -Thallium-201 chloride accumulates in tissue with high blood flow including normal thyroid, salivary glands, normal and abnormal parathyroid, thyroid nodules and thyroid carcinoma. -Technetium-99m accumulates in normal thyroid and salivary glands. -Technetium scan then subtracted from thallium revealing location of parathyroid tissue. -Identification of glands limited to those greater than 5- 7mm or 300-400mg in size. -False positives may result from thyroid disease, hodgkins lymphoma and sarcoid. -Patients who are on thyroid suppression will not have adequate subtraction of technetium. -Sensitivity in patients previously unexplored is 88-95% for adenoma and 56-80% for hyperplasia. Sensitivity drops to 27-47% in previously explored patients. -Increased sensitivity results from wide field scan as this will identify glands in mediastinum. -Working on monoclonal antibody with specific parathyroid uptake for improved sensitivity and specificity. 2. Ultrasound -Use high resolution real-time transducers of 10 or 7.5 MHz. -Can see glands >5mm. -Adenomas appear homogeneous, solid and hypoechoic. Thyroid appears hyperechoic. Parathyroids may be confused with lymph nodes though. -Ultrasound is of little value in the mediastinum and can not locate retroesophageal or retrotracheal glands secondary to inability to penetrate air. -Low morbidity and can be used to guide needle biopsy, it is for this reason that many feel this is the procedure of choice. -Sensitivity in previously unexplored patients is 71-80% this drops to ~40% in previously explored patients. Specificity is up to 95%. -Sensitivity of combined use of Thallium-Technitium scan and ultrasound is 91%. 3. CT Scan -Use of IV contrast important in enhancing thyroid and parathyroid glands as well as defining surrounding structures. Lymph nodes enhance to a similar degree as parathyroids. Can see glands >5mm. -See small enhancing structures surrounded by hypodense areas of fat. -More expensive than ultrasound and cannot differentiate glands intimately associated with thyroid. Good for identifying mediastinal glands. Can also be used to guide FNA. -Sensitivity is 70-80% in non-operated cases and 44-47 in previously operated subjects. Specificity is 89-92%. -Sensitivity increases to 88% when combined with Thallium- Technetium scan. 4. MRI -Can see glands >5mm. -Does not require contrast and good for mediastinum. -Difficult to distinguish thyroid from parathyroid. -Sensitivity in unoperated cases is 74-81%, drops to 50-75% with second surgery. Specificity is 85-95%. -Difficult to use to guide FNA. 5. IV Digital Subtraction Angiography -Subtraction of initial body images from images obtained post contrast. -Resolution substantially higher than other non-invasive methods. -Requires placement of central line and can get a lot of artifact with motion. Also need sophisticated software. -Sensitivity is 85%. 6. Cine Computed Tomography with Three Dimensional Modeling -CT combined with 3D computer reconstruction. -Can see normal parathyroids and very small adenomas(2- 3mm). -Particularly good at visualizing mediastinal glands. -Major disadvantage is need for sophisticated software. 7. Arteriography -Because of potential morbidity, use is confined to patients S/P unsuccessful exploration. -Selective injections of contrast into inferior and superior thyroid arteries combined with digital subtraction. -Can see glands 4mm in size, can also see ectopic glands fairly readily. -Sensitivity is 91-95%. -Potential complications include injections into costocervical trunk resulting in paralysis from contrast entering spinal cord. 8. Venous Catheterization -This is the only localizing study that provides functional assessment. -Samples are from thyroid venous plexus and thymic veins. -Allows differentiation of adenoma from hyperplasia in 90%. -Long, tedious, and invasive procedure requiring collections of 15-30 venous samples. -Good for evaluation of recurrent or metastatic carcinoma and for evaluation of implanted parathyroid tissue in forearm. V. Treatment of Parathyroidism A. Non-surgical Treatment of Hypercalcemia -Often must treat hypercalcemia prior to operation. -Goals are to increase urinary excretion, decrease intake and decrease shift to extracellular space by inhibiting bone resorption. -Expand extracellular fluid volume with isotonic saline as this will increase glomerular filtration rate and decrease reabsorption of calcium as well as dilute serum calcium level. Need to watch magnesium and potassium levels closely. -Loop diuretics such as furosemide will decrease calcium reabsorption. -Mithramycin decreases bone resorption by inhibiting osteoclastic activity. Give 25 micrograms/kg IV then repeat in 48 hours if no response. Calcium levels will go back up if no further treatment given. Complications include hepatotoxicity and thrombocytopenia. -Calcitonin decreases bone resorption and enhances urinary excretion of calcium. Give 2-32 mrc units/kg/day IM. Complications include rashes, N/V. Effect lasts 48 hours. -Biphosphates decrease resorption. Disodium etidronate is an example. Give 7.5mg/kg/day for 3-7 days then switch to oral phosphates 1-2gm/day. High creatinine is a contraindication. May get precipitation of calcium into soft tissues. -Dialysis can be used in patients with renal failure and hypercalcemia. -Estrogens and progestins may be used for more chronic treatment of hypercalcemia. Use 1.25mg of conjugated estrogens/day. Use norethindrone in women when estrogens are contraindicated. B. Interventional Radiologic Techniques -Should be used in patients who are of high surgical risk or patients with hypercalcemic crises. -Neither technique impairs further surgery. 1. Transcatheter ablation by interstitial, intratumoral extravasation of angiographic dye. Can use same catheter as used in diagnostic testing. Study out of UCLA resulted in 24 out of 24 patients responding with reduction of calcium to normal or subnormal levels within 48 hours. Overall cure rate was 65%. 2. Fine needle percutaneous tumor impalement and intratumoral injection of ethanol guided by ultrasound or CT scan. Complications include transient damage to RLN (74%). C. Surgical Management of Hyperparathyroidism 1. Indications -Most recommend surgical treatment for asymptomatic as well as symptomatic unless surgical risk too great as Mayo study on 147 patients with calcium <11mg/dl who were treated conservatively revealed 50% developed some complication of hypercalcemia within 10 years. Patients treated also receive such benefits as improved renal function and improved bone density. -Others recommend more conservative management in asymptomatic, mildly hypercalcemic, elderly patients. -First surgery for hyperparathyroidism performed at Mass. General Hospital in 1926. This patient had 6 operations over 7 years before gland found in mediastinum. 2. Technique -Low cervical incision, retract strap muscles (keep in mind that glands may be right under straps.), rotate thyroid medially, locate inferior thyroid artery and recurrent laryngeal nerve in attempt to locate inferior gland. Continue dissection superiorly preserving all arterial branches that don't enter thyroid parenchyma. Follow RLN into cricothyroid. -If parathyroids not identified after above, dissect downward between trachea and carotid to superior mediastinum, then dissect retroesophageal and dissect out thymus. Also must examine thyroid thoroughly for intrathyroidal parathyroid(1%) as well as thyroid nodules as 10-54% of patients will have thyroid lesion as well and up to 6% may be carcinoma. Palpable thyroid nodules should be resected and sent for frozen section. -Also important to inspect within carotid sheath to level of bifurcation. -If abnormal parathyroid not identified even after above, midline sternotomy may be necessary though most recommend not performing this during initial surgery unless calcium >14mg/dl. -Limited midline sternotomy to level of second or third intercostal space is an option during first surgery. -If abnormal gland identified, second gland should be located, biopsied, if second gland normal, surgery may be concluded. Some perform cursory exploration on contralateral side as they feel risk of asymmetric hyperplasia high and morbidity of contralateral exploration low in experienced hands. -Two options for treatment of hyperplasia, subtotal parathyroidectomy (three and one-half to three and three- fourths glands removed) verses total parathyroidectomy and reimplantation. Strong indications for total are patients with multiple endocrine neoplasias secondary to high incidence of recurrence, patients undergoing reoperation for recurrent disease, and patients with secondary hyperplasia refractory to treatment of underlying disease. -Proponents of subtotal parathyroidectomy quote less incidence of hypocalcemia post-op. -Following total parathyroidectomy, autotransplantation can be performed by cutting parathyroid tissue into 12-15 1mm pieces and embedding into sternocleidomastoid muscle or brachioradialis. Proponents of the latter report on easy access for venous sampling and removal in case of recurrent disease. -Prior to terminating parathyroid surgery, all remaining glands should be assessed for viability and those that are discolored should be removed, sliced and reimplanted into arm or SCM. -Many recommend removal of thymus when hyperplasia present secondary to 15% incidence of supernumerary glands. -Surgery for carcinoma should include removal of ipsilateral thyroid lobe, thymus and ipsilateral regional nodes with MRND if any nodes positive. These patients need to have calcium checked every three months in addition to baseline CXR, thallium-Technetium scan post- op and ~ every 4-6 months. -Pyrtek(1988) recommends lateral approach to parathyroid exploration under local anesthesia following localization studies in elderly patients or patients with increased risk of general anesthesia. -Parathyroid tissue removed at time of surgery should be cryopreserved for possible reimplantation at later time. 3. Reoperation -Thompson(1982) had a 4% incidence of unsuccessful exploration. 1.8% of these were due to mediastinal adenomas. -Clark recommends the following prior to reoperation: Ultrasound with FNA and PTH assay followed by Thallium-Technetium scan followed by MRI or CT scan. When the above non-invasive tests are non-contributary he recommends selective venous catheterization for PTH. When there is a two-fold or higher elevation in PTH, test is positive. 4. Complications a.Hypocalcemia -20-30% will have temporary hypocalcemia with lowest levels 1-3 days post-op many of these cases are due to "hungry bone syndrome". 4-14% will have persistent hypocalcemia with higher figure seen at hospitals performing less than 10 parathyroid surgeries/year. -Treatment is with calcium gluconate 2-4 grams in saline q 6 hours over 45 min.. When calcium within normal range may change to oral calcium 8-16gms./day and 0.2mg dihydrotachysterol or .25 micrograms of calcitriol/day with 50,000 units vit. D2 per day. b.Persistent hypercalcemia -6-15% of cases. -Cause of persistent hypercalcemia with experienced parathyroid surgeons is usually incorrect pre-op diagnosis, commonly malignancy. c. Recurrent laryngeal nerve injury d. Hematoma VI. Related Problems A. Familial Benign Hypercalcemia -Asymptomatic, non-progressive hypercalcemia early in life (<40 years). -Autosomal dominant inheritance. -Also have variable hypophosphatemia, mild hypermagnesemia, normal to minimally elevated PTH, low urinary excretion of calcium relative to serum calcium. -These patients have an abnormal calcium receptor mechanism for regulation of PTH secretion. -This is the diagnosis in ~9% of patients referred following unsuccessful parathyroid surgery. -Treatment: attempts to decrease serum calcium medically are uniformly ineffective. Surgical treatment with excision of parathyroids only indicated in symptomatic patients. B. Humeral Hypercalcemia of Malignancy -Also called pseudohyperparathyroidism. -The primary source of extracellular calcium is enhanced bone resorption followed by increased renal resorption. -These patients have secretion of parathyroid hormone related protein (PTHrP) from non-parathyroid neoplasms. The amino-terminal end of the protein is very similar to that of PTH. -Hypercalcemia of malignancy may also occur secondary to metastases to bone. This seen with prostate, thyroid, breast, lung, and renal carcinoma. C. Multiple Endocrine Neoplasia syndrome (MEN) type I (Wermer's Syndrome) -Pathological hyperfunction in at least two of the following: Parathyroid, pancreas, pituitary. -Prevalence is 0.02-0.2/1000. -Autosomal dominant in the familial form with variable expression. Gene for MENI mapped to chromosome 11. -Can also develop thyroid tumors, adrenocortical tumors, lipomas, and bronchial or intestinal carcinoids. -Hyperparathyroidism present in 90-97%, and is often the presenting problem. -Hyperparathyroidism is usually secondary to chief cell hyperplasia. -High incidence of persistent hypercalcemia post-op and total parathyroidectomy with autotransplantation indicated. Glands should be implanted into arm secondary to the high incidence of hyperfunction and possible need for removal. -Thymectomy should also be performed secondary to the high incidence of supernumerary glands. -Screen first degree relatives every 5 years after ten years of age with serum calcium levels. D. Multiple endocrine neoplasia syndrome (MEN) type IIA -Medullary thyroid carcinoma, pheochromocytoma, primary hyperparathyroidism. -Hyperparathyroidism occurs in 10-40%. -Locus is on chromosome 10. -In suspected patients who have normal calcium and PTH levels, infuse with calcium gluconate and repeat PTH levels. Patients with MENIIA will not suppress PTH levels. This finding usually predates onset of hypercalcemia. -All patients undergoing thyroidectomy for medullary carcinoma should have parathyroid glands identified and biopsied as indicated. E. Multiple endocrine neoplasia syndrome (MEN) type IIB -Marfanoid body habitus, medullary thyroid carcinoma, pheochromocytoma, ganglioneuromatosis and parathyroid hyperplasia. -Those with hyperplasia usually normocalcemic indefinitely and intervention not required. ------------------------------------------------------------------------------- BIBLIOGRAPHY 1. Basso, L., etal: Parathyroid Imaging: Use of Dual Isotope Scintigraphy for the Localization of Adenomas Before Surgery, Clinical Nuclear Medicine, May 1992, pg. 380-383 2. Blue, P., etal: Parathyroid Subtraction Imaging, Pitfalls in Diagnosis, Nuclear Medicine Atlas, January 1989 3. Coolens, J.L., DeRoo, M.J.K.: Mediastinal Parathyroid Localization: Possible Pitfall in Technetium-Thallium Subtraction Scintigraphy, European Journal of Nuclear Medicine, Vol. 13, May 1987, pg. 283-284 4. Cummings, etal: Otolaryngology-Head and Neck Surgery, Second edition, Mosby Year Book, pg. 2403-2413 and 2456-2470 5. 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Shepherd, J.: The Natural History of Multiple Endocrine Neoplasia Type 1, Archives of Surgery, Vol 126, August 1991, pg 935-952 19. Strichartz, S., Giuliano, A.: The Operative Management of Coexisting Thyroid and Parathyroid Disease, Archives of Surgery, Vol 125, Oct. 1990, pg 1327-1330 20. Tonner and Schlechte: Neurologic Complications of Thyroid and Parathyroid Disease, Medical Clinics of North America, Vol. 77, Jan. 1993, pg 258-261 -----------------------------END----------------------------------------------