REFERENCES 1. Greenspan FS: The Thyroid Gland. Basic and Clinical Endocrinology. Lange Medical Books/McGraw-Hill.2004 2.

Guyton and Hall. Textbook of Medical Physiology. 11th Edition. Elseviers Saunders. 2006. 3. Seidel. Basic Concepts in Physiology. A students survival guide. Mc

Graw-Hill. 2002. 4. Adam and Victors. Principles of Neurology, seventh ed , Mc-Graw Hill, 2001 5. Lewis P Rowland. Merritts Neurology eleven edition, Lippincott Williams & Wilkins 2005; 927, 1041-43

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ANATOMY AND HISTOLOGY OF THE PARATHYROID GLAND The parathyroids are 4 small glands - 3 x 6 mm with a total weight of about 0.4 g. They are located behind the thyroid gland, one at each end of the upper and lower poles, usually in the capsule that covers the lobes of the thyroid. Sometimes they are embedded in the thyroid gland. The parathyroid glands are derived from the pharyngeal pouches the superior glands from the 4th pouch and the inferior glands from the 3rd pouch. They can also be found in the mediastinum, lying beside the thymus, which originates from the same pharyngeal pouches. Each parathyroid gland is contained within a connective tissue capsule. These capsules send septa into the glands, where they merge with the reticular fibers that support elongated cordlike clusters of secretory cells. The endocrine cells of the parathyroid are arranged in cords. There are 2 types of cells: the chief, or principal, cells and the oxyphil cells.

The chief cells are small polygonal cells with a vesicular nucleus and a pale staining, slightly acidophilic cytoplasm. Electron microscopy shows irregularly shaped granules (200-400 nm in diameter) in their cytoplasm. They are the secretory granules containing parathyroid hormone, which is a polypeptide in its active form. Oxyphil cells constitute a smaller population. They are larger polygonal cells, and their cytoplasm contains many acidophilic mitochondria with abundant cristae. The function of the oxyphil cells is not known.

With increasing age, secretory cells are replaced with adipocytes. Adipose cells constitute more than 50 % of the gland in older people.

STRUCTURE OF PARATHYROID HORMONE (PTH) PTH is a polypeptide hormone, consists of 84 amino acids and secreted by parathyroid gland.

Structure of PTH: PTH1-34 (region 1-34) has full biologic activity region 25-34 is primarily responsible for receptor binding

Structure of pre- pro-parathyroid hormone

SYNTHESIS, REGULATORY MECHANISM AND SECRETION OF PTH Pre pro-PTH (115 amino acids) pro-PTH (90 amino acids) PTH The biosynthesis and secretion of PTH is regulated by the plasma Ca2 concentration: a. Acute Ca2+ plasma concentration PTH mRNA rate of PTH synthesis and secretion. PTH exists in storage vesicles, however most of the pro-PTH (80-90 %) synthesized is quickly degraded before it enters the storage vesicle, especially when Ca2+ in the parathyroid cells are high. PTH is secreted when Ca2+ in the parathyroid cells is low. Cathepsin B (a proteolytic enzyme) cleaves PTH into 2 fragments: PTH and PTH 37-84. PTH
37-84 1-36

is not further degraded, however PTH

1-36

is rapidly and

progressively cleaved into dipeptides and tripeptides. Most of the proteolysis of PTH occurs within the gland, but once PTH is secreted, is degraded in other tissue especially the liver by similar mechanism b. Ca2+ plasma concentration blocks production of PTH

Factors that contribute to the calcium metabolism: Calcitonin: tends to decrease plasma calcium concentration and in general has effects opposite to those of PTH. intestinal absorption: increased if blood calcium level is decreased, regulated by PTH and vitamin D. Vitamin D: promote intestinal calcium absorption, decreases renal calcium excretion and bone absorption leading to increased blood calcium level. protein binding for vitamin D: no information from Guyton or Seidel, please seek in the Biochemistry Textbook. 3

PTH plays a major role in regulating the activation of vitamine D: High PTH stimulates the production of 1,25 dihydroxycholecalciferol (the active form of vit. D = calcitriol) by the kidney, which in turn enhance the transfer of intestinal Ca2+ to the blood. Low PTH induces formation of inactive 24,25 dihydroxycholecalciferol {24,25(OH)2D}. In bone, PTH and calcitriol act synergistically to promote bone resorption. In the kidney, PTH and calcitriol inhibit calcium excretion by stimulating calcium reabsorption in the distal renal tubules.

Dietary sources: low or high calcium diet will initially influence blood calcium level, however various factors involving in calcium metabolism (first line, and second line of defense) will take part to cope with that problem.

THE VARIOUS PARATHYROID DISORDERS, THE CAUSES OF HYPOPARATHYROISISM a. Hypoparathyroidism Surgical Idiopathic Neonatal Familial

Deposition of metals (Fe, Cu andAl) Postradiation Infiltrative Functional (in hypomagnesemia)

b. Resistance to PTH action Pseudohypoparathyroidism c. Primary hyperparathyroidism Sporadic Associated with MEN 1 or MEN 2A d. Variant forms of hyperparathyroidism Familial benign hypocalciuric hypercalcemia Lithium therapy Tertiaty hyperparathyroidism in chronic renal failure Familial After renal transplantation

HE CLINICAL PICTURE AND LAB FINDING IN HYPOPARATHYROIDISM

The signs and symptoms are those of chronic hypocalcemia. Biochemically, the hallmarks of hypoparathyroidism are hypocalcemia, hyperphosphatemia (because the phosphaturic effect of PTH is lost), and an inappropriately low or undetectable PTH level.

CLINICAL FEATURES Most of the symptoms and signs of hypocalcemia occur because of increase neuromuscular excitability (tetany, paresthesias, seizures, organic brain

syndrome) or because of deposition of calcium in soft tissues (cataract, calcification of basal ganglia). A. Neuromuscular manifestation Clinically, the hallmark of severe hypocalcemia is tetany. Tetany is a state of spontaneous tonic muscular contraction. Overt tetany is often heralded by tingling paresthesias in the fingers and about the mouth, but the classic muscular component of tetany is carpopedal spasm. This begins with dduction of the thumb, followed by flexion of the metacarpophalangeal joints, extension of the interphalangeal joints, and flexion of the wrists to produce the main dacconcheur posture. These involuntary muscle contractions are painful. Although the hands are most typically involved, tetany can involve other muscle groups, including life-

threatening spasm of laryngeal musdes. Electromyographically, tetany is typified by repetitive motor neuron action potentials, usually grouped as doublets. Tetany is not specific for hypocalcemia. It also occurs with hypomagnesemia and metabolic alkalosis, and the most common cause of tetany is respiratory alkalosis from hyperventilation. Lesser degrees of neuromuscular excitability (eg, serum calcium 7 9 mg/clL) produce latent tetany, which can be elicited by testing for Chvosteks and Trousseaus signs. Chvosteks sign is elicited by rapping the facial nerve about 2 cm anterior to the earlobe, just below the zygoma. The response is a contraction of facial muscles ranging from twitching of the angle of the mouth to hemifacial contractions. The specificity of the test is low; about 25% of normal individuals have a mild Chvostek sign. Trousseaus sign is elicited by inflating a blood pressure cuff to about 20 mm Hg above systolic pressure for 3 minutes. A positive response is carpal spasm. Trousseaus sign is more specific than Chvosteks, but 14% of normals have positive Trousseau signs. Hypocalcemia predisposes to focal or generalized seizures. Other central nervous system effects of hypocalcemia include pseudtumor cerebri,

papilledema, confusion, lassitude, and organic brain syndrome. Twenty percent of children with chronic hypocalcemia develop mental retardation. The basal ganglia are often calcified in patients with long-standing hypoparathyroidism or pseudohypoparathyroidism. This is usually asymptomatic but can produce a variety of movement disorders. B. Other manifestation of hypocalcemia 1. Cardiac effectsRepolarization is delayed, with prolongation of the QT interval. Excitation-contraction coupling may be impaired, and refractory congestive heart failure is sometimes observed, particularly in patients with underlying cardiac disease. 2. Ophthalmologic effectsSubcapsular cataract is common in chronic

hypocalcemia, and its severity is correlated with the duration and level of hypocalcemia.

3. Dermatologic effectsThe skin is often dry and flaky and the nails brittle. A dermatitis known as impetigo herpetiformis or pustular psoriasis is peculiar to hypocalcemia. B. LABORATORY FINDINGS Serum calcium is low, serum phosphate high, urinary calcium low, and alkaline phosphatase normal. Parathyroid hormone levels are low. Serum magnesium should be determined since hypomagnesemia frequently accompanies

hypocalcemia and may exacerbate symptoms and decrease parathyroid function. C. IMAGING Radiographs or CT scans of the skull may show basal ganglia calcifications; the bones may be denser than normal. Cutaneous calcification may occur. D. OTHER EXAMINATIONS Slit-lamp examination may show early posterior lenticular cataract formation. The ECG shows prolonged QT intervals and T wave abnormalities.

THE PRINCIPLES OF MANAGEMENT OF HYPO- AND HYPERCALCEMIA TREATMENT OF HYPOCALCEMIA a. Acute Hypocalcemia Patients with tetany should receive intravenous calcium as calcium chloride (272 mg calcium per 10 mL), calcium gluconate (90 mg calcium per 10 mL), or calcium gluceptate (90 mg calcium per 10 mL). Approximately 200 mg of elemental calcium can be given over several minutes. The patient must be observed for stridor and the airway secured if necessary. Oral calcium and a rapidly acting preparation of vitamin D should be started. If necessary, calcium can be infused in doses of 4001000 mg/24 h until oral therapy has taken effect. Intravenous calcium is irritating to the veins. Caution must be exercised in patients taking digitalis, since they are predisposed to toxicity by infusion of calcium.

B. Chronic Hypocalcemia The objective of chronic therapy is to keep the patient free of symptoms and to maintain a serum calcium of approximately 8.5 9.2 mgIdL. With lower serum calcium levels, the patient may not only experience symptoms but may be predisposed over time to cataracts. With serum calcium concentrations in the upper normal range, there may be marked hypercalciuria, which occurs because the hypocalciuric effect of PTH has been lost. This may predispose to nephrolithiasis, nephrocalcinosis, and chronic renal insufficiency. In addition, the patient with a borderline elevated calcium is at increased risk of overshooting the therapeutic goal, with symptomatic hypercalcemia. The mainstays of treatment are calcium and vitamin D. Oral calcium can be given in a dose of 1.53 g of elemental calcium per day. These large doses of calcium reduce the necessary dose of vitamin D and allow for rapid normalization of calcium if vitamin D intoxication subsequently occurs. Numerous preparations of Calcium are available. A short-acting preparation of vittamin D (calcitriol) and the very long-acting preparations such as vitamin D2 (ergocalciferol) are available. By far the most inexpensive regimens are those that use ergocalciferol. In addition to economy, they have the advantage of rather easy maintenance in most patients. The disadvantage is that ergocalciferol can slowly accumulate and produce delayed and prolonged vitamin D intoxication. Caution must be exercised in the introduction of other drugs that influence calcium metabolism. For example, thiazide diuretics have a hypocalciuric effect. By reducing urinary calcium excretion in treated patients, whose other adaptive mechanisms, PTH and 1,25(OH)2D3, are n000perative and who are thus absolutely dependent on renal excretion of calcium to maintain the serum calcium level, thiazides may produce severe hypercalcemia. In a similar way, intercurrent illnesses that compromise renal function may produce dangerous hypercalcemia in the patient who is maintained on large doses of vitamin D. Short-acting preparations are less prone to some of these effects but may require more frequent titration and are much more expensive than vitamin D2.

CAUSES OF HYPERCALCEMIA. 1. Primary hyperparathyroidism Sporadic Associated with MEN 1 or MEN 2A Familial After renal transplantation 2. Variant forms of hyperparathyroidism Familial benign hypocalciuric hypercalcemia Lithium therapy Tertiaty hyperparathyroidism in chronic renal failure 3. Malignancies o Humoral hypercalcemia of malignancy o Caused by PTHrP (solid tumors, adult T cell leukemia syndrome) o Caused by 1,25(OH) (lymphomas) o Caused by ectopic secretion of PTH (rare) o Local osteolytic hypercalcemia (multiple myeloma, leukemia, lymphoma) 4. Sarcoidosis or other granulomatous diseases 5. Endocrinopathies Thyrotoxicosis Adrenal insufficiency Pheochromocytoma VIPoma 6. Drug-induced Vitamin A intoxication Vitamin D intoxication Thiazide diuretics Lithium Milk-alkali syndrome Estrogens, androgens, tamoxifen (in breast carcinoma) 7. Immobilization 8. Acute renal failure 9. Idiopathic hypercalcemia of infancy 10. ICU hypercalcemia 11. Serum protein disorders

Clinical Features A number of symptoms and signs accompany the hypercalcemic state: central nervous system effects such as lethargy, depression, psychosis, ataxia, stupor, and coma; neuromuscular effects such as weakness, proximal myopathy, and hypertonia; cardiovascular effects such as hypertension, bradycardia (and eventually asystole), and a shortened QT interval; renal effects such as stones, decreased glomerular filtration, polyuria, hyperchloremic acidosis, and

nephrocalcinosis; gastrointestinal effects such as nausea, vomiting, constipation, and anorexia; eye findings such as band keratopathy; and systemic metastatic calcification. This constellation of clinical findings has led to the mnemonic for recalling the signs and symptoms of hypercalcemia: stones, bones, abdo minal groans, and psychic moans

Symptoms and signs The typical clinical presentation of primary hyperparathyroidism has evolved considerably over the past two decades. As the disease is detected increasingly by multiphasic screening that includes determination of serum calcium levels, there has been a marked reduction in the frequency of the classic signs and symptoms of primary hyperpararthyroidism, renal disease-renal stones, decreased renal function, and occasionally nephrocalcinosis, and the classic

hyperparathyroid bone disease osteitis fibrosa cystica. In fact, about 85% of patients presenting today have neither bony nor renal manifestations of hyperparathyroidism and are regarded as asymptomatic or minimally symptomatic. At the same time, we have begun to recognize more subtle manifestations of hyperparathyroidism in some patients. This has presented a number of questions about the role of parathyroid surgery in primary hyperparathyroidism.

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1. Hyperparathyroid bone disease. The classic bone disease of hyperparathyroidism is osteitis fibrosa cystica. Formerly common, this disorder now occurs in less than 10% of patients. Clinically, osteitis fibrosa cystica causes bone pain and sometimes pathologic fractures. The most common laboratory finding is an elevation of the alkaline phosphatase level, reflecting high bone turnover. Histologically, there is an increase in the number of bone-resorbing osteoclasts, marrow fibrosis, and cystic lesions that may contain fibrous tissue (brown tumors) or cyst fluid. The most sensitive and specific radiologic finding of osteitis fibrosa cystica is subperiosteal resorption of cortical bone, best seen in high-resolution films of the phalanges. A similar process in the skull leads to a salt-and-pepper appearance. Bone cysts or brown tumors may be evident as osteolytic lesions. Dental films may disclose loss of the lamina dura of the teeth, but this is a nonspecific finding also seen in periodontal disease.

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The other important consequence of hyperparathyroidism is osteoporosis. Unlike other osteoporotic disorders, hyperparathyroidism typically results in predominant loss of cortical bone. In general, both the mass and the mechanical strength of trabecular bone are relatively well maintained. Patients who are followed medically for mild primary hyperparathyroidism often do not experience progressive bone loss even when they are osteoporotic at diagnosis. This may be due to the fact that PTH under certain circumstances has anabolic effects on the skeleton to increase bone mass. Although osteoporosis is generally considered to be an indication for surgical treatment of primary hyperparathyroidism, its impact on morbidity is hard to assess .

2. Hyperparathyroid kidney disease. Once common in primary hyperparathyroidism, kidney stones now occur in less than 15% of cases. These are usually calcium oxalate stones. From the perspective of a stone clinic, only about 7% of calcium stone formers will prove to have primary hyperparathyroidism. They are difficult to manage medically, and stones constitute one of the agreed indications for parathyroidectomy. Clinically evident nephrocalcinosis rarely occurs, but a gradual loss of renal function is not uncommon. Renal function is stabilized after a successful parathyroidectomy, and otherwise unexplained renal insufficiency in the setting of primary

hyperparathyroidism is also considered to be an indication for surgery because of the risk of progression. Chronic hypercalcemia can also compromise the renal concentrating ability, giving rise to polydipsia and polyuria.

3. Nonspecific features of primary hyperparathyroidism. Although stupor and coma occur in severe hypercalcemia, the degree to which milder impairments of central nervous system function affect the typical patient with primary hyperparathyroidism is unclear. Lethargy, fatigue, depression, difficulty in concentrating, and personality changes occur and in some patients appear to benefit from parathyroidectomy. Frank psychosis will also respond to surgery on occasion. Muscle weakness with characteristic electromyographic 12

changes is also seen, and there is good evidence from controlled clinical trials that surgery can improve muscle strength. It was formerly thought that the incidence of hypertension was increased in primary hyperparathyroidism, but more recent evidence suggests that the appreciable incidence in this patient group is probably no greater than in age-matched controls, and parathyroidectomy appears to be of no benefit. Dyspepsia, nausea, and constipation all occur, probably as a consequence of hypercalcemia, but there is probably no increase in the incidence of peptic ulcer disease. The articular manifestations of primary

hyperparathyroidism are several. Chondrocalcinosis occurs in up to 5% of patients, but acute attacks of pseudogout are less frequent.

Lab Findings Hypercalcemia is virtually universal in primary hyperpararhyroidism, though the serum calcium sometimes fluctuates into the upper normal range. In patients with subde hyperpararhyroidism, repeated serum calcium measurements over a period of time may be required to establish the pattern of intermittent hypercalcemia. Both total and ionized calcium are elevated, and in most clinical instances there is no advantage to measuring the ionized calcium level. Patients with normocalcemic primary hyperparathyroidism, in whom the possibility of subtle forms of vitamin D deficiency has been eliminated, are being recognized more frequently. In patients with primary hyperparathyroidism, the serum phosphorus level is low-normal (< 3.5 mg/dL) or low (< 2.5 mg/dL) because of the phosphaturic effect of PTH. A mild hyperchloremic metabolic acidosis may be manifest as hyperchloremia.

Diagnosis The diagnosis of primary hyperparathyroidism in a hypercalcemic patient can be made by determining the intact PTH level with a two-site assay. An elevated or even upper-normal level of PTH is clearly inappropriate in a hypercalcemic patient and establishes the diagnosis of hyperparathyroidism (or one of its variants familial benign hypercalciuric hypercalcemia or lithium-induced hypercalcemia). The reliability of the two-site intact PTH assay allows the diagnosis of primary 13

hyperparathyroidism to be definitive. In a patient with a high PTH level, there is no need to screen for metastatic malignancy, sarcoidosis, etc. Determinations of renal function and a plain abdominal radiograph for renal stones are often obtained for prognostic reasons. A determination of urinary calcium concentration and urinary creatinine excretion should be obtained to exclude familial benign hypocalciuric hypercalcemia.

Treatment of hypercalcemia Initial management of hypercalcemia consists of assessing the hydration state of the patient and rehydrating as necessary with saline. The first goal is to restore renal function, which is often impaired in hypercalcemia because of reduced glomerular filtration and dehydration. Hypercalcemia impairs the urinary concentrating ability, leading to polyuria, and at the same time impairs the sensorium, diminishing the sense of thirst. Once renal function is restored, renal excretion of calcium can be further enhanced by inducing a saline diuresis. Because most of the filtered calcium is reabsorbed by bulk flow in the proximal tubule along with sodium chloride, a saline diuresis will markedly increase calcium excretion. However, a vigorous saline diuresis will also induce substantial urinary losses of potassium and magnesium, and these must be monitored and replaced as necessary. After these initial steps, attention should be given to finding a suitable chronic therapy. It is important to start chronic therapy soon after hospitalization, as several of the most useful agents take up to 5 days to have their full effect. Intravenous bisphosphonates (pamidronate or zoledronic acid) are the first choice for most patients. Bisphosphonates act by inhibiting osteoclastic bone resorption. The initial dose of pamidronate is 6090 mg by intravenous infusion over 4 hours, and the dose of zoledronic acid is 4 mg infused over 15 minutes. In two large trials, 88% and 70% of patients with malignancy-associated hypercalcemia normalized their serum calcium values after infusions of zoledronic acid (4 mg) and pamidronate (90 mg), respectively. Zoledronic acid produced a longer duration of response32 days versus 18 days for pamidronate. The nadir of

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serum calcium does not occur until 4-5 days after administration of either agent. Re-treatment with either agent can be conducted after recurrence of

hypercalcemia. Transient fever and myalgia occur in 20% of patients who undergo intraveilous bisphosphonare therapy. Increased serum creatinine (0.5 mg/dL) occurs in about 15% of patients. Intravenous bisphosphonates should be usect cautiously and at reduced doses when the baseline serum creatinine exceeds 2.5 mg/dL. In patients with severe hypercalcemia and those with renal insufficiency that is refractory to rehydration, it may be necessary to use a second antiresorptive agent for a few days while awaiting the full therapeutic effect of bisphosphonates. For this purpose, synthetic salmon calcitonin may be administered at a dose of 4 8 lU/kg subcutaneously every 12 hours. This is a useful adjunct acutely, but most patients become totally refractory to calcitonin within a few days, so it is not suitable for chronic use. The use of an antiresorptive agent together with saline diuresis provides for a twopronged approach to hypercalcemia. Other agents besides bisphosphonates may be considered (eg, plicamycin or gallium nitrate), but their toxicity and lack of superior efficacy tend to discourage their use. Both agents act to inhibit osteodastic bone resorption. Glucocorticoid administration is first-line treatment for hypercalcemia in patients with multiple myeloma, lymphoma, sarcoidosis, or intoxication with vitamin D or vitamin A. Glucocorticoids are also beneficial in some patients with breast carcinoma. However, they are of little use in most other patients with solid tumors and hypercalcemia.

Parathyroidectomy. The surgical strategy depends on the ability of localizing studies such as sestamibi scanning to identify one clearly abnormal gland and the availability of intraoperative PTH determinations to verify that the disease-producing lesion has been removed during surgery. If multiple enlarged glands are suspected, the likely diagnosis is parathyroid hyperplasia or double adenoma. In patients with 15

hyperplasia, the preferred operation is a 3 gland parathyroidectomy, leaving a remnant sufficient to prevent hypocalcemia. Double parathyroid adenomas axe both removed in affected patients. The pathologist is of little help in distinguishing among normal tissue, parathyroid adenoma, and parathyroid hyperplasia: these in essence are surgical diagnoses, based on the size and appearance of the glands. The recurrence rate of hypercalcemia is high in patients who have parathyroid hyperplasia particularly in those with one of the MEN syndromes, because of the inherited propensity for tumor growth. In such cases, the parathyroid remnant can be removed from the neck and implanted in pieces in forearm muscles to allow for easy subsequent removal of some additional parathyroid tissue if hypercalcemia recurs. In competent hands, the cure rate of parathyroid adenoma is over 950/0. The success rate in primary parathyroid hyperplasia is somewhat lower, because of missed glands and recurrent hyperparathyroidism in patients with MEN syndromes. There is a 20% incidence of persistent or recurrent hypercalcemia However, parathyroidectomy is difficult surgery: the normal parathyroid gland weighs only about 40 mg and may be located throughout the neck or upper mediastinum. It is mandatory not only to locate a parathyroid adenorna but also to find the other gland or glands and determine whether they are normal. Complications of surgery include damage to the recurrent laryngeal nerve, which passes close to the posterior thyroid capsule, and inadvertent removal or devitalization of all parathyroid tissue, producing permanent hypoparathyroidism. In skilled hands, the incidence of these complications is less than 1%. It is critical that parathyroid surgery be performed by someone with specialized skill and experience. Localization studies of the parathyroid glands in patients with primary hyperparathyroidism and intraoperative PTH testing are critical components of the contemporary management of patients presenting for initial surgical procedures. If these studies clearly indicate a single abnormal gland and if intraoperative PTH testing is available, surgical management now typically consists of unilateral exploration and limited parathyroidectomy. Localization studies continue to be essential in the management of patients with recurrent or persistent

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hypeparathyroidism. The most successful procedures are Tc-sestamibi scanning, computed tomography, MRI, and ultrasound. Individually, each has a sensitivity of 6080% in experienced hands. Used in combination, they are successful in at least 80% of reoperated cases. Invasive studies, such as angiography and venous sampling, are rarely performed. There is no definitive medical therapy for hyperparathyroidism. In postmenpausal women, estrogen replacement therapy in high doses (1.25 mg of conjugated estrogens or 3050 ig of ethinyl estradiol) will produce an average decrease of 0.51 mgldL in the serum calcium and an increase in bone mineral density. The effect of estrogen treatment is on the bone response to PTH. PTH levels do not fall limited data are available on bisphosphonates and selective estrogen response modulators. Calcimimetic agents that activate the parathyroid calcium-sensing receptor, currently in clinical trials, may offer an alternative to surgery in the future. The relatively asymptomatic state of most patients today presents a dilemma: Which of them should be subjected to surgery? To answer this question definitively, it would be necessary to know more than we presently do about the natural history of untreated primary hyperparathyroidism. However, in

observational studies over as many as 10 years, it is clear that most patients are stable with regard to serum calcium, stone disease, and renal function. Recent data also indicate that osteoporosis, when present, is usually nonprogressive. On the other hand, surgery is usually curative. In experienced hands, surgery has a low morbidity rate. Although parathyroid surgery has a substantial initial cost, over the long term the cost-benefit ratio may be favorable when compared with a lifetime of medical follow-up. Moreover, there is a masked improvement in bone density after surgery, with sustained increases over at least 5 years postoperatively. These changes remain stable over years. Some surgeons also argue that the nonspecific symptoms often present may improve with surgery, but no controlled trial has excluded the placebo effect of surgery as a possible explanation for these results.

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A 1990 NIH Consensus Development Conference considered the issue of surgery in primary hyperparathyroidism and arrived at the following

recommendations: 1. if the serum calcium is markedly elevated (above I 1.4-12 mg/dL [2.83 mmol/L]); 2. if there has been a previous episode of life-threatening hypercalcemia 3. if the creatinine clearance is reduced below 70% of normal; 4. if a kidney scone is present; 5. if the urinary calcium is markedly elevated (>400 mg124 h); 6. if bone mass is substantially reduced (less than 2 SD below normal for age, sex, and race, ie, two Z-scores below normal); or 7. if the patient is young (under 50 years of age, particularly premenopausal women).

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