Primary hyperparathyroidism is a disorder of the parathyroid glands resulting in autonomous parathyroid hormone secretion and presents clinically as hypercalcaemia or the sequela of long-standing hypercalcaemia. Although the aetiology of this condition can be either sporadic or familial, surgical excision of the affected parathyroid glands represents the only curative treatment for primary hyperparathyroidism. In the appropriately selected patient, and in experienced surgical hands, cure rates of 90 to 95 per cent of patients for initial neck explorations can be expected. In these patients undergoing successful parathyroidectomy, abrupt changes in calcium balance can be expected. Because these patients may have impaired calcium homeostasis, special vigilance is warranted by the team responsible for the patient's care.

Primary hyperparathyroidism is an idiopathic disorder due to autonomous function of one or more affected parathyroid glands. Primary hyperparathyroidism is distinct from secondary hyperparathyroidism in that the latter condition represents excessive parathyroid hormone as a consequence of hypocalcaemic stimulus to the parathyroids. Tertiary hyperparathyroidism represents autonomous parathyroid function from long-standing secondary hyperparathyroidism and is usually seen in patients with end-stage renal disease.

The incidence of primary hyperparathyroidism peaks in the sixth decade of life in both men and women at 92 and 188 per 100 000 population, respectively. Data from North America, England, and Europe indicate that the prevalence of primary hyperparathyroidism is nearly 1:1000 with an age-adjusted incidence of 27.7 per 100 000 population. These data indicate that, as the population of developed countries continues to age, primary hyperparathyroidism will continue to be a common endocrinological problem.

Autonomous secretion of parathyroid hormone (PTH) can be the consequence of either idiopathic or genetic influences. The majority of cases of primary hyperparathyroidism (90 per cent) are sporadic cases (i.e., with no familial inheritance). Although a weak association has been made between a history of prior neck irradiation and subsequent development of primary hyperparathyroidism, the vast majority of patients will lack this history of exposure. In most series the female to male ratio is nearly 2:1. Molecular biological techniques have defined that in a given subset of patients, parathyroid adenomas are monoclonal in origin. Moreover, these parathyroid adenomas contain rearrangements of the PTH gene itself. Through unknown mechanisms, this clonal expansion of parathyroid tissue results in an alteration of the set-point between ionized extracellular fluid calcium and PTH release. Sporadic cases of hyperparathyroidism are usually the consequence of a single adenoma. These patients respond well to surgery.

Familial causes of primary hyperparathyroidism are seen in the multiple endocrine neoplasia (MEN) syndromes (types I and IIa), where hyperparathyroidism can be the presenting endocrinopathy. Familial parathyroid adenomas have also been described with other endocrinopathies, but this manifestation is extremely rare. Genetic rearrangements, including the q13 region of chromosome 11, have been described. The majority of cases of hyperparathyroidism in the MEN syndrome are associated with diffuse hyperplasia of all four parathyroid glands. Suspicion of a diagnosis of MEN syndrome is important not only for screening other family members, but also for determining the appropriate strategy for surgical exploration. Because all four parathyroid glands are likely to be hyperplastic, bilateral neck exploration is justified. Moreover, the expectations for postsurgical outcomes are different; parathyroidectomy can control hypercalcaemia in these patients, but rarely cures the condition.

Maintenance of ionized calcium within the extracellular and intracellular fluids is critical to a variety of processes, including membrane polarization, neuromuscular activity, hormone release, and hormone action. In humans, calcium is found in three states in the extracellular fluid. Approximately 47 per cent of calcium is bound to circulating proteins. The major calcium binding protein is albumin, accounting for 70 per cent of protein-binding in serum, with 12 calcium binding sites per molecule. Ten per cent of extracellular calcium is found in complexes with bicarbonate and citrate. The remaining 43 per cent represents free ionized calcium which is the physiologically relevant form of calcium. Calcium in the serum is regulated within a narrow concentration range between 1.14 and 1.30 mmol/l. Because of the importance of albumin as a calcium binding protein, total calcium levels will vary as a function of albumin concentration. As an approximate rule, for every 1 g/dl drop in serum albumin, the total calcium concentration will drop 0.8 mg/dl, and the free ionized calcium will not be affected. This relationship is important in postoperative dilutional states where antidiuretic hormone (ADH) release and intravenous fluid administration can produce a significant dilutional hypoalbuminaemia that does not result in hypocalcaemic symptoms. In contrast, shifts between protein-bound and ionized calcium can be affected acutely by alterations in plasma pH. Under conditions of alkaline pH, a shift in the equilibrium between protein-bound and ionized calcium will occur, with more calcium being protein-bound and less available in the free fraction. In this manner, hyperventilation can cause hypocalcaemic symptoms, even in the presence of normal total serum calcium.

Parathyroid hormone (PTH) is the major extracellular calciumregulating hormone in man. Parathyroid hormone is a classic pre-prohormone that is synthesized in the chief cell of the parathyroid gland. After the 21 amino acid amino terminal sequences (the pre-pro-sequences) are processed, parathyroid hormone is secreted as an intact 84 amino acid peptide. Intact PTH (1–84) is rapidly cleaved into N-terminal (1–33) and C-terminal (34–84) fragments that are biologically inactive. Intact PTH (1–84) has an estimated half-life of 5 min, whereas the biologically inactive metabolites are cleared much more slowly. These immunologically cross reacting fragments have hampered the development of precise radioimmunoassays for clinical use. PTH acts at three major target organs (kidney, bone, and intestine) directly and indirectly to regulate calcium balance. In the distal convoluted tubule of the kidney, PTH acts to stimulate calcium transport by increasing calcium resorption of the glomerular filtrate. In the proximal tubule, PTH increases the enzymatic activity of 1&agr;-hydroxylase, an essential enzyme for the generation of the active metabolite of vitamin D, 1,25-(OH)&sub2;-vitamin D. Independently, PTH produces phosphaturia and bicarbonaturia through a cyclic AMP-mediated mechanism, a process that accounts for the hypophosphataemia and metabolic acidosis clinically observed in patients with primary hyperparathyroidism. At the level of the bone, the second target organ for PTH effect, PTH mobilizes calcium from this reservoir through rapid effects on a calcium pool in equilibrium with the extracellular fluid and slower effects through induction of lysosomal enzymes in PTH-responsive osteoclasts. Almost paradoxically, PTH stimulates osteoblast activity and increases bone deposition as well, underscoring its important role as a regulator of bone remodelling. The third target organ, the intestine, is only indirectly affected by PTH. The action of PTH on the proximal tubule of the kidney results in elevated 1,25-(OH)&sub2;-vitamin D production. This steroid hormone plays an important role in PTH action on bone, but also induces active calcium absorption in the small bowel. Under normal physiological situations, the three major target organs of PTH serve to normalize ionized calcium levels through increased kidney resorption, increased calcium mobilization from skeletal reserves, and increased dietary absorption in the gut.

Knowledge of the target organ effects of PTH applies to the pathological condition of primary hyperparathyroidism. In primary hyperparathyroidism affected parathyroid glands are functionally shifted in the calcium dose-response relationship of PTH release. These parathyroid glands have an altered ‘set-point’ and regulate ionized calcium concentrations at a level higher than desirable. Patients with primary hyperparathyroidism are hypercalcaemic due to PTH stimulus on the kidney to reabsorb calcium, on the bone to mobilize calcium, and from the gut to increase the fractional absorption of dietary calcium in spite of normal or even high total serum calcium levels. Although the direct effect of PTH on the kidney is to increase fractional reabsorption of calcium from the glomerular filtrate, the consequence of excess secretion of PTH is an elevated urinary calcium due to the high filtered load of calcium. Thus, the clinical consequences of long-standing autonomous parathyroid secretion are then predictable: renal disease due to nephrocalcinosis or nephrolithiasis, bone involvement (pain, pathological fractures, bone cysts) due to excessive bone resorption, and severe hypercalcaemia with neurological symptoms (anorexia, nausea/vomiting, and confusion).

Since the advent of simultaneous multianalyser (SMA) technology for routine analysis of serum calcium, the initial presentation of primary hyperparathyroidism has changed dramatically. Before 1960, the majority of patients presented with the classic clinical syndromes of bone disease (osteitis fibrosa cystica) or renal disease (nephrocalcinosis and/or nephrolithiasis). Now, the single largest category of patients are those diagnosed during the evaluation for asymptomatic (or minimally symptomatic) hypercalcaemia (50–80 per cent in most series).

The diagnosis of primary hyperparathyroidism is usually made during the evaluation for hypercalcaemia. Eighty per cent of patients are either asymptomatic or mildly symptomatic with non-specific constitutive symptoms such as fatigue, weakness, polydipsia, polyuria, arthralgia, and constipation. Although the majority of outpatients evaluated for hypercalcaemia (roughly 50 per cent) will be diagnosed as hyperparathyroid, other causes of hypercalcaemia must be considered. These include hypercalcaemia of malignancy (multiple myeloma, squamous cell carcinomas of head and neck), granulomatous disease (sarcoidosis), milk-alkali syndrome, endocrine disorders (thyrotoxicosis, adrenal insufficiency), vitamin D toxicity, drug use (thiazide diuretics, lithium), immobilization hypercalcaemia (particularly in patients with Paget's disease), and (benign) familial hypocalciuric hypercalcaemia. Hypercalcaemia on independent occasions in the setting of elevated levels of intact parathyroid hormone is diagnostic of primary hyperparathyroidism. However, this diagnosis must be made when thiazide diuretics or lithium-containing medications are withdrawn prior to evaluation, and when blood samples are taken with minimal venous occlusion to avoid artefactual hypercalcaemia due to haemoconcentration. The PTH assays available commercially are two-site immunoradiometric assays using one antiserum directed against the 1–34 amino acid portion of the PTH molecule and the second against the 39–84 amino acid sequence of the PTH molecule. Because this PTH immunoradiometric assay recognizes only intact PTH, cleavage fragments do not cross-react in the assay. Discrimination between hypercalcaemic patients with hypercalcaemia of malignancy and hyperparathyroidism is now quite good. Normal PTH values are reported between 10 and 65 pg/ml. Intact PTH values for patients with primary hyperparathyroidism will be in the high normal range or frankly elevated. In contrast, the majority of patients with hypercalcaemia of malignancy have suppressed PTH values (<1 pg/ml). Moreover, the advent of two-site assays for parathyroid hormone related peptide (PTHrp), the humoral agent implicated in humoral hypercalcaemia of malignancy, adds further discriminatory power to the work-up of the hypercalcemic patient.

In addition to calcium and PTH hormone assays, other evaluation of the patient with suspected primary hyperparathyroidism may be indicated. Albumin and ionized calcium concentrations help to determine the degree of ionized hypercalcaemia. Ionized calcium measurements are sometimes unreliable and generally only interpretable when specimen pH is concomitantly measured and is normal. Serum alkaline phosphatase may indicate underlying bone disease. Renal function assays, blood urea nitrogen, and creatinine may be useful to guide fluid and electrolyte therapy during the postoperative period, and may be helpful in predicting those patients prone to the development of postoperative hypocalcaemia and hypophosphataemia. Urinary calcium/creatinine ratios are sometimes helpful in differentiating primary hyperparathyroidism from patients with familial hypocalciuric hypercalcaemia.

Although the indications for surgical intervention in the truly asymptomatic patient are debated, parathyroidectomy represents the only curative modality available. Currently accepted indications for parathyroidectomy include patients with objective manifestations of primary hyperparathyroidism. Those include nephrolithiasis, reduced creatinine clearance, markedly elevated 24-h calcium excretion (250 mg/24 h), severe hypercalcaemia (greater than 12 mg/dl), recurrent pancreatitis, young patients (<50 years of age), or patients in whom periodic assessment is not feasible. However, surgical intervention in the truly asymptomatic patient, in the absence of other considerations, is frequently justified on the basis of published series where 20 per cent of asymptomatic patients develop end-organ involvement within 5 years of the identification of hypercalcaemia, regardless of its severity.

Non-invasive preoperative localization has not had a significant impact on the 95 per cent success rate for initial neck exploration by the experienced parathyroid surgeon. Importantly, these anatomical studies are not used to make the diagnosis of primary hyperparathyroidism; they are used merely as a guide for the surgical exploration for patients in whom the diagnosis for primary hyperparathyroidism is established and in whom surgical intervention is contemplated. Localization techniques include the 10-MHz real-time ultrasonography with predictive accuracy of 75 to 80 per cent for enlarged parathyroid glands located in the neck. Ultrasound studies are not helpful for the localization of mediastinal parathyroid glands and do not discriminate parathyroid glands from hyperplastic lymph nodes well; however, they can be extremely useful for the evaluation of coexisting thyroid disease. Thallium-201 chloride–technetium–99m-pertechnetate scanning utilizes computer-aided subtraction to localize parathyroid glands with 75 per cent accuracy. This technique is particularly well suited for parathyroid adenomas located away from the thyroid gland. Magnetic resonance imaging (MRI) appears to be particularly helpful for mediastinal tumours and differentiating parathyroids from lymphatic or fatty tissue. CT scans require intravenous contrast and are prone to streaking artefacts in the supraclavicular region. Selective venous catheterization with PTH sampling is reserved for patients on whom reoperation is planned and in whom tumour localization is problematic. The selection of these localization techniques is due to the above considerations as well as the clinical picture, local radiological expertise, and, finally, preferences of the parathyroid surgeon. In general, however, the majority of these localization techniques are reserved for the uncured patient in whom repeat surgical exploration is planned.

Experienced parathyroid surgeons appreciate the importance of understanding the embryology of the parathyroid gland as a determinant for successful parathyroid surgery. Because the parathyroid glands derive from the endodermal germ layers of the third and fourth branchial pouch and migrate caudally, the location of any individual gland can be highly variable. Nevertheless, the locations of the ectopic parathyroid gland follow the pathway of this caudal migration, and this knowledge facilitates the search for parathyroid glands (see Section 11.2.2 84).

The lower parathyroid glands originate from the third branchial pouch and migrate along with the thymus to assume a position at the lower poles of the thyroid gland. These lower glands can also be found associated with the thymus in the anterior mediastinum if the gland fails to disassociate from the thymus, or alternatively, can be localized cephalad to the upper pole of the thyroid sometimes still associated with thymic tissue. The upper parathyroid glands arise from the fourth branchial pouch. They remain almost stationary until they reach their final location at the upper pole of the thyroid. Consequently, these glands are the most predictable in their location; they receive their blood supply from the inferior thyroidal artery. With regard to the number of parathyroid glands, 87 per cent of patients have four, 6 per cent have fewer, and 6 per cent have five or more glands. Ninety per cent of glands are in the neck.

The majority of patients with primary hyperparathyroidism will manifest single parathyroid adenomas upon histological examination. Some 80 to 85 per cent of patients present with a single adenoma, usually chief cell histology, that varies in size between 100 mg and 40 g. Patients with large parathyroid adenomas represent a distinct abnormal entity. These patients have greater degrees of calcium elevation and are at greater risk for postoperative hypocalcaemia. Large excised glands also need to be carefully examined for the presence of mitotic figures and vascular or capsular invasion to exclude the possibility of parathyroid carcinoma (3 per cent of all cases). In 10 to 15 per cent of patients, depending on referral patterns, hyperparathyroidism is due to parathyroid hyperplasia. Microscopically, hyperplastic glands are also of the chief cell type. As a single gland, it cannot be distinguished from a parathyroid adenoma. The distinction between adenoma and hyperplasia is made upon the biopsy of an uninvolved gland. In the case of an adenoma, the uninvolved gland is histologically normal, with an increase in the fat content of both the chief and stromal cells. In the case of hyperplasia, an unsuspected gland may be smaller, but shows histological evidence of hypercellularity.

Controversy exists as to whether unilateral or bilateral neck explorations are indicated. Some argue that the findings of a unilateral adenoma and an atrophic gland on the ipsilateral side are sufficient evidence for the diagnosis of parathyroid adenoma. They cite an extremely low incidence of bilateral adenomas (<1 per cent). Nevertheless, most experienced surgeons advocate selective bilateral neck exploration with identification of all four parathyroid glands and removal of only one adenoma and normal gland if only one abnormal gland is identified. Proponents of this approach cite a 10 per cent incidence of multiple adenomas or asymmetric hyperplasia. This approach is necessary for patients with suspected hyperplasia. In these patients, a subtotal resection of the smallest gland followed by removal of all remaining abnormal glands is recommended.

As with many surgical procedures, the outcome and complications of parathyroidectomy vary with surgical expertise. In a review of primary hyperparathyroidism persistent hypercalcaemia was found in 6 per cent of cases in specialized centres compared with 15 per cent of cases in hospitals treating fewer than 10 cases per year. Likewise, the incidence of permanent hypoparathyroidism varied between 4 and 14 per cent. Additional complications include recurrent laryngeal nerve palsy (<0.1 per cent), mortality (<0.1 per cent), and exceedingly rare case reports of postoperative pancreatitis and obstructive ureteropathy. Captain Charles Martell, the first North American patient successfully surgically treated for hyperparathyroidism, died in 1932 of obstructive ureteropathy after surgery. Management of non-metabolic outcome to parathyroid surgery is discussed in Section 11.2.2 84.

In patients undergoing curative parathyroidectomy, an abrupt challenge to calcium homeostasis can be expected. Autonomously functioning hyperplastic or adenomatous parathyroid glands with an elevated calcium set-point suppress the normal parathyroid tissue by constant exposure to hypercalcaemia. This suppression is manifested by increases in fat content both of the chief cells and the stromal tissue of the normal, suppressed parathyroid glands. After the removal of the affected parathyroid glands, the normal glands must respond to the hypocalcaemic stimulus, and a lag phase is frequently seen for the recovery of the normal glands.

After successful parathyroidectomy, a rapid correction of most metabolic complications of primary hyperparathyroidism will be observed. The serum calcium begins to fall 4 to 12 h after surgery and its nadir is usually seen 48 to 72 h postoperatively. Immediately after parathyroidectomy, the urinary calcium level rises transiently until serum calcium falls; subsequently, urinary calcium becomes undetectable. Most patients report symptoms of hypocalcaemia 1 to 2 days before the nadir in serum calcium. These symptoms are usually circumoral or acral paraesthesiae. Total serum calcium falls 2 to 3 mg/dl within the first 24 to 48 h after successful surgery. This period is due to relative ‘functional’ hypoparathyroidism, and rarely lasts more than 2 to 3 weeks.

Numerous studies underscore the important relationship between excessive parathyroid gland biopsy and the incidence of transient hypocalcaemia. In one series, 37 per cent of patients with minimal biopsies became hypocalcaemic on postoperative days 2 to 3, whereas 62 per cent of patients with extensive biopsies of bilateral parathyroid glands became hypocalcaemic. This relationship is likely to be the consequence of injury or ischaemia to the remaining suppressed parathyroid glands, occurrences that delay their response to curative parathyroid surgery.

In addition to alterations in serum calcium, postoperative metabolic acidosis, declines in serum uric acid levels, and hypomagnesaemia have all been described during the immediate postoperative period. These changes are ascribed to either the lack of PTH hormone on the kidney, or the consequences of bone accretion (magnesium is deposited in the bone).

Since PTH acts via adenylate cyclase, detection of changes in nephrogenous cyclic AMP (NcAMP) have been used as indices for monitoring changes in PTH secretion after successful surgery for hyperparathyroidism. NcAMP falls to 50 per cent of preoperative values within 30 to 90 min after surgery, and is consistent with the estimated half-life of intact PTH in plasma. With the advent of the highly sensitive two-site PTH (1–84) immunoradiometric assays more detailed investigation of PTH dynamics in the postsurgical patient is now being undertaken. This assay can differentiate between normal and suppressed PTH values.

Evidence is accumulating that suppressed intact PTH (1–84) values during the early postoperative period are indicative of successful parathyroidectomy, and may be predictive of long-term cure in patients with intact parathyroid glands that remain after surgery. Some investigators have noted that extensive gland manipulation or biopsy can falsely elevate the intact PTH (1–84) values; caution should be used in interpreting detectable levels in the immediate postoperative period in those patients undergoing extensive neck explorations and gland biopsies.

How long the suppressed glands require to recover from long-term hypercalcaemic suppression has been addressed using the highly sensitive two-site PTH immunoradiometric assays. Functional hypoparathyroidism appears to be relatively brief, with demonstration of de novo PTH secretion by atrophic glands in more than 50 per cent of patients 20 h postoperatively, and 85 per cent of patients by 30 h postoperatively.

We routinely measure total and ionized calcium, albumin, and magnesium daily or twice daily depending on the degree of suspicion for the development of hypocalcaemia. Severe postoperative hypocalcaemia, defined as hypocalcaemia on postoperative day 3 or later requiring supplemental calcium to prevent tetanic symptoms, occurs in 10 to 20 per cent of patients in reported series. The differential diagnosis is presented in Table 1 254, and includes functional hypoparathyroidism from suppressed or ischaemic parathyroid glands, hypomagnesaemia impairing PTH release, true hypoparathyroidism from surgical removal of all parathyroid tissue, or the ‘hungry bones syndrome’ due to remineralization of the skeleton.

Evaluation of the hypocalcaemic patient includes elicitation of physical signs as well as biochemical evaluation of serum. Classic physical signs of hypocalcaemia include the Chvostek's sign, the spasm of facial muscles innervated by the VIIth cranial nerve, produced by tapping the nerve as it exits the base of the skull. A Chvostek's sign can be non-specific, since 15 per cent of normal patients can have a positive test, so this sign is useful only if it was tested for and was not elicited preoperatively. Trousseau's sign is carpal spasm produced by elevating a blood pressure cuff above systolic blood pressure for 3 min. More serious forms of neuromuscular irritability include alterations in QT interval on electrocardiogram with ventricular irritability as well as seizures. These physical signs do not aid in the differential diagnosis of the different causes of hypocalcaemia, but do dictate the need and the urgency for therapeutic intervention.

Serum studies useful in the evaluation of the hypocalcaemic patient include total and ionized calcium, albumin (to assess the relative degree of protein binding), serum phosphate, magnesium, and when indicated PTH (1–84) by the two-site immunoradiometric assay. Anticipated laboratory values for the major causes of postoperative hypocalcaemia are tabulated in Table 2 255. Of the laboratory parameters, the most useful for separating functional from surgical hypoparathyroidism is the intact PTH immunoradiometric assay. By 3 days postoperatively all patients with functional hypoparathyroidism in our series had detectable PTH values. In contrast, patients with permanent surgical hypoparathyroidism had PTH values that were undetectable (<1 pg/ml). Serum phosphate measurements are the most reliable in distinguishing patients with hypoparathyroidism from those with ongoing remineralization of the skeleton (‘hungry bones’ syndrome). Because of the phosphaturic effect of PTH, patients with hypoparathyroidism tend to have normal–high serum phosphorus values. In the ‘hungry bones’ syndrome, however, extensive remineralization of the skeleton drives calcium, phosphate, and magnesium into healing bone, and patients become hypocalcaemic, hypophosphataemic, and hypomagnesaemic. In a recent retrospective study of unselected patients undergoing parathyroidectomy at a tertiary centre, patients manifesting hypocalcaemia and hypophosphataemia after curative parathyroid surgery constituted 12 per cent of the study population, indicating that although radiographically evident bone disease was not a prominent feature, the physiology of skeletal remineralization can still be seen. This is particularly evident after total parathyroidectomy, with or without implantation of part of a gland in the forearm, for secondary hypoparathyroidism in patients with chronic renal failure.

The symptoms in most patients can be managed with institution of oral calcium carbonate 2 to 4 g/day (260 mg elemental calcium per 650 mg tablet) or a high calcium diet. A high calcium diet, also high in phosphate, is reserved for those patients with normal serum phosphate values. Functional postoperative hypoparathyroidism is transient, lasting from 3 days postoperatively to between 2 and 3 weeks postoperatively. The duration, in part, may depend on the extent of biopsy or manipulation of normal parathyroid glands. Patients undergoing bilateral neck exploration or reoperative procedures are at greater risk for permanent postoperative hyperparathyroidism, and these patients should be monitored accordingly. The incidence of permanent postoperative hypoparathyroidism varies from 0.3 to 14 per cent depending on the surgical expertise.

Severe hypocalcaemia, with symptoms or signs of tetany, needs to be more vigorously managed. Patients with severe hypocalcaemia (total calcium <6.5 mg/dl (<1.6 mmol/l)) demonstrating signs of neuromuscular or cardiac irritability (tetany) or those unable to take calcium by mouth may need to be treated with parenteral calcium. The goal of parenteral treatment of symptomatic hypocalcaemia is to provide 200 to 300 mg of elemental calcium acutely. The preferred treatment is two to three ampoules of 10 per cent calcium gluconate (93 mg elemental calcium/ampoule), while monitoring ECG and respiration, until tetany is controlled. Calcium gluconate is preferred to calcium chloride because of the lower incidence of thrombophlebitis with use of calcium gluconate. This can be followed by an infusion of 15 mg/kg elemental calcium over 4 to 6 h. Following acute parenteral therapy, oral therapy must be initiated (2–4 g/day elemental calcium). Vitamin D may also be necessary to increase oral absorption of calcium in patients with hypoparathyroidism or ‘hungry bones’ syndrome. In chronic renal failure patients, vitamin D therapy is standard practice and this should be continued after total parathyroidectomy.

In the presence of severe hypomagnesaemia and normal renal function, magnesium sulphate (1–2 g as 10 per cent solution) can be administered over a 6-min period. Because the normal magnesium concentration is necessary for normal PTH release, hypomagnesaemia should be considered and treated in the management of functional hypoparathyroidism. Moreover, because magnesium is deposited in the skeleton in the ‘hungry bones’ syndrome, magnesium replacement may also be necessary in this condition.

Several studies have implicated the extent of surgical biopsy as an important determinant of postoperative hypocalcaemia. Twice as many patients are likely to develop hypocalcaemia with bilateral neck exploration and multiple gland biopsy compared with matched controls undergoing unilateral neck exploration. Some 60 to 70 per cent of patients undergoing second operations because initial surgery failed are likely to develop permanent hypoparathyroidism. Importantly, the size of the parathyroid adenoma, as assessed by ultrasound volume or by the weight of excised parathyroid gland, is a strong indicator of greater degrees of preoperative hypercalcaemia and subsequent postoperative hypocalcaemia. In one study, this parameter was closely linked to postoperative hypocalcaemia and hypophosphataemia (‘hungry bones’ syndrome). Three additional preoperative variables of independent predictive value for the development of hungry bones syndrome identified by multivariate analysis were, in addition to the volume of adenoma (determined at surgery), the preoperative blood urea nitrogen, alkaline phosphatase, and patient's age. These patients had a significantly longer hospital stay than similarly treated counterparts. These data need to be verified on a prospective population, but raise the possibility that patients at risk for development of postoperative hypocalcaemia can be identified by routine preoperative screening. Identified patients could then be monitored more closely and treated more aggressively.

Parathyroidectomy is expected to normalize serum calcium in uncomplicated patients undergoing initial neck exploration for parathyroid adenoma in 90 to 95 per cent of patients in active surgical centres. Patients with neuromuscular symptoms can be expected to improve after surgery. Evidence of type II muscle fibre atrophy was documented in a series of patients with proximal muscle weakness and primary hyperparathyroidism. After parathyroidectomy, their muscle strength improved. The incidence of recurrent nephrolithiasis is decreased, and some reports indicate an improvement in renal function in patients with declining glomerular filtration rate. The effect of parathyroidectomy on psychiatric symptoms of mental dullness and confusion is seen within days of surgery. However, anxiety, depression, and psychotic syndromes generally are not improved by surgical treatment.

Classic hyperparathyroid bone disease (osteitis fibrosa cystica) will heal rapidly and is one unambiguous indication for parathyroidectomy. Osteoporosis is used as a criteria for surgery; however, the response to surgery appears to be transient. Quantitative CT of vertebral density in one series demonstrated a non-sustained increase in bone density of 13 per cent after 4 months. In a separate study dual photon absorptiometry demonstrated a 10 per cent increase in vertebral or forearm bone density 3 months after successful surgery; there was no further increase in bone mass with time, however. Although more studies will be needed to clarify this issue, the effect of parathyroidectomy on the reversal of osteoporosis appears to be modest.

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