Surgery of the parathyroid glands

 

NICHOLAS DUDLEY

 

 

SURGICAL ANATOMY

Size and number

There are normally four parathyroid glands in the human but developmental anomalies can give rise to a smaller or larger number. Gilmore's much quoted autopsy study of 428 cadavers found two glands in 0.2 per cent, three in 6.1 per cent, five in 6 per cent, and six in 0.5 per cent of individuals. In other words in only 87 per cent of the population is there the normal complement of four glands. It is possible that amongst the 6.2 per cent of individuals with fewer than four glands some are instances of fused upper and lower parathyroid tissue or of failed identification. Normal parathyroids also vary in size, shape and location. Typically they measure 3–5 × 2–4 × 0.5–2 mm. The combined weight of the four glands is approximately 120 mg, the superior glands usually being smaller (between 20—40 mg), and the inferior ones from 30 to 50 mg.

 

Embryological development

The upper parathyroids arise from the dorsal endoderm of the fourth branchial pouch, the ventral part of which is fused laterally to the developing thyroid gland on the floor of the primitive pharynx. Thus some 92 per cent of the upper parathyroids remain in close contact with the posterolateral aspect of the thyroid lobes, just above and behind the level at which the recurrent laryngeal nerve crosses the inferior thyroid artery (Fig. 1) 774.

 

When the upper parathyroid glands are ectopic they become progressively more dorsally displaced. As a result, the upper parathyroids may, in a small number of individuals, come to lie between the thyroid and oesophagus or behind the oseophagus in the upper posterior mediastinum (Fig. 2) 775. It has been suggested that parathyroid enlargements favours dorsal displacement due to the forces of deglutition and negative intrathoracic pressure. Aberrant superior glands may also be found rarely within the carotid sheath.

 

The lower parathyroid glands develop from the dorsal endoderm of the third branchial pouch which also gives rise to the thymus. In contrast to the fourth pouch derivatives which remain fairly static during embryological development the structures developing in association with the third pouch undergo caudal migration which is often excessive. The third pouch leap-frogs over the fourth and divides, leaving a discrete mass of parathyroid tissue on each side, usually within 2 cm of the lower pole of the thyroid (Fig. 3) 776, and the thymus as a bilobed structure in the anterior mediastinum overlying the great vessels. Excessive fragmentation produces thymic rests and accessory parathyroid glands. Failure to fragment results in intrathymic parathyroid tissue which accounts for the location of 20 per cent of parathyroids, half of which are bilateral. The area where ectopic lower parathyroids may be found is shown in Fig. 4 777.

 

Blood and nerve supply

The arterial supply to the upper and lower parathyroids is almost exclusively from the inferior thyroid artery on each side—indeed tracing out the terminal branches of this artery can aid recognition of the gland. Although the final arterial blood supply to each gland is an end artery, collateral circulation occurs proximal to the hilum, this being derived principally from the superior thyroid artery but also from oesophageal and tracheal vessels. The nerve supply arises either directly from the sympathetic chain (superior and middle cervical ganglia) or indirectly by a plexus on the back of the thyroid.

 

Macroscopic and microscopic appearance

The parathyroid glands vary from a tan to yellow or reddish-brown colour depending on the fat content and vascularity. The fat content increases after puberty and may comprise up to 80 per cent of the total volume in the elderly. Unlike lymph nodes and fat lobules, with which parathyroids are easily confused, the consistency is softer (like blancmange) and they are typically tongue shaped. The base comprises the vascular hilum and there is often a sharp leading edge to one side. Normal and abnormal glands are frequently found in a fatty envelope within which they are freely mobile and can be displaced by probing. Microscopically two main cells are seen in parathyroid tissue—chief cells and oxyphil cells. The chief cells are of three types—light chief cells rich in glycogen with few secretory granules, dark chief cells with little glycogen but with many secretory granules, and water clear cells which are large (up to 40 &mgr;m diameter) and have clear vaculated cytoplasm rich in glycogen. The oxyphil cells are variable in size, appear after puberty, and have pink cytoplasm and small dense nuclei.

 

PATHOPHYSIOLOGY

Much of this aspect has already been discussed in detail in Section 11.2.1 83, but some aspects of the pathophysiology bear repeating from the surgical perspective.

 

Primary hyperparathyroidism

(a)Aetiology The cause of primary hyperparathyroidism (HPT) is unknown but the prevalence with increasing age, especially in females, is so high that it almost seems to be part of the ageing process and may be influenced by the menopause. Radiation to the head and neck area in childhood increases the risk of adenoma and hyperplasia of the parathyroids developing later in life. Hyperplasia is a notable feature of the multiple endocrine neoplasia (MEN) syndromes described in the thyroid section (Section 11.1) 82. In those instances a clear chromosomal abnormality has now been identified.

(b)Incidence Long-term studies of large well defined populations in Sweden and the United States indicate an incidence of 10 cases per 100000 population per year in those aged under 40. Over the age of 60 however there is a steep rise in incidence—92 per 100000 per year for men, 188 per 100000 for women. The incidence of symptomatic HPT which tends to be diagnosed as a result of illness rather than screening is highest in the third to fifth decades.

(c)Pathology (Table 1) 256 In over 80 per cent of cases primary HPT is due to a single chief cell adenoma affecting one parathyroid gland. The pathologist distinguishes an adenoma from a normal parathyroid gland by the finding of a rim of compressed normal parathyroid tissue to one side of the adenoma (Fig. 5) 778. Within the cells of the adenoma itself there is nuclear pleomorphism and the cellular cytoplasm contains little fat. Rarely the adenoma consists of oxyphil or water clear cells. Multiple adenomata are well documented but occur infrequently. Hyperplasia of all four parathyroids is typical of secondary HPT. However hyperplasia is responsible for the primary disease in about 5 to 10 per cent of cases and may affect two or more glands. The chief cells are again most frequently involved but oxyphil and water clear cell hyperplasia may be seen. In contrast to an adenomatous gland a hyperplastic parathyroid shows no rim of normal tissue and the overall appearance is uniform with a marked increase in parenchymal cells and few lipocytes. Nodular hyperplasia is a feature strongly associated with the MEN syndrome.

Parathyroid carcinoma is the rarest cause of primary HPT (less than 3 per cent of cases) and its recognition depends more on the surgeon than on the pathologist since the diagnostic criteria are more clinical than histological. Typically a carcinoma is firm to hard, grey in colour, and adherent to adjacent tissues. The capsule of the gland eventually becomes invaded and metastases develop frequently in the local lymph nodes. Distant metastases in liver and bone are a late feature and indicate terminal disease.

(d)Disturbance of physiology This arises because of increases in both the circulating PTH and calcium. The production of PTH is said to have become ‘autonomous’ and fails to switch off as the plasma calcium rises. The hypercalcaemia causes the renal tubular absorption of calcium to be increased so that at any given filtered load more is lost in the urine and reflected in an increase in the 24-h urinary calcium. Bone turnover is also increased with reabsorption exceeding deposition, whilst more calcium is absorbed from the intestine because of stimulated calcitriol production in the kidneys.

 

Secondary hyperparathyroidism

(a)Aetiology This condition results from prolonged hypocalcaemia and is caused most frequently by chronic renal failure. Vitamin D deficiency and gluten-sensitive enteropathy are other provocative states.

(b)Incidence No precise figures are available but it is inevitable that patients with end-stage renal failure will develop secondary hyperparathyroidism unless prophylactic therapy with vitamin D analogues is given.

(c)Pathology Typically all four glands are enlarged and histologically they show the same features seen in hyperplasia due to primary HPT. The chief cells are the predominant cell type affected.

(d)Disturbance of physiology When the kidney starts to fail the reduction in glomerular filtration causes an increase in plasma phosphate. This in turn produces a reduction in the plasma ionized calcium to which the parathyroids respond by undergoing hyperplastic change.

 

Tertiary hyperparathyroidism

This condition identifies those patients with long-standing secondary HPT who develop the same sort of autonomous gland function described in primary HPT. The physiological sequelae are similar with hypercalcaemia coexisting with a raised PTH level. It is most frequently seen in patients on long-term dialysis for chronic renal failure and after renal transplantation. The glands are hyperplastic but may additionally produce adenomata, sometimes referred to as quarternary hyperparathyroidism.

 

Pseudohyperparathyroidism

This condition is mentioned because it gives rise to biochemical disturbances similar to those seen in primary HPT. Oat cell and squamous carcinoma of the lung, head, and neck, and carcinoma of the kidney and ovaries may all rarely produce parathyroid-like adenolate cyclase stimulating proteins. These interact with the PTH receptors and can mimic some of the effects of primary HPT.

 

CLINICAL FEATURES OF HYPERPARATHYROIDISM

The widespread use of multichannel autoanalysers for routine biochemistry screening has brought to light an increasing number of individuals with hypercalcaemia who on further investigation are shown to have HPT. Frequently the diagnosis is made so early that signs and symptoms have not had time to develop. Mildly symptomatic or asymptomatic patients identified in this way now account for more than 50 per cent of the total in most large series. In the 12 years prior to 1980, 54 per cent of the 200 patients coming to surgery in Oxford had originally presented with significant bone and renal disease. In the following decade a further 200 patients underwent surgery but the number of those with symptomatic bone and renal disease had fallen to 35 per cent. The time-honoured rhyme ‘bones, stones, abdominal groans, and psychic moans’ is still a useful prompt for the symptoms associated with HPT.

 

Bones

Disturbance of calcium metabolism causes vague bony aching and arthralgia especially in secondary HPT. It becomes acute and site specific if the weakened bone fractures. Very severe arthralgia is a feature of chondrocalcinosis (pseudogout) in which the surface of the articular cartilage becomes the site of metastatic calcification.

 

Stones

Long-standing severe hypercalcaemia may present with renal pain. The increased filtered load of calcium and the passage of alkaline urine leads to the formation of renal calculi. Less frequently nephrocalcinosis occurs with calcification of the renal parenchyma, i.e. outside the collecting system. The stones pre-dispose to renal colic, urinary infection secondary to obstructive uropathy, and renal failure. Once established renal damage caused by HPT is irreversible and the stones tend to persist even after calcium homeostasis has been restored following successful surgery.

 

Abdominal groans

Mild abdominal pain is often due to large bowel colic related to the chronic constipation brought on by dehydration and hypercalcaemia. More severe epigastric pain arises in 5 to 10 per cent of patients with HPT due to peptic ulceration. This disorder may be causally related if the hypothesis is true that hypercalcaemia stimulates gastrin production and thereby increases basal gastric acid secretion. Certainly ulcer symptoms usually remit after successful parathyroid surgery and studies have shown that the gastric acid secretion returns to normal. There is a rare association in MEN type I patients with a Zollinger-Ellison type syndrome which probably represents an extreme gastrin response. Because surgical removal of the diseased parathyroid glands in such patients results in cure without the need for gastric surgery, the term pseudo Z-E syndrome has been proposed. The link between HPT and pancreatitis, both acute and chronic, is well described. It may be explained simply on the basis of metastatic calcification within the common bile duct causing acute pancreatitis (common channel theory) or throughout the pancreas in the chronic form. Alternatively it has been postulated that hypersecretion of glucagon by the &agr;-cells of the inflamed pancreas causes hypoglycaemia which stimulates the parathyroids to become hyperplastic.

 

Psychic moans

Mental symptoms range from subtle mood change and behavioural disorder to marked organic psychosis and dementia. Loss of concentration, mild depression, and lassitude are frequent.

 

Hypercalcaemia per se induces anorexia, nausea, vomiting, and thirst, and is associated with polydipsia and polyuria. The most extreme form of hypercalcaemic syndrome is seen in acute hypercalcaemic crisis—a fulminating HPT state in which all the above symptoms are exaggerated. Unless this medical and surgical emergency is recognized and treated quickly the outcome can be fatal.

 

Physical signs

There are few signs associated with primary HPT but if the calcium is markedly elevated a parathyroid tumour in the neck may be palpable. Band keratopathy is occasionally visible on slit lamp examination of the cornea (Fig. 6) 779. Proximal myopathy is a rare finding with related wasting and motor weakness. Diffuse osteitis fibrosa cystica first described by von Recklinghausen in 1891 with gross skeletal deformity, loss of height, etc., is unlikely ever to be seen again in developed countries due to earlier diagnosis. However focal swellings of bone, notably the lateral end of the clavicles due to the presence of ‘brown tumours’, are occasionally encountered (Fig. 7) 780. In patients with secondary HPT soft tissue calcification especially in arteries, muscles, and subcutaneous tissues particularly around joints is common and scratch marks due to pruritus are frequent. The physical signs of tertiary HPT include all the foregoing, pruritus being even more severe with skin necrosis occasionally seen due to subcutaneous calcium deposition.

 

INVESTIGATION OF HYPERPARATHYROIDISM

The single most important criterion for a diagnosis of primary HPT is a persistent and significant increase in the plasma calcium concentration. However primary HPT accounts for only approximately 20 per cent of all symptomatic patients with hypercalcaemia and a careful history and physical examination is necessary to exclude other causes, notably metastatic bone disease (primary breast, lung, etc.) and multiple myeloma. A more comprehensive list of causes of hypercalcaemia is summarized in Table 2 257. Distinguishing primary HPT from these other causes rests on three key biochemical tests.

 

1.Plasma calcium (normal range 2.35–2.55 mmol/l) A minimum of three estimations should be performed and where hypercalcaemia is modest it becomes more important to draw an uncuffed venous sample when the patient has been fasted. Normocalcaemic HPT is an accepted entity and tends to affect patients with recurrent renal stone formation. This small group exhibits the rare biochemical profile of a calcium level usually towards the top of the normal range but with an inappropriately high PTH level.

2.Plasma albumin (normal range 35–50 g/l) This should be estimated at the same time and under the same circumstances as for plasma calcium. Albumin is the main calcium binding protein in the plasma so alternations in the albumin level have to be taken into account and the plasma calcium corrected appropriately. A simple and reliable method is addition of 0.02 mmol/l of calcium for every 1g/l of albumin below 40 and subtraction of 0.02 mmol/l for every 1 g/l above.

3.Immunoradiometric intact PTH assay (IRMA) (normal range 0.9–5.4 pmol/l) This should be estimated at the same time as the two foregoing tests. Two site IRMA assays measuring the level of the intact PTH molecule in the plasma have only recently become standardized and more readily available in kit form. In the past radioimmunoassays using antisera raised either against the mid, carboxy, or the N-terminal fragments of the PTH molecule could erroneously measure similar PTH polypeptides produced by some occult malignancies. Squamous and oat cell carcinoma of the lung and renal cell carcinoma as mentioned earlier are notable examples of tumours with this ability to elaborate PTH-like provoking hypercalcaemia in the absence of bony metastases.

 

Complementary tests that support the diagnosis and identify patients who have associated deleterious effects of HPT are as follows.

 

1.Plasma phosphate (normal range 0.8–1.45 mol/l) As the tubular reabsorption of calcium increases, that for phosphate decreases with more phosphate lost in the urine relative to calcium. The plasma level falls, notably in patients with advanced disease. Conversely, elevated plasma phosphate in the presence of hypercalcaemia and normal renal function suggest bony metastases or vitamin D intoxication.

2.Plasma creatinine (normal range 70–150 mmol/l) This is a useful indicator of renal function and if clearance falls significantly in a patient with HPT (> 30 per cent) in an otherwise asymptomatic patient, it signals renal damage and the need for surgical intervention.

3.Alkaline phosphatase (normal range 80–250 i.u./l) This is a useful indicator of bone disease; if in the normal range significant skeletal involvement is ruled out and there is no need for extensive radiological investigations of the skeleton.

4.Plasma magnesium (normal range 0.75–1.05 mmol/l) Hypomagnesaemia has been reported in up to 15 per cent of patients with primary HPT and may need to be corrected especially after the patient has been operated upon (see Section 11.2.1 83).

5.Urinary calcium (normal range 2.5–7.5 mmol/l per 24 h) An increase in the 24-h urinary calcium supports the diagnosis of HPT but a markedly elevated urinary calcium above 9 mmol/l characterizes non-PTH mediated hypercalcaemia. Perhaps the most important value of this test is to identify the rare patient with familial hypocalciuric hypercalcaemia. This condition frequently presents at a young age with symptoms of hypercalcaemia but the 24-h urinary calcium is less than 2.5 mmol/l and the patient has no parathyroid pathology. A relative who has undergone a failed neck exploration should alert one to the strong possibility of this condition.

 

The foregoing biochemical tests diagnose and quantify primary HPT in 95 per cent of suspected cases but the following tests are sometimes required to reinforce the diagnosis when the data are marginal or conflicting.

 

1.Renal tubular absorption of phosphate (normal range 0.8—1.35) This is a sophisticated method of identifying the effect of excessive PTH on the renal tubular absorption of phosphate. Simultaneous measurements of urinary phosphate, plasma phosphate, plasma creatinine, and urinary creatinine enable the relationship between filtered load and renal excretion of phosphate, i.e. phosphate clearance to be compared with creatinine clearance. It is expressed as a ratio, referring to a standard nomogram. In primary HPT the ratio is below 0.8.

2.Urinary cyclical adenosine monophosphate (normal range < 2.5 nmol/100 ml of glomerular filtrate) Raised levels have been claimed in nearly 90 per cent of patients with primary HPT in some series. False-positive and false-negative results reported by others limit the usefulness of the test.

3.Hydrocortisone suppression/Dent test This test has largely been rendered obsolete since the introduction of IRMA measurement of the intact PTH molecule. Administering high doses of hydrocortisone (40 mg three times a day for 10 days) does not usually lower the hypercalcaemia produced by primary HPT but if the corrected plasma calcium falls on day 4, 7, and 10 into the normal range or more than 0.25 mmol/l, the hypercalcaemia is likely to be due to causes other than primary HPT.

 

Radiological findings are rarely in themselves diagnostic of HPT and more usually complement the biochemical data. They may reinforce the need to offer surgery. The most frequent radiographic changes seen in both primary and secondary HPT are those affecting the skeleton.

 

1.Bony radiographic changes The overall picture is that of bone density loss (osteopenia) and subperiosteal reabsorption of bone. These are seen especially in the middle phalanges of the hand on the radial side together with loss of the terminal phalangeal tufts (Fig. 8) 781. Subperiosteal absorption is seen in many other bones especially the lateral ends of clavicles, upper tibia, pubic symphysis, and sacroiliac joints. Localized areas of osteoclastic bone resorption with marrow fibrosis are seen in advanced bone disease. In the most severe form bone cysts and ‘brown’ tumours consisting of massive aggregations of osteoclasts (oestoclastoma) together make up osteitis fibrosa cystica (von Recklinghausen's disease) which as remarked earlier is now largely a medical curiosity. Generalized bone loss at a variety of sites has attracted some colourful descriptive nomenclature such as Rugger jersey spine (Fig. 9) 782 and pepper-pot skull (Fig. 10) 783, all of which aptly describe the osteoporosis and small osteolytic lesions. Absorption of the lamina dura around the teeth is reported but is an unconvincing radiological sign.

2.Renal radiographic changes Discrete renal stones or diffuse calcification throughout the renal parenchyma (nephrocalcinosis) may be found and should be looked for on plain abdominal radiographs in patients with HPT even in the absence of symptoms. Sometimes the findings are unexpectedly dramatic (Fig. 11) 784. An intravenous urogram may be indicated in the assessment of upper tract obstruction and overall renal function.

3.Metastatic calcification Mention has been made of the calcification which may be felt or seen radiologically in the skin and around blood vessels and joints. This phenomenon is readily confirmed on radiography of the relevant part.

 

LOCALIZATION OF PARATHYROID TUMOURS

Opinion is divided about the need to attempt localization of parathyroid tumours before the neck is explored surgically for the first time. In that situation an experienced surgeon can identify the pathology without any assistance in approximately 90 per cent of patients. None of the localization procedures to be described approach such a degree of accuracy and some are no better than 50 per cent accurate. Unfortunately localization techniques are least helpful when most needed, i.e. when the tumour is small (< 1 cm in diameter, < 100 mg in weight), ectopic (close to the heart and great vessels), or when the patient has a bulky neck due to obesity or coexistent thyroid enlargement. In view of the time and cost involved in such studies they are hard to justify except for patients who have had a previous unsuccessful neck exploration. The following localizing procedures are of proven value.

 

Selective venous sampling with PTH assay

This technique is the single most reliable method. It is based on the measurement of PTH concentration in samples obtained from the superior vena cava, innominate vein, internal jugular, and the multiple small veins draining the thyroid and mediastinum. The sampling catheter is introduced via the femoral vein and each sample numbered with the site noted precisely. A map can then be constructed plotting the samples to look for the vein(s) draining the source of highest PTH concentration on radioimmuno assay (Fig. 12) 785. Although good at lateralization in single gland disease (levels twice normal to that found in the background peripheral circulation being diagnostic) it cannot distinguish between an adenoma in the neck or one that has descended into the mediastinum leaving its venous drainage behind. Raised PTH concentration in all the thyroid veins suggest multigland hyperplasia. The drawback to this technique is that it is time consuming, expensive, and highly operator dependent.

 

Thallium/technetium subtraction scanning

A double tracer scintigram is performed using technetium–99m as sodium pertechnetate for imaging the thyroid and then thallium-201 (as thallous chloride) for imaging the thyroid and parathyroid glands simultaneously. A gamma-camera with on-line computer facilities substracts the pertechnetate image from the scatter corrected thallium image. Abnormal parathyroid tissue may then be demonstrated very convincingly (Fig. 13) 786. However, the success rates reported from various centres have varied widely. False-positive results may be produced by thyroid adenomas and abnormal lymph nodes. False-negative results arise in cases of parathyroid hyperplasia and tumours close to the heart and great vessels which are lost in the normal high concentration of isotope in the central mediastinum.

 

Ultrasound

This technique has the merit of being quick and inexpensive but cannot scan behind the sternum and is confined to identification of parathyroids which may or may not be in the neck. It lacks the resolution to pick up small tumours (< 0.5 cm) but can raise suspicion with intrathyroidal tumours, those in the carotid sheath, and those between the trachea and oesophagus.

 

Computerized tomography (CT) and nuclear magnetic resonance imaging (MRI)

There is no consensus on which of these imaging techniques is best, but used in conjunction with selective venous sampling one or other may improve localization for the difficult reoperative case (Fig. 14) 787.

 

INDICATIONS FOR SURGERY

Asymptomatic primary hyperparathyroidism

This is one of the controversial areas of HPT management and opinion is divided. Unfortunately only limited information is available about the natural history of primary HPT and although 20 per cent of asymptomatic patients in Purnell's series reported from the Mayo Clinic came to surgery over a 10-year follow-up period, not all were operated upon because of the adverse effects of the disease. Over 50 per cent, indeed, showed no deterioration over 5 years. The longer-term effects on renal function, bone density, hypertension, and survival itself remain unclear. Meanwhile asymptomatic patients are being diagnosed with increasing frequency, as mentioned before, and in the absence of prospective trials randomizing patients to surgery or observation alone (attempted but failed in the United Kingdom) a policy has emerged in the United States and the United Kingdom that identifies those patients for whom surgery is most clearly indicated (Table 3) 259.

 

Symptomatic primary hyperparathyroidism

There is good evidence that treatment is effective. The incidence of renal stones and infection decreases, osteitis fibrosa cysticica improves, subperiosteal resorption resolves, and patients with bone and joint pain are dramatically relieved. Where peptic ulceration is present it regresses and psychological disturbance may well resolve. Hypertension, which is found in 40 per cent of sufferers, is not in itself an indication for treatment and indeed deterioration after parathyroid surgery can occur. However, there should be no hesitation in advising surgery unless there are overwhelming medical contraindications. Alternative but less satisfactory options include embolization and CT or ultrasound guided laser or alcoholic destruction of an adenoma, if it can be confidently localized.

 

Secondary and tertiary hyperparathyroidism

The majority of patients whose parathyroids undergo hyperplastic change in response to chronic renal failure, or rarely chronic intestinal malabsorption, can be controlled non-operatively. Correction of the hypocalcaemia with vitamin D which enhances calcium absorption from the gut, high calcium intake, restricted dietary phosphate, and the use of phosphate binding agents such as aluminium hydroxide are effective standard medical measures. Where the patient is undergoing dialysis secondary HPT can be controlled by increasing the level of calcium in the dialysate, having first lowered the serum phosphate to avoid ectopic calcification. Surgery is indicated when these measures fail and the patient has intractable bone pain, pruritus, or when soft tissue deposition has led to ischaemic skin necrosis and joint pain. Tertiary or autonomous HPT tends to be less responsive to the foregoing treatment and where the patient is not responding and is unlikely to receive a renal transplant, total parathyroidectomy is gaining momentum as the best treatment option. An alternative strategy is either to perform a subtotal parathyroidectomy and accept a high recurrence rate or to remove all the parathyroids in the neck and cryopreserve all but 60 mg of tissue which is then implanted into the forearm (see below for precise details of this technique). The hypercalcaemia seen following a successful renal transplant can usually be reversed by oral phosphate supplements and is slowly self-limiting.

 

OPERATIVE SURGERY ON THE PARATHYROIDS

Preoperative preparation

In general this is identical to the broad recommendations for thyroid patients (see Section 11.1) 82 but the following special measures apply. Those with primary HPT and raised alkaline phosphatase and most renal bone disease sufferers (secondary) HPT should receive 2 to 4 &mgr;g per day of 1&agr;-hydroxycholecalciferol 2 to 3 days prior to surgery. This practice helps to combat the profound hypocalcaemia and tetany that is unleashed when the parathyroid disease is removed and the ‘hungry bones’ then take up all available calcium. Grossly hypercalcaemic patients, some of whom may present in crisis with coma, delirium, anorexia, vomiting, and abdominal pain, pose a particularly difficult diagnostic challenge. Where rapid investigation excludes other possible causes of hypercalcaemia, fluid and electrolyte balance must be corrected as a matter of urgency. If large volumes of intravenous saline fail to reverse the dehydration oliguria and azotaemia provoked by the vomiting and polyuria, then a vigorous diuresis stimulated by frusemide or ethacrynic acid is appropriate. If renal function is severely compromised then peritoneal or haemodialysis may need to be considered.

 

Preoperative localization studies have already been discussed and are only advocated in those patients who have undergone a previous neck exploration. However, intraoperative localization is greatly assisted by giving the patient a vital dye, methylene blue, which selectively stains parathyroid tissue and makes recognition easier. It is given in a dose of 5 mg per kg body weight, diluted in 500 ml dextrose saline, infused over an hour prior to neck exposure. A larger dose up to 10 mg per kg body weight may be indicated in obese patients based on lean muscle mass but care is needed to avoid cardiotoxic effects. The intensity of staining is most impressive in four gland hyperplasia due to secondary HPT (Fig. 15) 788 but many adenomas are equally recognizable appearing navy blue/purple depending on the degree of subcapsular haemorrhage (Fig. 16) 789. Normal glands have a subtle pale greenish tinge.

 

Exposure and technique of exploration

This is identical to that described for the thyroid (Section 11.1) 82 but is refined to meet the objective of identifying the four parathyroids and where they are all normal—a supernumerary abnormal gland. In meeting this objective there is no substitute for a patient systematic routine of neck exploration unconstrained by time. Meticulous haemostasis is crucial especially when the thyroid is freed from the strap muscles and the space is opened between the gland and carotid sheath. Where present the middle thyroid veins must be divided to allow full mobilization of the thyroid lobes forwards and medially. Finger retraction on a gauze swab is preferable to the use of grasping forceps which can traumatize the thyroid and lead to bleeding. If blood extravasates it stains the local tissues and makes identification of the parathyroids much more difficult. The inferior thyroid artery and recurrent laryngeal nerve are identified and gently retracted with linen or silastic vascular slings. These not only reduce the risk of damage to the nerve which may be adherent to the capsule of a parathyroid adenoma but also helps identification of the parathyroids which, as stated earlier, frequently derive their blood supply from one of the branches of this artery. Exposure of the superior parathyroid gland may require incision of the fascia binding the thyroid posteromedially to the trachea. If this is extended up to the level of the superior thyroid vessels the whole upper pole can be rolled forward. This manoeuvre also provides excellent access to ectopic superior parathyroid sites without the need to divide the superior thyroid pedicle. Some 90 to 95 per cent of upper parathyroids, however, are closely related to the inferior thyroid artery as it breaks up on the posterior surface of the gland, i.e. within a 2-cm radius of this vessel. Not infrequently it is tucked round behind the upper branches (see Fig. 1 774). The inferior parathyroid glands are less constant in position but 80 per cent are still found within a 2-cm radius of the lower pole of the thyroid and many are quickly identified on the anterolateral aspect (see Fig. 3 776).

 

By this stage the experienced surgeon will usually have identified one or more normal parathyroids which narrows down the field of search for the missing pathological gland(s). Close inspection of the thyrothymic ligament which includes the inferior thyroid veins, lower polar fat, and the thymic horns as they extend into the anterior mediastinum will reveal the vast majority of these ectopic lower glands (20 per cent). If not, the next step is to search between the tracheo-oseophageal groove and behind the oesophagus. If a lower parathyroid is still elusive then it may lie within the thyroid (1–2 per cent of cases). Embryologically this is only possible if the parathyroid has become indented into a cleft in the thyroid so close inspection and palpation should detect a ‘bulge’ and opening up a cleft or incising the lower pole anterolaterally will display the missing gland without the need to do a blind thyroid lobectomy. Failing that, ectopic parathyroid may reside within the carotid sheath which should be opened right up to the carotid bifurcation near the angle of the jaw especially if a suspected abnormal upper parathyroid is still missing. A transcervical thymectomy is the last manoeuvre to be performed and may reveal the missing parathyroid when the thymus is sectioned. The entire routine described will have taken several hours but if unsuccessful (only 1—2 per cent of patients) a formal mediastinal exploration via a median sternotomy is not in the patient's best interest at this stage. When hypercalcaemia is severe it can always be moderated until urgent localization studies are performed. The basic requirement after sternotomy is to clear all remaining thymic and fatty tissue, notably around the innominate veins, great vessels, and within the aortopulmonary window.

 

Surgical strategy for primary hyperparathyroidism

In the majority of patients (80 per cent) a single adenoma is responsible for the condition and removing it will cure the patient. The tumour is removed with considerable care since there is a real danger of autotransplantation and recurrent disease if the capsule is ruptured and cells are split. When the pedicle can be located easily it is clipped between mosquito forceps and the gland then gently lifted up and dissected clear from the surrounding connective tissues with iris scissors. The pedicle is ligated with a non-degradable suture. Frozen section microscopy confirms the diagnosis. Two main strategies are then possible. (a) Identify the three other parathyroids which will involve exploration of the contralateral side and, relying on clinical judgement alone, conclude, if they look normal, that the patient has single gland disease and do nothing more. This strategy can be justified if the surgeon is experienced and acknowledges the fact that even if a macroscopically normal parathyroid appears hypercellular on biopsy this is of doubtful clinical importance. The majority of such patients are cured by removing the adenoma alone and more aggressive resection runs the risk of an increased incidence of hypoparathyroidism. If other macroscopically enlarged glands are found this raises the possibility of multigland disease and biopsy helps identify a second adenoma in 2 per cent of patients or genuine two to four gland hyperplasia in 10 to 15 per cent of patients with primary HPT. (b) Identify the other ‘normal’ gland on the ipsilateral side and submit it to frozen section. If normal the contralateral side of the neck is left undisturbed (Tibblin strategy). This strategy chooses to ignore the 1 per cent chance of another adenoma being present on the other side of the neck and neglects the chance to double check whether the patient might have multigland hyperplasia. For these reasons this strategy cannot be recommended.

 

When all four glands are enlarged due to hyperplasia, a subtotal (three and a half) parathyroidectomy is recommended. Initially the two largest glands are removed, and then one-half of each of the remaining glands is excised, ensuring that the half left behind has an intact blood supply. After a brief interval these two halves are inspected and the one which appears less viable is removed and the other is left in situ clearly marked with a titanium clip. If the patient becomes hypercalcaemic at a later date this facilitates recognition for further resection.

 

Surgical strategy for secondary and tertiary hyperparathyroidism

The challenge with these patients who require surgery is to identify all the hyperplastic glands (up to 6 per cent may have a supernumerary fifth gland), and excise sufficient parathyroid tissue to relieve the symptoms of renal osteodystrophy but leave an adequate amount to preserve normal parathyroid function. There is controversy about how this goal is best achieved. There are those who advocate subtotal parathyroidectomy and others who promote total parathyroidectomy. The disadvantage of subtotal parathyroidectomy, especially for patients with tertiary HPT whose calcium and PTH levels are both elevated, is the high recurrence rate. If renal transplantation is likely in due course, which would slowly correct the patient's hyperparathyroidism, then subtotal parathyroidectomy avoids the risk of unmasking vitamin D resistant osteomalacia which is sometimes encountered after total parathyroidectomy and is very difficult to treat. An alternative strategy that theoretically overcomes both these problems is to remove all the parathyroid tissue from the neck, implant 50 to 60 mg in the forearm, and to cryopreserve the rest. If the forearm transplant is too generous and hypercalcaemia persists or recurs then the surgeon has easy access to reduce the volume of transplanted tissue. If the patient becomes hypocalcaemic then the cryopreserved tissue is brought out of storage and some more is implanted. Whilst freshly transplanted parathyroid cells function well in over 90 per cent of patients, implanted cryopreserved tissue functions in no more than 70 per cent of patients. The precise technique is to remove all parathyroid tissue from the neck, confirm this histologically, and then dice one parathyroid on a flat surface into 1-mm cubes with a scalpel. Some 50 to 60 mg is transplanted into three or more separate muscle pockets in the brachioradialis muscle of the non-dominant forearm (Fig. 17) 790. This is a delicate task requiring fine instruments to avoid crushing the fragments and haematoma which compromises the viability of the transplant. Each pocket is closed with a fine non-absorbable suture such as Prolene which prevents extrusion and is easily recognized if removal is required later. The rest of the parathyroid tissue from the other three or four glands is sectioned into 1 × 1 × 3 mm slices and placed in polypropylene vials containing tissue culture medium, antibiotics, dimethyl sulphoxide, and autologous serum. Freezing to−80°C is commenced quickly in a controlled manner after harvesting and the tissue is then stored in a liquid nitrogen freezer. Reversing the process is done in a 37°C water bath and successful transplantation has been reported as long as 18 months after storage.

 

Surgery for parathyroid carcinoma

The surgeon should be alerted to the possibility of a parathyroid carcinoma if the plasma calcium is appreciably elevated above 3.5 mmol/l especially if recorded in the presence of a palpable neck mass. It is at operation, however, that suspicion should be raised if the affected parathyroid is firmer than normal, grey in colour, and adherent to the local tissues. Lymph node involvement is frequent. The surgical strategy is to perform an en-bloc resection of the tumour and surrounding soft tissue which usually implies an ipsilateral thyroid lobectomy and nodal dissection. Local recurrence may be eliminated by postoperative localized external beam radiotherapy.

 

Surgery for MEN syndromes

The MEN type I syndrome is characterized by asymmetrical hyperplasia of the parathyroids with a high percentage of supernumerary glands. Nearly all of these patients develop HPT eventually. Partial thyroidectomy and cervical thymectomy is therefore advocated to reduce the chance of recurrent hyperparathyroidism. The MEN type IIA syndrome, by comparison, only leads to hyperparathyroidism in approximately 30 per cent of sufferers and is due to adenomatous change in one or two glands. Removal of just one or two of these obviously enlarged glands is necessary to secure a normocalcaemic state.

 

POSTOPERATIVE RESULTS, COMPLICATIONS, AND MANAGEMENT

The care of a patient after exploration for HPT is identical to that described for a routine thyroidectomy in Section 11.1 82. The same potential complications can arise but the risk of haemorrhage and recurrent laryngeal nerve damage is much less. The metabolic responses to parathyroidectomy are discussed in detail in Section 11.2.1 83, but temporary hypocalcaemia is a frequent occurrence, especially in those patients with metabolic bone disease. As already described in the section on preoperative preparation, this can be treated expectantly with 1&agr;-hydroxycholecalciferol which modifies the fall in the plasma calcium. Permanent hypoparathyroidism is a rare problem and affects 1 per cent of patients. In primary HPT an experienced surgeon will at the first operation successfully correct the hypercalcaemia in 95 per cent of patients with no recurrence over a 2-year period. Operative mortality approaches zero (0.2 per cent in the author's series). Eight per cent of patients undergoing subtotal parathyroidectomy for secondary and tertiary HPT, i.e. multigland involvement, have persistent or recurrent hyperparathyroidism. This figure rises to 30 per cent in those affected with the MEN I syndrome, who also suffer a greater risk of permanent hypoparathyroidism (4 per cent). Total parathyroidectomy with immediate autotransplantation of fresh parathyroid tissue achieves a functioning graft in over 90 per cent of patients. When the initial graft proves inadequate to maintain the level of plasma calcium, cryopreserved tissue can be successfully grafted after 18 months storage, but 35 per cent of these grafts fail.

 

Strategy after failed cervical exploration for hyperparathyroidism

Frequently patients in this category have had their primary surgery performed in a non-specialized unit. The validity of the diagnosis should be challenged with review of the original biochemical data. Whether there are discrepancies or not biochemical results will need to be rechecked. The possibility of familial hypocalciuric hypercalcaemia should be borne in mind as this syndrome has been implicated in 9 per cent of patients with failed neck exploration. The disease likewise should be reviewed in case multigland disease has been overlooked. Assuming the diagnosis is confirmed, the next crucial information to be checked is in the operation note. This should have recorded the precise location and appearance of all parathyroid tissue. When three normal glands have been found, the side of the missing fourth is established and the field of search narrowed. If four normal glands have been identified, the missing fifth is likely to be mediastinal. If there is incomplete documentation then a methodical re-exploration of the neck may be necessary unless localization studies have clearly shown the missing parathyroid(s) to be in the chest. The choice of localization study will depend on the local availability and expertise.

 

FURTHER READING

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Clark OH, et al. Localization studies in patients with persistent or recurrent hyperparathyroidism. Surgery, 1985; 98: 1083–94.

Dudley NE. Methylene blue for the rapid identification of the parathyroids. Br Med J, 1971; 3: 680.

Dunlop DAB, et al. Parathyroid venous sampling: anatomic considerations and results in 95 patients with primary hyperparathyroidism. Br J Radiol, 1980; 53: 183.

Edis AJ, Beahrs OH, van Heerden JK, Akwari OE. ‘Conservative’ versus ‘liberal’ approach to parathyroid neck exploration. Surgery 1977; 82: 466–73.

Gilmour JR. The gross anatomy of the parathyroid glands. J Pathol Bacteriol, 1938; 46: 133–49.

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