Hyperparathyroidism

Hyperparathyroidism is a more common condition than had been previously believed

The symptomatic presentation may vary but the increased use of auto analysers has resulted in ‘asymptomatic’ hypercalcaemic patients being the largest group.

 A corrected serum calcium concentration above the upper limit of normal and a simultaneous elevation of serum parathyroid hormone level are mandatory for the diagnosis.

Surgery should only be performed by an experienced parathyroid surgeon.

Long-term follow-up is essential as there is a significant increase in risk of death from cardiovascular disease. Hyperparathyroidism is associated with an increased secretion of parathyroid hormone. This occurs in:

Primary hyperparathyroidism, which is an un stimulated and inappropriately high parathyroid hormone secretion for the concentration of plasma ionised calcium, and is due to adenoma or hyperplasia, and very rarely carcinoma.

     A single adenoma is the commonest finding (multiple in 6 per cent). The whole gland is usually considerably enlarged, darker in colour, firmer and more vascular than normal; in some a rim of normal parathyroid tissue may be seen surrounding the adenoma. The histological appearances are the same as in hyperplasia, with a predominance of chief and water-clear cells. Carcinoma of the parathyroids is extremely rare, less than 1 per cent. It tends to invade locally and recur after operation. Blood-borne metastases have been described.

Secondary hyperparathyroidism is associated with chronic renal failure or malabsorption syndromes. The stimulus for the hyperplasia is chronic hypocalcaemia. All four glands are involved.

Tertiary hyperparathyroidism is a further stage in the development of reactive hyperplasia where autonomy occurs as the parathyroids no longer respond to physiological stimuli.

Cinical features

Hyperparathyroidism, rarely found in the first decade of life, is commoner in women than men, and most commonly found between the ages of 20 and 60 years. The clinical features vary enormously, even when the biochemical changes are similar.

Asymptomatic cases

The most common presentation is the detection of unsuspected and asymptomatic hypercalcaemia by routine biochemical screening.

Bones, stones, abdominal groans and psychic moans’

Only 50 per cent of patients suffer from any of these.

Nonspecific symptoms

Nonspecific symptoms include muscle weakness, thirst, polyuria, anorexia and weight loss — a challenge to the astute clinician!

  Bone disease

  There may be generalised decalcification of the skeleton, as in osteitis fibrosa cystica (von Recklinghausen’s disease), single or multiple cysts, or pseudotumours of any bone. The latter are particularly common in the jaw bones. Early radiological changes first appear in the skull and in the phalanges (Fig. 45.4), with loss of density and subperiosteal erosions. Many patients presenting with vague pains in the bones and joints are mistakenly diagnosed as rheumatic.

Renal stones

Hyperparathyroidism must be considered in every patient presenting with renal tract stone or nephrocalcinosis (Fig. 45.5), and even in those cases of renal colic where no stone can be demonstrated.

Dyspeptic cases

Patients with nausea, vomiting and anorexia are relatively common. Peptic ulcer and pancreatitis are not infrequently found in association with hyperparathyroidism, but the relationship is not as yet fully understood.

Psychiatric cases

Psychiatric cases are not uncommon; women, complaining of tiredness, listlessness and with obvious personality changes, are often wrongly labelled ‘neurotic’ or ‘menopausal’. Patients have been admitted to mental institutions because of irrational behaviour.

  Acute hyperparathyroidism

  This diagnosis is difficult and only too often made after death. Nausea and abdominal pain is followed by severe vomiting, dehydration, oliguria and finally coma. The serum calcium is very high. Treatment is urgent after rehydration, which is vital. Biphosphonates (disodium etidronate and pamidronate) are specific inhibitors of bone resorption. They are highly effective given parenterally and may also be used in the preoperative, short-term medical management of severe hypercalcaemia in primary hyperparathyroidism.

Clinical examination and investigation

Clinical examination may be unrewarding but the cause of dehydration or confusion may be found in the eyes. Corneal calcification  may be detected. It begins on the lateral and medial borders of the limbus (which distinguishes it from arcus senilis) and is best seen through a hand lens by the light of a bright torch reflected off the iris. Less common is band keratopathy in which a transverse band of calcification forms across the front of the cornea, and conjunctival calcification where redness of the eye also occurs. Hypertension may be present in up to 50 per cent of cases. There may be electrocardiographic changes with a shortened QT interval, primarily by an effect on the length of the S—T segment. A parathyroid adenoma is very seldom palpable in the neck. The diagnosis is confirmed with the following biochemical findings:

elevation of serum calcium (upper limit of normal 2.6 mmol/litre). Serum calcium occurs as calcium ions complexed to citrate and bound to albumin. Therefore the serum albumin concentration should be known in order to apply a correction factor: corrected serum calcium (mmol/litre) = measured serum Ca (mmol/litre) + (40 —A) x 0.02, where A = serum albumin (g/litre);

diminution of serum phosphorus (lower limit of normal 0.8 mmol/litre);

increased excretion of calcium in the urine (upper limit of normal 62 mmol per 24 hours for females, 75 mmol for males);

elevation of the serum alkaline phosphatase in cases with bone disease;

elevation of serum parathormone concentration.

The diagnosis of hyperparathyroidism largely depends on confirmed hypercalcaemia, exclusion of other causes of hypercalcaemia (see below) and a raised parathormone level. Present day immunoradiometric assays (upper limit of normal varies according to the laboratory) for biologically active intact parathormone are highly reliable and a raised level is even more reliable. Detectable levels of parathormone within the normal range, in the presence of hypercalcaemia, are suggestive of the diagnosis.

Preoperative localisation

Provided the surgeon is experienced in parathyroid surgery, preoperative localisation tests may do little to enhance the ability to detect 95 per cent of abnormal glands at surgery. However, a multimodal approach combining thallium—technetium isotope scanning, neck ultrasonography and magnetic resonance imaging (MRI) may yield precise information which will clearly facilitate surgery and reduce unnecessary dissection of tissue. Localisation tests are particularly indicated before re-exploration when the initial operation has failed, but may also be helpful to less experienced surgeons.

The simplest localisation test is an ultrasonic scan but results vary according to the skill and experience of the investigator.

   Computerised tomography is of most value in localising a lesion in the mediastinum rather than the neck.

Thallium—technetium isotope subtraction imaging may locate up to 90 per cent of parathyroid adenomas before surgery (Fig. 45.6). Like ultrasonography, subtraction scintigraphy is more accurate the larger the adenoma, and is inaccurate in parathyroid hyperplasia.

MRI is improving rapidly with some centres reporting up to 64 per cent detection prospectively. A low signal is obtained from the parathyroid glands on a T1-weighted image while a T2-weighted image appears in early studies to produce good contrast resolution from the surrounding tissues.

Invasive techniques such as selective angiography and selective venous sampling may be helpful in locating an abnormally situated gland after a failed initial exploration.

Differential diagnosis

Other causes of hypercalcaemia must be remembered and excluded. They are:

  secondary cancer in bone (breast, prostate, bronchus, kidney and thyroid);

carcinoma with endocrine secretion (bronchus, kidney and ovary);

multiple myeloma;

vitamin D intoxication;

•sarcoidosis;

•thyrotoxicosis;

•immobilisation;

medication: thiazide diuretics, lithium.

The differential diagnosis presents no problem if the parathormone level is estimated. In none of the above-mentioned conditions will parathormone be detectable in the blood.

Treatment

The only corrective treatment is surgical removal of the overactive gland or glands. In symptomatic patients, the indications for operation are clearcut. Many patients, however, in whom hypercalcaemia has been discovered incidentally, are not overtly symptomatic and a decision in favour of operation is more difficult.

Preoperative treatment is not usually necessary except in acute cases, when rapid correction of dehydration and electrolyte imbalance is necessary, with a careful daily check on the serum calcium. Drugs used would have been discussed earlier.

A recent international survey of operative strategy shows that the approach is changing. Removal of the adenoma with biopsy of the other glands has been supplanted by removal of the adenoma, a peroperative histological diagnosis and then biopsy of one normal gland. If the peroperative biopsy is that of a hyperplastic gland, then removal of all four glands with auto transplantation is indicated. Approximately 90 per cent of cases of primary hyperparathyroidisrn are associated with single-gland disease (adenoma). Ten per cent of cases are associated with multiple-gland disease, either hyperplasia or more than one adenoma. Adenomas, single or multiple, are removed.

In approximately 10 per cent of cases even the most experienced surgeon in this field may find difficulty in locating a parathyroid adenoma.

Parathyroid tissue can be successfully autotransplanted into the arm, a useful technique to avoid repeated potentially difficult explorations of the neck. The indications are tertiary hyperparathyroidism in patients undergoing chronic renal dialysis, and recurrent hyperparathyroidism. The technique is to excise all of the parathyroid tissue from the neck and to implant eight 1-mm3 fragments into a pocket in the forearm muscle mass, marking the site with nonabsorbable sutures. Postoperative vitamin D and calcium replacement therapy is required for varying periods. Recurrent hypercalcaemia is an indication for exploration of the implantation site and to excise further parathyroid tissue.

Prognosis

With successful surgery in severe cases, bones will recalcify and pseudotumours resolve. Renal stones will not disappear, but the incidence of recurrence after surgical removal is reduced and deterioration in renal function is prevented. Psychiatric patients show an early and often remarkable recovery. Many patients who are not overtly symptomatic

beforehand are aware of an improvement in well-being after correction of hypercalcaemia. In a small minority of cases, hyperparathyroidism recurs after several years and may warrant further surgery. In some of these, autotransplantation (above) offers reasonable prospects of control; Wells has reported excellent results when auto transplantation has been used for recurrent and familial hyperparathyroidism.

Hypertension associated with hyperparathyroidism is common, but the mechanism is unclear.

Long-term survival has been studied in 900 patients in Sweden. Despite successful surgery for primary hyperparathyroidism, the risk of premature death from cardiovascular and malignant diseases remained significant. Thus long-term follow-up is important as this indicates that primary hyper­parathyroidism causes damage that is not reversed by surgery.

Patients with persistent and recurrent primary hyperparathyroidism are a difficult management problem. For patients in whom initial exploration fails, reoperation is associated with a higher morbidity and a greater chance of failure. Accurate diagnosis and review of the initial pathology are essential, a family history of multiple endocrine neoplasia should be excluded, together with occult malignancy. Preoperative venous sampling of the neck and thorax is particularly valuable in localising a missed adenoma which is the most common cause of failure at the first operation.

Mild asymptomatic hypercalcaemia is a relative contraindication to further surgery but regular follow-up is mandatory. With an experienced surgeon, up to 90 per cent of missed lesions may be found but persistent postoperative hypocalcaemia may occur in up to 10 per cent of patients and recurrent laryngeal nerve injury is seen in about 6 per cent.

Parathyroid carcinoma

Parathyroid carcinoma is a rare condition to be considered when a high serum calcium is associated with a palpable lump in the neck. At operation it has a characteristic grey—white colour and is adherent because of local invasion of adjacent soft tissue. The best results are obtained by early recognition, avoiding rupture of the tumour capsule, and aggressive surgical management including ipsilateral thyroid lobectomy. Surgical clips should be used to outline the tumour bed for postoperative radiotherapy.

Multiple endocrine neoplasia syndrome APUD cells

Always consider that a patient with hyperparathyroidism may also have multiple endocrine adenomas. The cells involved, irrespective of the site, have the common chemical characteristics of amine precursor uptake and decarboxylation and are thus known as APUD cells. The disorder is inherited as an autosomal dominant, the manifestations in any one family tend to be similar and all members of the family should be investigated.

Type I

This most common variant involves the parathyroid glands (90 per cent), pancreatic islets (80 per cent), pituitary (65 per cent), thyroid and adrenal cortex. There is hyperplasia of the parathyroid glands and a chromophobe adenoma of the pituitary which may result in increased prolactin production or acromegaly. The pancreatic tumour may produce gastrin (the Zollinger—Ellison syndrome) or insulin, glucagon, somatostatin or vasoactive intestinal peptide (VIP) causing watery diarrhoea. Treatment is surgical excision.

Type IIa

A genetic abnormality located on chromosome 10 has been identified in MEN type ha syndrome. Fifty per cent have parathyroid hyperplasia. The associated lesions may be a medullary carcinoma of thyroid, which produces calcitonin, and a phaeochromocytoma. The latter should be excluded or be the first priority for treatment before exploration of the neck (see also Chapter 44).

  Type II b

This is differentiated from type IIa because of additional neurological abnormalities. Mucosal neuromas produce ‘lumpy and bumpy’ lips (Fig. 44.42) or eyelids, and there is a characteristic Marfanoid facial appearance. Megacolon and ganglioneuromatosis are also - found (see also Chapter 44).