Parathyroid

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Contents

Introduction

There are four parathyroid glands, two on each side, having a postero-lateral relationship to the lateral lobes of the thyroid gland. The two superior parathyroid glands arise from the fourth pharyngeal pouch and ultimobranchial body, and migrate medially early in foetal development along with the C cells to meet the developing thyroid gland. They are generally very constant in position in relation to the lateral lobe or to the Tubercle of Zuckerkandl. The two inferior parathyroid glands arise from the third pharyngeal pouch and then descend into the anterior neck along with the thymus. They often are very variable in position and may be found in relation to the inferior pole of the thyroid gland, within or adjacent to the thymus, or in the anterior mediastinum. Ectopic or supernumary parathyroid glands are common, being found in over 10% of the population. They may be located in a variety of positions such as the pericardium, or within the carotid sheath. If parathyroid glands enlarge, they may migrate from their original location. Superior parathyroid glands, as they enlarge, often move down along the oesophagus, presumably aided by peristalsis, and can end up in the posterior mediastinum. Enlarged inferior glands may be found in the anterior. The course of the recurrent laryngeal nerve acts as a marker to the location of the parathyroid glands with abnormal superior glands usually located posterior, and abnormal inferior glands located anterior, to the nerve. The normal parathyroid gland weighs 30–35. The glands derive their primary blood supply from branches of the inferior thyroid artery although superior glands may receive branches from the superior thyroid artery.

The parathyroid glands secrete parathyroid hormone (PTH), an 84—amino acid peptide, which has a half-life of about 5 minutes, which is rapidly broken down into N-terminal and C-terminal fragments in the reticulo-endothelial cells of the liver. PTH acts on bone to promote calcium by stimulation of osteoclast activity, leading to bone resorption. PTH also acts on the kidney to increase calcium resorption in the proximal convoluted tubule and inhibit resorption of both phosphate and bicarbonate. An additional renal effect is the production by the proximal tubule of 1,25-dihydroxy vitamin D, which results in calcium absorption by the small intestine.

Diseases affecting the parathyroid glands result essentially in disorders of function, either excess or reduced PTH secretion. They include

  • Primary hyperparathyroidism
  • Secondary and tertiary hyperparathyroidism
  • Hypoparathyroidism

Disorders of the parathyroid glands

Primary hyperparathyroidism

Pathology

Primary hyperparathyroidism is due to a parathyroid adenoma, either single or multiple in more than 90% of cases. It may also be due to parathyroid hyperplasia or, rarely, parathyroid carcinoma. It may occur as a sporadic phenomenon, or may be associated with one of the familial endocrine syndromes including MEN I, MEN IIA, or familial hyperparathyroidism. Hyperparathyroidism is also associated with a history of previous exposure to ionising radiation.

Clinical presentation

Primary hyperparathyroidism occurs predominantly in women, with the highest incidence being in the fifth to sixth decades. The commonest presentation is in apparently asymptomatic individuals who are found to have hypercalcaemia during routine blood testing, or who present for routine bone mineral density testing and are found to have osteopoenia or osteoporosis. Symptoms specifically associated with primary hyperparathyroidism include neuropsychological manifestations such as tiredness, lethargy and depression, musculoskeletal manifestations such as bone pain and muscle weakness, renal stones, abdominal pain from constipation or peptic ulceration, polyuria and polydipsia.

Investigations

The diagnosis of primary hyperparathyroidism is confirmed by the finding of an elevated serum calcium level in association with an inappropriately raised PTH level. The PTH may well be in the normal range despite the presence of primary hyperparathyroidism, for with all other causes of hypercalcaemia (eg metastatic malignancy), an elevated serum calcium will be associated with a suppressed PTH level. Measurement of 24-hour urinary calcium secretion must also be performed to exclude the rare but confounding genetic disorder of familial hypocalciuric hypercalcaemia, in which an elevated serum calcium may be associated with a marginally raised PTH level.

A careful family history will generally exclude an association with one of the familial endocrine syndromes. If the patient has MEN I, tumours of the pituitary and pancreatic islet cells need to be excluded, whereas if they are part of an MEN IIA family, serum calcitonin and urinary catecholamines need to be measured to exclude medullary thyroid carcinoma and phaeochromocytoma.

Once a diagnosis of primary hyperparathyroidism has been confirmed, and there are no exclusion criteria for minimally invasive parathyroidectomy, for example family history, then parathyroid localisation studies should be undertaken. A sestamibi parathyroid scan will demonstrate uptake in a single parathyroid adenoma in more than 70% of cases, with neck ultrasound providing valuable additional information.

Treatment

The only successful treatment for primary hyperparathyroidism is parathyroidectomy. Current NIH guidelines argue that asymptomatic patients may be treated by observation subject to a set of strict criteria; however there is increasing evidence that even “asymptomatic” patients obtain significant benefit in relation to improvements in non-specific neuropsychological symptoms following normalisation of serum calcium levels after surgery. As such most patients, unless there are specific contraindications to surgery, are now offered parathyroidectomy as initial therapy.

Secondary hyperparathyroidism

Pathology

Secondary hyperparathyroidism is the result of prolonged hypocalcaemia and is usually due to chronic renal failure, although vitamin D deficiency and glutensensitive enteropathy must be excluded as causes. The prolonged hypocalcaemia results in chief cell hyperplasia and PTH secretion. In chronic renal failure, this appears to be due to difficulties with excretion of phosphate with secondary hyperphosphataemia and hypocalcaemia, and increases in PTH result in osteodystrophy much greater than that normally seen in primary disease.

Clinical features

The osteodystrophy of secondary hyperparathyroidism causes bone and muscle pain and may lead to pathological fractures. There may be deposition of calcium in soft tissues resulting in skin itch, and even necrosis and severe conjunctivitis.

Investigations

Secondary hyperparathyroidism is characterised by hypocalcaemia, hyperphosphataemia (due to failure of excretion) and an elevated PTH level. Significant bone disease is indicated by elevation of serum alkaline phosphatase. Hypercalcaemia may occur secondary to vitamin D treatment. Radiology demonstrates much grosser changes in the skeleton than is usual in primary hyperparathyroidism in the modern context, with irregular bone density loss and subperiosteal absorption of bone. This produces the classical appearance of the “pepperpot skull”, the “rugger jersey” spine and the less dramatic but more frequent loss of the outer third of clavicle and scalloping of the radial side of the middle phalanges. Metastatic calcification can be seen around vessels and in the capsules of joints.

Treatment

Secondary hyperparathyroidism occurs to some degree in all patients with chronic renal failure but the symptoms can usually be controlled by calcium supplementation and the administration of 1,25-dihydroxyvitamin D at the time of dialysis if there is progression to end-stage renal failure. Phosphate binders may also be used to reduce intestinal absorption of phosphate although he use of binders containing aluminium must be avoided to prevent the development of aluminium bone disease and an irreversible dementia. Although the treatment of secondary hyperparathyroidism is therefore largely medical in nature, 20% of patients will not achieve satisfactory symptom or biochemical control. Indications for surgery include the development of hypercalcaemia, because this is likely to lead to metastatic calcification and persistent elevation in alkaline phosphatase, which is an indication of continuing major bone disease. Clinical indications include intractable itch or bone pain. These patients should be treated by total parathyroidectomy with or without parathyroid autotransplantation.

Tertiary hyperparathyroidism

Tertiary hyperparathyroidism results from the hyperplasia of secondary hyperparathyroidism when the glands become autonomously hyperfunctioning rather than responsive to the original stimulus. This is most clearly seen after a successful renal transplant has been performed where the restoration of normal renal function and the appropriate production of 1,25-dihydroxyvitamin D could be expected to restore normal calcium balance. Most patients should receive active medical treatment in an attempt to avoid endorgan damage, and will usually show a return to normal calcium metabolism within a period of 6 months. In the small number of patients whose symptoms are not controlled or in whom the hypercalcaemia persists in spite of adequate treatment and normal renal function, the glands must be assumed to have developed some degree of autonomy and parathyroidectomy is required. The extent of surgery is dictated by the operative findings, with either subtotal or total parathyroidectomy with autotransplantation being undertaken depending on the number of glands involved in this process.

Hypoparathyroidism

Hypoparathyroidism may be due to congenital absence of the parathyroid glands, idiopathic autoimmune failure of the parathyroid glands or, most commonly, due to surgical removal or damage to the parathyroid glands after total thyroidectomy. Temporary hypoparathyroidism is common after total thyroidectomy, especially if devascularised parathyroid glands have been autotransplanted during the procedure. Such patients may be asymptomatic or may present with paraesthesiae in the limbs and around the mouth. This is easily managed by replacement therapy with oral calcium and 1,25-dihydroxyvitamin D for several weeks awaiting recovery of the autotransplanted glands.

Operative management

Parathyroidectomy

Patients with primary hyperparathyroidism and concordant localisation to a single site can undergo minimally invasive parathyroidectomy. Patients with primary hyperparathyroidism where localisation has not been successful are more likely to have multiple gland disease and should undergo open parathyroidectomy and four-gland exploration. Patients with secondary and tertiary hyperparathyroidism require either subtotal parathyroidectomy or total parathyroidectomy with or without forearm autotransplantation. Successful detection and removal of the involved parathyroid tissue will occur in 98% of patients. In the small percentage of patients in whom the gland is not detected at the time of primary surgery, it is likely to lie in an ectopic position, e.g. pericardium or middle mediastinum and additional, localisation studies such as CT scanning and selective venous sampling will be required prior to a second operation.

Complications of parathyroidectomy

The complications of parathyroidectomy include all the general complications of any operation, such as bleeding, wound infection, and reaction to the anaesthetic agent. In addition, there are specific complications, including:

  • damage to the recurrent laryngeal nerves and to the external branch of the superior laryngeal nerves
  • failure to locate abnormal parathyroid tissue
  • hypoparathyroidism
Recurrent nerve palsy leads to a hoarse voice that usually recovers but may require procedures such as vocal cord medialisation. If the external branch of the superior laryngeal nerve is damaged, the patient may lose the ability to sing, shout or project their voice. Failure to locate abnormal parathyroid tissue may be due to the adenoma being in an ectopic site such as the mediastinum. Further localisation studies and surgery will be required. If more than one parathyroid gland is involved, subtotal parathyroidectomy may lead to hypoparathyroidism, which may require short-term administration of oral calcium and 1,25-dihydroxyvitamin D for several weeks.
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