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March 2007: Blood testing diagnostic for parathyroid disease

What are the presenting features of hyper- and hypo-parathyroidism?

Which patients should GPs refer to hospital?

What complications occur after surgery?

What are the presenting features of hyper- and hypo-parathyroidism?

Which patients should GPs refer to hospital?

What complications occur after surgery?

Parathyroid disease is common and can present in many ways. However, once parathyroid disease is suspected, confirmation of hyperparathyroidism is relatively straightforward. All cases of hypercalcaemia in the presence of abnormal parathyroid hormone (PTH) levels should be referred to an endocrine surgeon.

The parathyroid glands are oval structures the size of millet seeds. There are generally four and they lie on the posterior surface of the thyroid gland. They are usually arranged symmetrically, with two superior and two inferior parathyroid glands.

There can be some variation in the number (5 per cent of people have more than four glands)1 and location of the glands. They are sometimes as high as the hyoid bone or low in the mediastinum.

The parathyroid glands are involved in the control of blood calcium levels. They secrete one principal hormone, PTH, which acts to raise blood calcium levels in response to hypocalcaemia. Hypermagnesaemia also promotes the release of PTH.

PTH raises blood calcium in three main ways:

• Osteoclast activation causes resorption of bone, releasing some of the calcium stored

• Stimulation of the kidney to reabsorb calcium and excrete phosphate

• Promotion of the activation of vitamin D precursors in the kidney. Active vitamin D (1,25 cholecalciferol) promotes the uptake of calcium from the small intestine.

As the calcium level returns to normal the rising calcium exerts a negative feedback on the release of PTH.

The other main hormone involved in calcium regulation is calcitonin, which is produced by the parafollicular cells of the thyroid gland. Calcitonin is released in response to a rising calcium level and acts to reduce it by inhibiting osteoclastic resorption of bone and reducing calcium resorption by the kidney. However, the role of calcitonin in calcium regulation is still not fully understood.

As with all endocrine disorders, abnormalities are associated with both over- and under-production of the relevant hormone. Parathyroid disease can be divided into hyperparathyroidism and hypoparathyroidism. Both states can be caused by a variety of conditions and can give rise to a large range of symptoms, or be asymptomatic.


Hyperparathyroidism occurs for a number of reasons.?Symptoms range from none to all the characteristic features of hypercalcaemia.

The causes can be divided into three types.

In primary hyperparathyroidism, the abnormality lies with the parathyroid glands. This is the most common cause.

In secondary hyperparathyroidism, PTH levels are raised in response to a disease process causing hypocalcaemia.

Tertiary hyperparathyroidism is rare.

It occurs when the parathyroid glands become autonomous when calcium levels are low, and continue to secrete PTH even when calcium levels return to normal.

Primary hyperparathyroidism

Three disorders affecting the parathyroid glands cause spontaneous excessive secretion of PTH. They are all amenable to surgery. The disorders are:

• Parathyroid adenoma. A single benign parathyroid tumour is the cause in 80 per cent of cases1

• Parathyroid hyperplasia, caused by two or more enlarged glands. This accounts for 19 per cent of cases

• Parathyroid cancer. This is present in 1 per cent of cases.2

As with thyroid tumours, both malignant and benign parathyroid tumours may be induced by irradiation of the neck.

In Sipple's syndrome, multiple parathyroid tumours may co-exist with tumours of the adrenal and thyroid glands. This is part of multiple endocrine neoplasia (MEN) type 2 syndrome, where mutation in genes such as the RET proto-oncogene predispose individuals to tumours within several endocrine glands.

Parathyroid hyperplasia commonly occurs in MEN type 1 syndrome in association with pancreatic, pituitary and adrenal tumours.

Primary hyperparathyroidism affects one person per 1,000 in the UK.3 It is twice as common in women as men, and occurs most frequently in the fifth decade of life.

Approximately 2 per cent of post-menopausal women have relatively mild primary hyperparathyroidism, which suggests that the menopause may mask the condition.

Hyperparathyroidism is asymptomatic in 50 per cent of all cases and the diagnosis is often made by routine blood testing.

Patients with hyperparathyroidism may have:

• Fatigue and anaemia

• Muscle weakness and joint pain

• Constipation and nausea

• Polydipsia (sometimes with haematuria)

• Mood change with confusion

• Abdominal pain caused by ulcers

• Renal colic

• Bone pain caused by erosions

or fractures

• Hypertension.

The diagnosis is made by confirming the biochemical abnormality. More than one sample of blood for calcium and PTH should be obtained and the patient should have a normal kidney function.

A positive test will show a raised calcium level and an abnormal PTH; in non-parathyroid causes of hypercalcaemia, PTH is low.

A magnesium level should also be obtained, as hypermagnesaemia can cause the release of PTH.

There appears to be a suprisingly high incidence of primary hyperparathyroidism in the Asian population. This is particularly interesting because parathyroid disease is relatively rare in the Indian subcontinent. It is not certain that the apparent increased incidence of primary hyperparathyroidism in the UK Asian population is a true phenomenon, but if it is, it may well be related in part to the high incidence of vitamin D deficiency in Asians in the UK, which may induce primary hyperparathyroidism.

Vitamin D deficiency is extremely common in the Asian community because of three factors:

• High incidence of vegetarianism within the community

• Avoidance of sunlight

• The widespread use of chapatti flour, which binds vitamin D and stops its absorption from the gut.

Patients with parathyroid tumours often exhibit low calcium and a raised PTH. As their vitamin D deficiency is cured their calcium rises to abnormal levels while their PTH remains high. However, in patients who are purely vitamin D deficient, calcium remains normal and their PTH returns to normal with vitamin D treatment. This phenomenon occurs in all patients who have vitamin D deficiency, irrespective of the cause.

PTH assays are discriminating and there are very few situations where a raised PTH does not indicate true primary hyperparathyroidism. One exception is familial benign hypercalcaemia, a rare cause of raised serum calcium that does not require surgery. In this condition the parathyroid calcium receptor is incorrectly set because of a genetic defect, which results in a moderately high calcium with a raised PTH. This condition can be differentiated from true hyperparathyroidism because the urine contains very little calcium.


There is currently no effective medical treatment to control primary hyperparathyroidism. Conservative management consists of watchful waiting. Surgery is required when complications occur or when bone density deteriorates.

Hormone replacement therapy is advised in post-menopausal women if there are no contraindications.

When a conservative approach is used, patients must be checked yearly for any deterioration in calcium levels, kidney function and/or bone density.

Novel treatments that involve the parathyroid calcium receptor are currently in development.

Cinacalcet was approved in January 2007 by NICE as a treatment for patients with secondary hyperparathyroidism on dialysis, with very high levels of parathyroid hormone that cannot be lowered by other treatment, and who cannot have surgery.

Patients who receive cinacalcet should have regular checks. The treatment should be stopped if the parathyroid hormones in the blood do not fall substantially within four months.?In the future, cinacalcet, or its derivatives, may be useful or supersede surgery for primary hyperparathyroidism itself. However, cinacalcet is extremely expensive and at the moment should not be used for primary hyperparathyroidism, with the possible exception of patients with parathyroid carcinoma.


Surgical removal of parathyroid tissue is currently the only definitive treatment for primary hyperparathyroidism.

Surgery is indicated if hypercalcaemia is present in a patient under 50 years of age, if:

• Hypercalcaemia is greater than 3mmol/l

• Hypercalcaemia is symptomatic

• There is deterioration in renal function

• Progressive reduction in bone density

• Excessive excretion of calcium in the urine

• Any suggestion of malignancy.

The patient needs to be fully assessed and prepared before surgery. Serum calcium must be less than 3mmol/l. If the patient is operated on with a calcium level above 3mmol/l there is a risk of anaesthetic complications, and an increased risk of the surgical complication of acute pancreatitis.

Mild to moderate hypercalcaemia can be improved with oral hydration and dietary restriction of milk products.

In severe cases, when calcium levels are greater than 3mmol/l, patients will need to be admitted to hospital, sometimes several days before surgery is scheduled, for intravenous hydration and possibly intravenous pamidronate to lower their serum calcium to within safe limits.

The parathyroid tumour or tumours need to be localised. Six preoperative imaging tests are currently used.4

First-line investigation is by ultrasound and sestamibi subtraction scanning.

CT, MRI, arteriography and selective venous sampling are used for more difficult cases and re-exploration surgery.

The aim of surgery is to remove abnormal parathyroid tissue. The optimal result is a normal serum calcium, a normal PTH level, an unchanged voice and an almost invisible scar.

The traditional surgical approach is to use general anaesthesia. A small incision is made in the neck to allow the surgeon to explore all parathyroid glands. Any problematic glands are then removed. The approach is safe and 98 per cent effective.5

There are three surgical options available:

• Subtotal parathyroidectomy, in which abnormal tissue is removed, leaving some normal parathyroid tissue

• Total parathyroidectomy, in which all parathyroid tissue is removed

• Total parathyroidectomy with auto-transplantation. In this the glands are removed, but some normal parathyroid tissue, dissected from the patient's own glands, is implanted into the patient's forearm. This implant will act as normally functioning parathyroid tissue.

In some centres, high-quality scanning highlights 80 per cent of parathyroid tumours,6 and highly sophisticated biochemical intra-operative assays allow the surgeon to measure serum PTH accurately during the operation and remove only abnormal tissue, as the PTH level will return to normal when this has been excised.

This approach, known as scan-directed parathyroidectomy, is performed through an incision measuring less than 2cm and enables surgeons to explore only one area of the neck and remove the parathyroid tumour, with a 95 per cent chance of cure.

The advent of improved anaesthesia has also resulted in parathyroidectomy being performed under local anaesthesia in carefully selected patients.


The failure rate for initial exploration is less than 3 per cent and in subsequent explorations with sophisticated imaging this rate does not increase. As a general rule, secondary procedures on patients who have already had failed surgery should not be undertaken at a district general hospital, but at a specialist unit. In such units the final failure rate is less than 1 per cent.

Low serum calcium is very common in the first few days after surgery but usually settles within a day or two. Calcium supplements are occasionally required. If the bones have been affected, supplementary calcium and vitamin D are given until the bones heal. Regular calcium monitoring is required.

The risk of voice change is well below 1 per cent, but is higher in patients who have had previous surgery.

Small amounts of blood or serum may collect under the wound. At worst, these only require needle aspiration without anaesthetic. Surgery to resolve serious bleeding occurs in around 0.1 per cent of cases.

Hypertrophic or keloid scars are common in black patients and fair-skinned, red-headed patients.

Secondary and tertiary hyperparathyroidism

In secondary hyperparathyroidism the parathyroid glands excrete excess PTH in response to an initial low blood calcium. The main cause is renal failure. The kidney fails to convert 25-cholecalciferol into 1,25-cholecalciferol, the active form of vitamin D, leading to decreased absorption of calcium from the small intestine. The kidney also fails to excrete sufficient phosphate. Both factors contribute to an increased secretion of PTH.

Another cause is sprue, a disorder in which there is a generalised malabsorption of nutrients from the diet. This results in hypocalcaemia, which triggers PTH secretion.

In the case of vitamin D and/or calcium deficiency, secondary hyperparathyroidism is treated by targeting the underlying cause. Surgery is only considered in tertiary hyperparathyroidism, when there is evidence that the glands are becoming autonomous and hypercalcaemia develops.


Hypoparathyroidism is rare and results in hypocalcaemia. This causes a variety of symptoms including paraesthesia, cramps, tetany, agitation and seizures. The most common cause is damage to the parathyroid glands during surgery.

Autoimmune disease may also cause hypoparathyroidism. For example, in polyglandular autoimmune syndrome type 1, hypoparathyroidism occurs with adrenal insufficiency, thyroid disease and type 1 diabetes.

It is important to remember that hypoparathyroidism is not the only cause of hypocalcaemia. Other causes include hypomagnesaemia, pseudohypoparathyroidism, hypo-albuminaemia and various drugs.

Treatment of hypocalcaemia is with oral calcium and vitamin D supplements. The best vitamin D drug to use is calcitriol (1,25 dihydroxyvitamin D), as the kidney cannot efficiently process other forms of vitamin D when PTH levels are low.


Mr John Lynn
consultant endocrine and breast surgeon, Cromwell Hospital, London

Dr Tim Patel
specialist registrar in emergency medicine,
St Mary's Hospital, London

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