Hyperparathyroidism
Fig.1: A typical benign parathyroid tumourHyperparathyroidism (HPT) is a condition caused by the parathyroid glands secreting excessive amounts of parathyroid hormone. It is generally picked up when the blood calcium is found to be elevated.
The most common form of the disease is primary hyperparathyroidism (PHPT), which may affect approximately 1 in 100 of the beneral population. The incidence is increasing with more frequent calcium measurements as part of GP visits, and better diagnostic tools.
It is two to three times more common in women than in men, although under the age of 45 years the incidence is similar in both sexes. In women over the age of 45 years the incidence may reach 1 in 200, and even up to 2% in the elderly.
The average age at diagnosis is 55 years, with the majority of patients presenting between the ages of 40-70 years.
Primary hyperparathyroidism is the most common endocrine disorder after diabetes and thyroid disease. It is also the number one cause of hypercalcaemia (raised serum calcium) in both the inpatient and outpatient setting.
In addition, up to 29% of hyperparathyroidism patients will have co-existing thyroid pathology, of which 2% will have an occult thyroid cancer. Thus it is important that all parathyroid patients have a thyroid ultrasound as part of their workup.
Causes of Hyperparathyroidism
Hyperparathyroidism can occur for a number of reasons, but in the most common form (primary hyperparathyroidism) we usually don't know the cause.
Possible contributing factors may be found in:
- molecular genetic defects - the vast majority of patients do not have a family history of HPT, but occasionally it can run in families (see Familial HPT below for more information). Less than 5% of cases can be linked to an inherited problem, the prime example being in MEN-1 Syndrome. Generally the older the age at presentation, the less likely is a heritable form of hyperparathyroidism - up to 10% less than 50 years, but <1% over 50 years.
- radiation exposure - like thyroid tumours, parathyroid tumours may be associated with radiation to the neck, with one study suggesting a near 3-fold increase in the incidence of HPT in those who had previously received neck irradiation therapy. Radioactive iodine therapy and external radiation therapy can both increase the risk of parathyroid tumours. An interesting recent study found that women receiving radiation treatment for breast cancer more often developed parathyroid tumours on the same side as the radiation treatment.
- drugs - long term use of the psychiatric drug, lithium, can cause enlargement of all parathyroids (hyperplasia)
The exact mechanism of why a parathyroid tumour develops remains unclear: it is either a primary abnormality in the control of cell growth, with a secondary change in CaR expression and function, or it could be the other way round with the primary problem occurring in the calcium-sensing pathways, or possibly it is a combination of both.
Familial Hyperparathyroidism
This accounts for about 5% of cases. It should be considered when there is a young age (<30 years) at diagnosis; there is a family history of hypercalcaemia, neuroendocrine tumours, or both; the presence of skin lesions or jaw tumours; or any combination of these. In this case all first degree relatives should have their calcium and PTH levels screened for abnormalities.
Fig. 2: Genetic causes of primary hyperparathyroidism in comparison with FHHThere are several types of genetic abnormalities which can be associated with hyperparathyroidism (Fig. 2), which tend to occur in clusters within family groups:
- MEN-1 (parathyroid disease is severe – see webpage on MEN-1). Parathyroid hyperplasia commonly occurs in MEN-1 syndrome, in association with pancreatic, adrenal and pituitary tumours, and is associated with mutations in the MENIN gene.
- MEN-2 (parathyroid disease is mild - see webpage on MEN-2). In this syndrome, caused by mutations in the 'ret' proto-oncogene, multiple parathyroid tumours may co-exist with tumours of the adrenal and thyroid glands.
- Familial hypocalciuric hypercalcaemia (FHH) (also known as familial benign hypercalcaemia). This disease is caused by a defect in the CASR gene, which codes for the parathyroid "calcium sensor (CaR)". The mutation sets the sensor incorrectly, leading to abnormally high serum calcium levels. The family history, mild hypercalcaemia, detectable parathyroid hormone level and low urinary calcium excretion make the diagnosis. The 24 hour urinary calcium and creatinine level should be measured to rule out FHH; a calcium:creatinine clearance ratio of less than 0.01 suggests the diagnosis, further supported if hypercalcaemia is found in any first degree relatives. The disease does not require surgery, except in neonates with severe hypercalcaemia, and can trap even the most experienced endocrine surgeon.
- Hyperparathyroidism-Jaw Tumour Syndrome (HPT-JT). This is related to a defect in the CDC73 (formerly HRPT2) gene, which encodes parafibromin. It is associated with a higher rate of parathyroid cancer (15-20%), osseous tumours of the mandible and maxilla, and renal and uterine tumours.
Types of Hyperparathyroidism
There are three types of hyperparathyroidism (HPT):
Primary HPT
This is the most common, where the abnormality lies within the parathyroids themselves (see webpages on Primary Hyperparathyroidism).
Secondary HPT
This is where parathyroid hormone (PTH) levels are raised due to any disease process which causes low calcium levels, thus stimulating the parathyroids to become overactive (see webpage on Secondary Hyperparathyroidism).
Tertiary HPT
If the causes of secondary hyperparathyroidism persist for some time, one or more parathyroid glands may become autonomous. The cells start producing excessive amounts of PTH even once the stimulus of low calcium is removed (e.g. after medical treatment). This is known as tertiary hyperparathyroidism. It can also occur when excessive PTH secretion continues after renal transplantation (sometimes known as quaternary HPT). Further information can be found on the webpage for Secondary Hyperparathyroidism.