What are the primary causes of hyperparathyroidism?

The parathyroid glands, located behind the thyroid, are endocrine glands that secrete the hormone that regulates calcium. A change in the parathyroid glands’ function, such as in hyperparathyroidism, results in abnormal calcium levels, affecting bones, kidneys and our overall health.

Here to provide an expert insight into hyperparathyroidism, including causes, symptoms, and diagnosis, is Mr Ioannis Christakis, renowned consultant endocrine surgeon.

What is hyperparathyroidism?

Hyperparathyroidism is a hormonal disorder in which the parathyroid glands produce too much parathyroid hormone.

The parathyroid hormone regulates calcium in the blood. When calcium levels are too low, the lack of calcium activates the parathyroid glands into producing – exactly the right amount – of parathyroid hormone to raise calcium levels back to normal. The self-regulated system that controls this process is called a negative feedback loop.

In hyperparathyroidism, an atypical accumulation of cells in the parathyroid glands do not behave in a normal pattern and secrete excess amounts of parathyroid hormone. Due to the disruption in the negative feedback loop, the over-production will continue to occur even if calcium is already at normal levels.

Over time, too much parathyroid hormone will eventually lead to increased calcium levels (a condition called hypercalcaemia) and decreased clearance of renal calcium.

What are the different types of hyperparathyroidism?

There are three recognised forms of hyperparathyroidism.

• Primary hyperparathyroidism

Primary hyperparathyroidism develops after a disruption in the negative feedback loop that controls calcium levels.

The risk of having primary hyperparathyroidism is three times greater in women than men, and usually occurs among women who are between 46 to 60 years of age. Only eight per cent of all primary hyperparathyroidism cases affect women of child-bearing age.

• Secondary hyperparathyroidism

Secondary hyperparathyroidism develops after renal disease or vitamin D deficiency causes a disruption in mineral homeostasis, the process that controls the stability of calcium levels.

• Tertiary hyperparathyroidism

Tertiary hyperparathyroidism develops after a secondary cause of hyperparathyroidism stimulates hyperplasia in the parathyroid glands, the enlargement of the gland due to an increase in cell number. Eventually, hyperplasia causes an automatic hyperfunction that leads to the excess production of parathyroid hormone.

What are the signs and symptoms of hyperparathyroidism?

Patients with hyperparathyroidism can present with any combination of the below symptoms, including:

• fatigue
• polydipsia (excessive thirst)
• polyuria (frequent passage of excessive urination)
• bone and joint pain
• kidney stones
• recurrent urinary tract infections
• osteoporosis or bone fractures
• constipation
• nausea or reduced appetite
• pancreatitis (pancreas inflammation)
• gastric ulcers in the stomach lining
• depression
• brain fog, including difficulty with concentration or memory loss
• confusion, lethargy or fatigue

Every patient is unique and is affected differently by the disease. Some patients will be completely asymptomatic, even if their blood calcium levels are very high.

Symptoms can improve in most patients following a parathyroidectomy, the surgical removal of the parathyroid glands.

What are the causes of hyperparathyroidism?

The cause of primary hyperparathyroidism is usually a single benign tumour in the parathyroid glands, such as:

• A single chief cell adenoma

Single chief adenomas are benign tumours that affect only one of the parathyroid glands. This type of adenoma is present in most (up to 90 per cent) of all hyperparathyroidism cases.

• A double adenoma

Double adenomas are benign tumours that affect two of the parathyroid glands. This type of adenoma represents three to eight per cent of all hyperparathyroidism cases.

• Hyperplasia of all four parathyroid glands

Four-gland hyperplasias represent three to five per cent of all hyperparathyroidism cases. This type of hyperplasia is prevalent in cases of familial hyperparathyroidism, but it can also occur in isolated cases of hyperparathyroidism.

In many cases, the development of hyperplasia is linked to multiple endocrine neoplasia (MEN) syndromes, which are inherited endocrine system disorders.

• Parathyroid carcinoma

Parathyroid carcinomas are rare, but sometimes aggressive, tumours that are characterised by significant hypercalcaemia and a noticeable cervical mass. Although rare, parathyroid carcinomas can metastasize to regional lymph nodes and/or distant organs, such as the liver, the lungs and the bones.

As of now, it is impossible to predict the presence of parathyroid cancer before the operation. It is only the intraoperative appearance and the characteristics of the parathyroid tumour that should prompt the surgeon to consider this diagnosis. In the case of a parathyroid cancer, an oncologic operation (the removal of the parathyroid tumour en bloc with part of the thyroid +/- lymph node resection) may be required in order to ensure complete removal of the tumour.

What is the link between hyperparathyroidism and multiple endocrine neoplasia syndromes?

Primary hyperparathyroidism, pituitary tumours, and pancreatic endocrine tumours are the three diseases that are encountered in multiple endocrine neoplasia type 1 (MEN 1).

Although less frequently, hyperparathyroidism is also found in cases of multiple endocrine neoplasia type 2 (MEN 2A). This type of MEN syndrome is characterised by medullary thyroid cancer, pheochromocytoma (a type of adrenal cancer) and primary hyperparathyroidism.

In contrast, hyperparathyroidism very rarely occurs in cases of multiple endocrine neoplasia type 2B (MEN 2B).

How is hyperparathyroidism diagnosed? What do the investigations of hyperparathyroidism involve?

The diagnosis of primary hyperparathyroidism is done only by blood and urine tests. Ordering biochemical investigations to secure the diagnosis of primary hyperparathyroidism can be complex; while some patients may receive a clear-cut diagnosis, other patients may require a repeat of blood and urine tests.

Once the diagnosis of primary hyperparathyroidism is secure, the next step is to perform radiologic investigations to localise the culprit gland(s). These investigations may be a neck ultrasound, a Sestamibi parathyroid scan, or a 4D CT neck scan.

Some scan results can be completely negative for hyperparathyroidism. Other scans may misdiagnose thyroid nodules or lymph nodes as parathyroid tumours, or miss the presence of a very large parathyroid tumour. An expert parathyroid surgeon can find the culprit gland(s) even if the scans are completely negative or are wrong.

For this reason, a negative scan should not be taken as an indication to not have a parathyroidectomy.

If you require expert treatment and management for hyperparathyroidism, do not hesitate to book an appointment with Mr Christakis via his Top Doctors profile today.