ESE Clinical Update on Calcium and Bone

We were delighted to be invited by the SfE to attend this training session for the first time. Caroline Fryer was our representative and her report is below.

Genetic form of hyperparathyroidism (when to suspect it)

Prof Fadil Hannan – University of Oxford (UK)

Prof Fadil Hannan from the University of Oxford explained the germline mutations that can cause various versions of hyperparathyroidism including MEN1, CASR and CDC73. He explained when to suspect a genetic cause:

• early onset disease
• multi-gland parathyroid disease
• features consistent with a particular genetic disorder
• family history

He explained the process of making a genetic diagnosis and how it is not a simple task but requires taking multiple things into account, not just genetic tests.

He used Familial Hypocalciuric Hypercalcaemia (FHH) as an example. He pointed out that this presents as lifelong hypercalcaemia, and therefore any history of normal calcium immediately rules out this diagnosis. However, the raised calcium levels may not be severe and may be a similar level to that of patients with primary hyperparathyroidism. PTH is usually within normal range in FHH.

He recommends using 24 hour urine to test for FHH but pointed out that the cut off of <0.01 is not an exact number, and many people with FHH have levels above this. Likewise a substantial number of patients with primary hyperparathyroidism have levels lower than this cut off point, so they can be missed.

So, he recommends that FHH should be suspected if there are these conditions:

• Longstanding non-progressive hypercalcaemia
• Normal PTH
• 24 hr urine Ca:Creatinine clearance ratio <0.01 (but don’t exclude FHH if >0.01)

Then a family history would be collected, family members would also be tested for calcium. Family history is a key predictor of a positive gene test. Patients with a positive family history, aged under 40 at diagnosis are more likely to have a positive gene result. Crucially he said that a negative genetic test does not rule out a genetic cause, and that family testing is important.

Parathyroid carcinoma – diagnosis and treatment (when to suspect it, how to proceed)
Prof Maurizio Iacobone – Professor of endocrine surgery, University of Padua, Italy

Maurizio Iacobone explained that there are clues during surgery as to whether they have found a parathyroid carcinoma rather than an adenoma, including its appearance and interaction with surrounding tissue and it is distinctive under the microscope when dyes are used.

He also talked about atypical tumours, and the ways in which these could be differentiated. Clearly this is a challenge. Parathyroid carcinoma is commonly associated with the CDC73 gene, and may either be a sporadic mutation or hereditary.

It is important that the tumour isn’t biopsied as this can cause seeding of the tumour and can send cells into multiple random locations which can be hard to find again. Treatment is usually by surgical resection and may need to be repeated several times, at the moment this is the best treatment, as there is a lack of chemotherapy options, but new treatments are being tested. Surgery on suspected parathyroid carcinoma should be carried out by an experienced parathyroid surgeon with over 40 ops a year.

The ESE has put together new surgery guidelines for parathyroid carcinoma.

The following list can be used to assess the likelihood of parathyroid carcinoma:

• More common in males
• Aged 50-60
• Calcium > 3.5mmol/l
• PTH >500pg/ml
• Severe symptoms
• Large infiltrating mass

Surgical interventions for different types of hyperparathyroidism
Nancy Perrier (USA) – Chief Surgeon in the Surgical Endocrinology section at MD Anderson Cancer Center in Texas.

Dr Perrier gave detailed explanations of the options for surgical intervention including minimally invasive targeted surgery for single gland removal. At her hospital they have devised a way of naming all the possible locations of parathyroid adenomas, by a system of letters, denoting certain places to check during surgery, this enables all of the team including radiology to communicate more effectively about positions of glands and they can decide who does the surgery based on its complexity and risk to nearby nerves or arteries. For instance she joked that a ‘D’ position adenoma (next to the inferior thyroid artery) means ‘Don’t let the intern do it’. Other less common positions of adenomas include inside the thyroid gland and near or inside the thymus.

She also spoke about when they know when to stop during surgery – either when the PTH has dipped significantly or when they have located an obvious adenoma and can see another gland that is normal (ie there is not multi-gland disease such as hyperplasia).

She spoke about the genetic causes of hyperparathyroidism and emphasised how important it is not to do fine needle biopsies of parathyroid adenomas, particularly if they suspect they could be carcinoma, or a cystic neoplasm, as this can allow seeding of the tumour. In these cases they would aim to remove the whole tumour without breaking the capsule, often including sections of thyroid to be on the safe side.

She discussed the level of risk to patients diagnosed with parathyroid cancer which has a high chance of recurrence and currently no chemotherapy options.

New surgery techniques for hyperparathyroidism (what type of patients would benefit from them)
Prof Frederic Triponez – University Hospitals Geneva (Switzerland)

Prof Triponez began by talking about the discovery of parathyroid glands in 1850 in a rhinocerous at London Zoo, by Sir Richard Owen, and how these were named because of their proximity to the thyroid gland. And in 1908, in the Bulletin of the Johns Hopkins Hospital, WG MacCallum MD and C Voegtlin PhD wrote how the parathyroid glands impacted calcium, explaining their discovery that a calcium injection cured symptoms of tetany when a patient had had their parathyroids removed.

He showed graphs which illustrated the high risk of cardiovascular events for hypoparathyroid patients (post total thyroidectomy), and the increased risk of chronic kidney disease. While the rate of hypoparathyroidism is usually thought to be 0-3% post thyroidectomy, the current figures appear to show it’s more like 10% internationally (with the UK on 12%).

When doing thyroid surgery, fluorescent dyes can be used to highlight the parathyroid glands in order to protect them. The same technique can also be used to find them during parathyroid surgery. This is particularly useful when glands are hard to locate. It was interesting that normal parathyroid tissue glows more brightly than an adenoma, but this still helps to locate adenomas as they all contain a parathyroid gland which will glow. This also helps to check that there is at least one functioning parathyroid gland remaining at the end of a larger operation such as a total thyroidectomy or multi gland removal.

Using their own hospital data he illustrated that the risk of hypoparathyroidism post-surgery since 2015 when they introduced the ICG system above, has reduced from around 10% down to only 1% of patients. He also explained how you can see the difference between different types of parathyroid gland using this system.

Caroline Fryer, December 2024

https://www.ese-hormones.org/education-and-training/events-key-dates/ese-clinical-update-on-calcium-and-bone/