Diagnosis of Hyperparathyroidism

The diagnosis of hyperparathyroidism (like all endocrine surgical conditions) depends on confirming the biochemical abnormality and then performing imaging studies to localise the tumour.

Because the position of the parathyroid tumour can vary in the neck, localisation studies allow us to find the tumour before operation and make minimally invasive parathyroid surgery possible. Nearly all parathyroid surgery is now 'image-guided'.

1. Confirmation of the biochemical diagnosis

Patients suspected of primary hyperparathyroidism or PHPT have measurements of the following:

• serum calcium (+/- ionised calcium) + albumin
• intact PTH
• creatinine
• vitamin D
• 24hour urinary calcium with calcium/creatinine ratio (>0.01 indicates PHPT)
• other complementary tests: phophate and magnesium levels

A positive test is the finding of raised serum calcium with an inappropriate PTH level. PTH assays are discriminating and there are few situations where a raised PTH does not indicate true PHPT. One exception is FHH (see webpage Hyperparathyroidism), which can be excluded by measuring the 24hr urinary calcium/creatinine ratio (<0.01).

It is also possible to have a condition called normocalcaemic primary hyperparathyroidism, where the calcium level is either normal or only intermittently elevated. This can occur in up to 20% of patients with PHPT. It is not clear whether this is just an early stage of PHPT before hypercalcaemia develops, or if it is an entirely different disease. Measurement of serum ionized calcium levels appears to be particularly useful, being raised in 80-90% of patients. The underlying pathology seems to be the same however, with single gland disease being the most common finding.

It is important to emphasise that the Vitamin D level should be measured in all patients with suspected primary hyperparathyroidism. There is evidence that the disease is more active when subjects are Vitamin D insufficient or frankly deficient. There is also evidence that reductions in PTH levels can occur when insufficient levels are corrected.

Hypercalcaemia can be associated with an underlying malignancy, often mediated by a PTH-related protein, which does not cross-react with the PTH assay, resulting in a low or undetectable PTH. If the PTH level is elevated in a person with a known malignant condition, the most likely diagnosis is still just concomitant primary hyperparathyroidism, as ectopic production of PTH from a tumour is extremely rare.

Measurements may have to be repeated due to the episodic secretion of parathyroid hormone, which can result in periods with a normal calcium and PTH. A 24 hour urine collection for calcium will help to exclude FHH and lithium as causes of hypercalcaemia.  

2. Localising the tumour

Preoperative localisation of parathyroid tumours can locate abnormal glands in about 80% of cases, which allows minimally invasive techniques to be used, with the potential for operation under local anaesthesia.

The standard localisation workup is achieved by a combination of ^99mTc-sestamibi scan and high-resolution ultrasound. The Sestamibi scan gives a functional image, looking for an overactive gland, while the ultrasound gives an anatomical image, looking for an enlarged gland. If these scans are concordant, then removing the identified gland will lead to a cure in 95-98% of patients.

It is important to realise that more than three quarters of those patients who are not localised with investigations before operation still have a single adenoma (affected gland). Those who are not localised tend to have lower calcium and PTH levels in their blood, and the weight of the affected gland tends to be lower. In addition, Sestamibi scanning tends to be negative with hyperplasia of the glands, and when the pathology is chief cell adenoma (as the mitochondria count is lower).

Other more invasive investigations, such as selective angiography and venous sampling, 4D-CT and MRI may be needed if a second or subsequent operation is being planned due to persistent or recurrent disease.   

• Ultrasound

Fig.1: Ultrasound of parathyroid adenomaUltrasound is cheap, non invasive and gives an accurate anatomical picture of the neck, although it is extremely operator dependent.  Parathyroid adenoma is typically sonolucent (Fig. 1) and colour Doppler  will demonstrate the presence of an arterial signal at the vascular pole (Fig. 2).

Using high frequency probes both single parathyroid adenoma and multiple gland disease may be located. Normal parathyroids are not usually seen and there is a 20% failure rate to detect significant parathyroid pathology. It has a sensitivity of around 80% in the unexplored neck, dropping to 40% in patients who have had a previous exploration.

Fig.2: Colour Doppler signal of parathyroid adenoma demonstrating vascularityFalse positive results are due to thyroid nodules and lymph nodes, but the most common cause is operator inexperience. Rarely parathyroid tumours lie totally within the substance of the thyroid and pre-operative ultrasound may demonstrate such tumours very clearly. The weight of the parathyroid tumour is the most important factor in its visualisation, with the Mayo Clinic showing that tumours of 1000mg or more are visualised in over 95% of cases. Tumours weighing less than 200 mg however, are visualised in less than 5% of cases. Large parathyroid tumours may be missed by ultrasound if they are behind the oesophagus.

Ultrasound generally can only be used to locate adenomas in the neck, and is unable to visualise mediastinal pathology.

• Sestamibi scan

Fig.3: Fused Sestamibi & CT scan showing strong signal of a R lower parathyroid adenomaParathyroid adenoma concentrates ^99mTc-labelled sestamibi because of the higher number of metabolically active mitochondria (Fig. 3).  It can be used to locate glands in either the neck or mediastinum with or without the addition of SPECT (single photon emission computerized tomography) CT, which gives a three-dimensional view of the parathyroid.

Scanning can detect up to 85% of solitary adenomas, 55% of abnormal glands in patients with multiglandular disease and 75% of persistent or recurrent lesions in the previously explored neck. The most important factor influencing uptake is the weight of the parathyroid tumour. Negative or equivocal scans suggest that the weight of the tumour will most likely be less than 500mg.

It is very important to realise though that a negative sestamibi scan does not mean you do not have parathyroid disease.

Diffuse hyperplasia and chief cell adenoma will often lead to a negative scan as the parathyroid glands are less mitochondria-rich.

Being a radioactive scan, the sestamibi scan should not be used in pregnancy, so that hypercalcaemia in this case can only be investigated using high-resolution ultrasound. Further information can be found on the webpage Hyperparathyroidism in Pregnancy. 

• Computed tomography & 4D-CT 

A newer method of localising parathyroid tumours has recently been developed, called 4-dimensional computed tomography (4D-CT).

The name of the technique is derived from 3-dimensional CT scanning with the added dimension of time, looking at the changes in perfusion of contrast through a parathyroid tumour. 

Fig.4: 4D-CT scan of L upper parathyroid tumour, with 3D reconstruction (above) and cross-section (below)

4D-CT produces very detailed, multiplanar images of the neck and allows the visualization of differences in the perfusion characteristics of hyperfunctioning parathyroid glands (ie, rapid uptake and washout), compared with normal parathyroid glands and other structures in the neck (Fig. 4).

The images that are generated by 4D-CT provide both anatomical and functional information (based on the changes in perfusion) in a single study, unlike the conventional two study (US & Sestamibi) technique.

There are downsides to the technique however, as firstly it is not widely available, requiring a particular expertise. Secondly, there is some concern that the radiation dose to the thyroid appears to be more than 50 times higher than conventional techniques, raising the possibility of 4D-CT-related thyroid cancers developing in the future.

Fig.5: CT of upper mediastinum (chest) with ectopic parathyroid adenoma identified behind the oesophagus

A recent study in the World Journal of Surgery calculated the risk as 0.1% in a 20 year old woman, but only 0.01% in a 40 year old woman. This may be ameliorated in the future by the use of the latest low-dose CT scanners, which considerably decrease the exposure to radiation. Nevertheless it is probably prudent to avoid the use of 4D-CT in younger patients.

In view of these downsides, 4D-CT, or thin-slice high resolution conventional CT is more commonly employed to find a 'lost' gland after a failed exploration for a parathyroid tumour. It is becoming more common to use CT as a first line investigation in the unexplored neck, if the US and Mibi scans are negative. CT has the advantage that it will visualise ectopic parathyroids in the anterior mediastinum, where ultrasound cannot see (Fig. 5). 

• Selective venous sampling and angiography
  

Fig.6: Selective parathyroid angiography with ectopic parathyroid tumour (arrow)

In the patient who has had a previous failed exploration, perhaps due to a mediastinal adenoma, more invasive tests may be needed in addition to sestamibi scan and ultrasound, or 4D-CT.

Selective venous sampling is a useful technique requiring the passage of catheters from the groin into the arteries and veins of the neck. Multiple samples of venous blood can be taken from around the neck and upper mediastinum, allowing the identification of the greatest source of PTH, and thus the likely site of a parathyroid tumour. A map of the results can then be produced to guide the surgeon in a subsequent exploration (Fig. 4).

Selective angiography can also be added, looking for the characteristic 'blush' of contrast which identifies the abnormal parathyroid tissue.

Selective angiography will usually identify the missed gland, with a sensitivity of 90-95%, especially when combined with venous sampling for parathyroid hormone assay.  Almost all enlarged glands are hypervascular, with a distinctive angiographic “blush”, resulting in a low false positive rate.

• MRI and PET scanning

Magnetic resonance imaging or MRI may also very occasionally be useful, but usually only as an investigation prior to a re-exploration after failed surgery.

Fig.7: MRI scan with parathyoid adenoma identified low in the neck

CT and MRI can have a sensitivity up to 75-85% in an unexplored neck. This decreases to less than 45% for CT after previous surgery, but remains more accurate in this situation (50-75%) with MRI (Fig. 7).

11cmethionine PET is very rarely clinically indicated in highly pre-selected patients with recurrent PHPT as well as in secondary and tertiary HPT with an accuracy of up to 88% in successfully locating parathyroid adenomas.

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