Unsuccessful surgery

1.4.13.

For people who have had unsuccessful surgery for primary hyperparathyroidism:

• conduct a multidisciplinary team (MDT) review at a specialist centre that includes:

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  initial findings from surgery

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  previous imaging and histology

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  the clinical and biochemical indications for repeat surgery

• offer monitoring as set out in section 1.6.

1.4.14.

If repeat surgery is performed for primary hyperparathyroidism, it should be done at a centre with expertise in reoperative parathyroid surgery.

To find out why the committee made the recommendations on surgical management and how they might affect practice, see rationale and impact.

Type of serum calcium measurement

Although no evidence was available, the committee are confident, based on their knowledge and experience, that albumin-adjusted serum calcium measurement produces an accurate indication of the amount of calcium that is active in the body. Calcium that is bound to albumin is not active and does not have clinical effects. Adjusting for albumin compensates for this, and allows better identification of the active calcium that may be causing symptoms or signs.

Indications for serum calcium measurement

Limited evidence, and the committee’s experience, suggest that hypercalcaemia in primary hyperparathyroidism is associated with particular symptoms, notably thirst, frequent or excessive urination, or constipation, and with conditions such as osteoporosis, fragility fractures or renal stones. Diagnostic testing is therefore indicated for people with these symptoms or conditions. However, the committee noted that hypercalcaemia is often asymptomatic and agreed that an incidental finding of elevated albumin-adjusted serum calcium in a person without symptoms should also trigger diagnostic testing.

Noting that people with primary hyperparathyroidism sometimes have chronic non-differentiated symptoms, the committee agreed that diagnostic testing could be considered for people with these symptoms. Examples include fatigue, depression, mild confusion, anxiety, irritability, insomnia or digestive problems. The committee acknowledged that there could be multiple causes for these symptoms and that their association with primary hyperparathyroidism is uncertain.

Ionised calcium measurement

The committee agreed that ionised calcium should not be measured because point-of-care testing is not subject to the stringency of laboratory testing and the sample has to be handled very quickly, making ionised calcium measurement unreliable.

Repeating albumin-adjusted serum calcium measurement

Because serum calcium levels can vary with changes in blood pH or serum albumin, and the cost of measurement is relatively low, the committee agreed that albumin-adjusted serum calcium should be measured at least twice before moving on to more expensive measurement of parathyroid hormone (PTH).

Type of PTH measurement

No evidence was available on measurement of PTH in the diagnosis or assessment of primary hyperparathyroidism. The committee based their recommendations on the normal reference range for albumin-adjusted serum calcium as defined by the Association of Clinical Biochemistry, which is 2.2 to 2.6 mmol/litre, and their own experience.

Indications for PTH measurement

The committee noted that most people with primary hyperparathyroidism have an albumin-adjusted serum calcium level above 2.6 mmol/litre. However, they also discussed a type of primary hyperparathyroidism that affects a smaller number of people, in which the albumin-adjusted serum calcium level is within the normal range. This is known as “normocalcaemic primary hyperparathyroidism” and it often goes unrecognised. To address this, the committee added a lower criterion of 2.5 mmol/litre (with clinical suspicion of primary hyperparathyroidism) for PTH measurement.

Carrying out PTH measurement

The committee were in agreement that PTH measurement can be done at any time of day. Although there is a marginal diurnal difference, it is not enough to need adjusting for. They agreed that the PTH measurement needs to be interpreted in the context of a concurrent albumin-adjusted serum calcium measurement. They also agreed that there is no benefit in repeating the PTH measurement in primary care.

Interpreting PTH measurement and seeking specialist advice

The committee noted that PTH levels can vary widely from one individual to another, and that there is uncertainty about the level of PTH at which primary hyperparathyroidism can be ruled out. The reference range for PTH differs between laboratories so the committee were unable to specify numerical PTH thresholds.

The committee agreed, based on their experience, that advice from a specialist with expertise in primary hyperparathyroidism should be sought if:

• PTH is above the midpoint of the reference range and primary hyperparathyroidism is suspected, because these features indicate that primary hyperparathyroidism is likely
• PTH is below the midpoint of the reference range but albumin-adjusted serum calcium is raised, because this indicates that primary hyperparathyroidism cannot be ruled out.

If PTH is below the midpoint of the reference range and albumin-adjusted serum calcium is not raised, the committee agreed that primary hyperparathyroidism is unlikely.

Measuring vitamin D

No evidence was available on measuring vitamin D to assess primary hyperparathyroidism, so the recommendation is based on the committee’s knowledge and experience.

The committee noted that vitamin D deficiency can lead to a rise in PTH level, exacerbate bone disease and increase postoperative risk. It is therefore important to assess and correct vitamin D for people with primary hyperparathyroidism. However, the committee were aware that vitamin D testing is not available to all primary care providers, and that waiting for vitamin D to be measured, and corrected if necessary, before seeking specialist advice could delay diagnosis. They therefore concluded that vitamin D measurement and correction are best carried out in secondary care.

Excluding familial hypocalciuric hypercalcaemia

The committee agreed that it is important to exclude familial hypocalciuric hypercalcaemia (FHH) because it needs no operative treatment. Evidence showed that the 3 tests recommended are equally accurate in the diagnosis of FHH. The committee were not able to recommend thresholds for these measurements because the evidence is inconsistent.

Assessment after diagnosis

The committee agreed that baseline assessment will help to determine optimal management in secondary care. They did not recommend phosphate measurement because improvements in PTH assays have reduced its usefulness.

The committee acknowledged the potential of bone turnover markers to enable earlier and more accurate diagnosis of primary hyperparathyroidism but were unable to make a recommendation because of a lack of evidence. They therefore made a research recommendation.

Preoperative imaging

There was limited evidence on preoperative imaging so the committee also used their clinical knowledge and experience to make the recommendations. They agreed that the purpose of preoperative imaging is to help guide the surgical approach. It is not essential in all circumstances (for example, if a decision has already been made to perform 4-gland exploration).

Evidence suggested that ultrasound scanning is accurate in identifying abnormal parathyroid tissue. Ultrasound scanning is widely available, safe and does not involve any exposure to radiation. However, the committee noted that the accuracy of ultrasound depends on the expertise of the person performing it. They therefore recommended sestamibi as an alternative.

Although dual scanning using 2 different imaging modalities has the advantage of providing both anatomical and functional information, the committee agreed that a second imaging modality is only needed if it will further inform the surgical approach. Evidence suggests that sestamibi scanning is accurate in detecting single-gland disease. The committee did not make a recommendation on 4D CT scanning because there was no evidence available.

The committee agreed that if dual scanning fails to identify an adenoma or is discordant, further imaging will not add useful information and will expose the person to unnecessary radiation. They acknowledged that preoperative imaging does not detect all adenomas, so 4-gland exploration should be offered if preoperative imaging does not identify an adenoma.

Type of surgery

The committee agreed that, based on their experience, people whose preoperative imaging does not identify a single adenoma will more frequently have multigland disease and will benefit from 4-gland exploration. If the first-modality and second-modality scans are discordant, 4-gland exploration can be considered because the specific anatomical location of the adenoma cannot be assured.

For people with a single adenoma, a small amount of evidence shows that both focused parathyroidectomy and 4-gland exploration are safe and effective. The committee agreed that focused parathyroidectomy offers the potential advantages of lower temporary hypocalcaemia, a shorter surgery time and minor cosmetic benefit. However, it also carries a marginally (around 5%) higher chance of recurrence or persistent disease. They therefore agreed that people with a single adenoma should be offered a choice of focused parathyroidectomy or 4-gland exploration, and that the possible benefits and risks of each type of surgery should be discussed with them.

Intraoperative PTH monitoring

There was limited evidence on intraoperative PTH (IOPTH) monitoring. The committee noted that in their experience, there is a marginal benefit with the use of IOPTH, but this could be partially attributed to surgical expertise.

IOPTH monitoring is costly and its effectiveness in improving surgical outcomes is uncertain. The committee agreed that their experience together with the limited evidence did not support IOPTH monitoring as part of standard practice.

Follow-up after surgery

Based on their knowledge and experience, the committee agreed that people who have had parathyroid surgery can be considered biochemically cured if their albumin-adjusted serum calcium and PTH levels are within the reference range before discharge after surgery and their albumin-adjusted serum calcium level is within the reference range 3 to 6 months after surgery.

The committee acknowledged the potential of bone turnover markers to check bone health after surgery for primary hyperparathyroidism but were unable to make a recommendation because of a lack of evidence. They therefore made a research recommendation.

Unsuccessful surgery

There was no evidence on further surgical management for people who have had unsuccessful first surgery, and very limited evidence on drug therapy with cinacalcet compared with placebo. The committee agreed that input from a multidisciplinary team at a specialist centre should be sought, noting that repeat parathyroid surgery is relatively uncommon, failure rates are higher than in first surgery and it carries a higher risk. They also made a research recommendation on management after unsuccessful first surgery.

Calcimimetics

Cinacalcet is the only calcimimetic for which evidence was available. The committee noted that cinacalcet does not directly stop kidney problems or bone loss caused by primary hyperparathyroidism, and that surgery is the only definitive treatment for primary hyperparathyroidism.

Based on the evidence and their experience, the committee agreed that treatment with cinacalcet could be considered for the purpose of reducing symptoms and lowering the risk of a hypercalcaemic crisis for people who have not had surgery and those for whom surgery has not been successful. The committee agreed that, in their experience, cinacalcet can improve quality of life for people with symptoms of hypercalcaemia and an albumin-adjusted serum calcium level of 2.85 mmol/litre or above. For people with an albumin-adjusted serum calcium level of 3.0 mmol/litre or above, who are more at risk of hypercalcaemic crises, cinacalcet can both improve quality of life and help to prevent hypercalcaemic crises.

The committee agreed that treatment-related changes in serum calcium should be managed by basing initiation and continuation of treatment on albumin-adjusted serum calcium level and symptoms. They also agreed that treatment with cinacalcet should be continued if it produces a decrease in albumin-adjusted serum calcium or an improvement in symptoms, because discontinuation is likely to reverse these improvements. The committee noted that there is no evidence for and little likelihood of benefit from cinacalcet for people with normal calcium levels and no symptoms.

Bisphosphonates

There was evidence showing that bisphosphonate treatment improves lumbar spine bone mineral density for people with primary hyperparathyroidism. The committee based the recommendation on the NICE technology appraisal guidance on bisphosphonates for treating osteoporosis.

Based on the evidence and their clinical experience, the committee agreed that bisphosphonates should not be offered to reduce hypercalcaemia in the long term.

People who have had successful parathyroid surgery

Based on their knowledge and experience, the committee agreed that the risk of recurrent disease after successful parathyroid surgery is very low and therefore it is sufficient to monitor albumin-adjusted serum calcium levels once a year.

For people who have osteoporosis, although bone density improves after surgery, skeletal recovery can take some time and needs specialist monitoring. The risk of renal stones decreases after successful surgery, but the residual risk persists and the committee agreed that specialist opinion on monitoring should be sought.

People who have not had parathyroid surgery, or whose surgery has not been successful

Based on their clinical experience, the committee agreed that monitoring for people who have had unsuccessful surgery should be the same as for people who have had no previous surgery. Monitoring bridges the gap between first surgery and multidisciplinary review and reassessment in a specialist centre.

The committee noted the increased risk of renal stones and fractures in people who have had unsuccessful or no parathyroid surgery. Evidence suggests that around one-third of people who do not have symptoms or indications for surgery will go on to develop these. The committee agreed that monitoring will ensure that surgery, including repeat surgery, can be offered when needed.

People who have had parathyroid surgery for multigland disease, or have disease that recurs after successful surgery

The committee agreed that people with multigland disease, or disease that has recurred after successful surgery, have a slightly increased risk of future recurrence and will benefit from specialist endocrine opinion on monitoring.

All people with primary hyperparathyroidism

For all people with primary hyperparathyroidism, the committee agreed that there was no evidence to suggest that surgery modifies cardiovascular disease risk or fracture risk, so these should be assessed in line with NICE guidance.

The committee noted the limited evidence on long-term outcomes and made a research recommendation.

Care before pregnancy

The committee noted that having surgery for primary hyperparathyroidism before becoming pregnant allows women to start their pregnancy with a normal serum calcium level, which reduces their risk of pregnancy-associated complications of primary hyperparathyroidism. They noted that the risk of stillbirth and neonatal tetany increases with a serum calcium level above 2.85 mmol/litre.

Care during pregnancy

Based on their experience, the committee agreed that management of primary hyperparathyroidism during pregnancy should be discussed with a multidisciplinary team (MDT) because of the high risk of maternal and neonatal complications.

The safety and efficacy of cinacalcet for pregnant women is largely unknown, so the committee agreed that cinacalcet should not be offered during pregnancy. They also agreed that bisphosphonates are potentially harmful for the mother and the fetus.

There was no evidence on monitoring for pregnant women. The committee agreed that monitoring should be guided by a specialist centre MDT because of the risk of maternal or fetal complications. They also highlighted primary hyperparathyroidism as a risk factor for pre-eclampsia and hypertension.

There was little overall evidence on managing primary hyperparathyroidism during pregnancy so the committee made a research recommendation.